Trial Outcomes & Findings for A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia (NCT NCT02251548)

Last Updated: 2025-10-24

Results Overview

To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

85 participants

Primary outcome timeframe

2 months after completing combination therapy

Results posted on

2025-10-24

Participant Flow

The study opened to enrollment on 10/3/2014 and closed to enrollment on 4/24/2018. 58 participants were enrolled at Dana-Farber, 9 at Massachusetts General Hospital, 3 at Beth Israel Deaconess Medical Center, 9 at Duke University, 1 at University of Kansas, 3 at West Michigan Cancer Center, and 2 at University of Miami for a total of 85 enrolled.

Participant milestones

Participant milestones
Measure	FCR +420mg Ibrutinib Daily Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Overall Study STARTED	85
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	85

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	85 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	55 years n=5 Participants
Sex: Female, Male Female	30 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	81 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	82 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Region of Enrollment United States	85 Participants n=5 Participants

PRIMARY outcome

Timeframe: 2 months after completing combination therapy

Population: No prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment- Age greater than or equal to 18 years and less than or equal to 65 and must require therapy by standard IW-CLL 2008 criteria with adequate renal, hepatic, and hematologic function

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR	28 Participants

PRIMARY outcome

Timeframe: 2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance

Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

The objective response rate (ORR) was defined as the proportion of participants achieving CR+CRi+PR, Complete Response with incomplete count recovery (CRi) or partial response (PR) based on 2008 IW-CLL criteria criteria (Hallek et al., 2008).

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Overall Response Rate	0.96 proportion of participants

SECONDARY outcome

Timeframe: Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

CRR defined as the proportion of participants achieving complete response. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Complete Response Rate (CRR)	0.24 proportion of participants

SECONDARY outcome

Timeframe: Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

PRR defined as the proportion of participants achieving partial response. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Partial Response Rate (PRR)	0.61 proportion of participant

SECONDARY outcome

Timeframe: Disease will be evaluated through imaging cycle 3-6 day 1, and In long-term follow-up, after removal or until participant withdrawal, death, or removal from study. Median follow-up is: 63.24 months (range: 6.83-95.8).

Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) or death, or is censored at time of last dsease assessment.

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Median Progression-Free Survival (PFS)	NA months insufficient number of participants with events

SECONDARY outcome

Timeframe: Median follow-up is: 63.24 months (range: 6.83-95.8).

Overall Survival (OS) based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Median Overall Survival (OS)	NA months insufficient number of participants with events

SECONDARY outcome

Timeframe: After 3 cycles of iFCR for each patient completing 3 cycles

To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Rate of MRD Negative CR After 3 Cycles of iFCR	9 Participants

SECONDARY outcome

Timeframe: at 1 year

Combined response with MRD from bone marrow reported as the MRD-negative CR. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=85 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
1-year Combined Response With MRD From Bone Marrow	2 Participants

SECONDARY outcome

Timeframe: 12 months ( 1year) after starting therapy

To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=40 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance	2 Participants

SECONDARY outcome

Timeframe: 2 years (24 months) from start of therapy

MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=40 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment	9 Participants

SECONDARY outcome

Timeframe: Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=71 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Median Time to Bone Marrow MRD Negativity	3 months Interval 2.79 to 23.69

SECONDARY outcome

Timeframe: Response evaluated at 2 months post iFCR. Treatment up to 6 cycles (28 days each).

.MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)

Outcome measures

Outcome measures
Measure	FCR+ 420 mg Ibrutinib daily n=33 Participants Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib	0 Participants

Adverse Events

FCR+Ibrutinib 420mg Daily

Serious events: 24 serious events

Other events: 85 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	FCR+Ibrutinib 420mg Daily n=85 participants at risk Patients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing. Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Investigations Aspartate Aminotransferase Increased	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Lipase Increased	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Alanine Amintransferase Increased	3.5% 3/85 • Number of events 3 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Appendicitis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Anaplasmosis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Pneumatosis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypoglycemia	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Spondylosis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Cardiac disorders Non-Cardiac Chest Pain	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Cardiac disorders Atrial Fibrillation	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Pneumocystis Jivrocii Pneumonia	3.5% 3/85 • Number of events 3 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Secondary Malignancy- Myelodysplastic Syndrome	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders Sudden Death	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Psychiatric disorders Depression	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Hepatobiliary disorders Cholecystitis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Respiratory Syncytial Virus	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Appendiceal Mucocele	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Sepsis	2.4% 2/85 • Number of events 2 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Immune system disorders Hemophagocytic lymphohistiocytosis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Febrile Neutropenia	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Cellulitis	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Diarrhea	1.2% 1/85 • Number of events 1 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.

Other adverse events

Other adverse events
Measure	FCR+Ibrutinib 420mg Daily n=85 participants at risk Patients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing. Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities
Skin and subcutaneous tissue disorders Rash acneiform	30.6% 26/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Aspartate aminotransferase increased	29.4% 25/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hyponatremia	27.1% 23/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Pain in extremity	27.1% 23/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Nervous system disorders Headache	24.7% 21/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Skin and subcutaneous tissue disorders Skin/subcutaneous tissue disorders; Other, specify	24.7% 21/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Lymphocyte count increased	23.5% 20/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Myalgia	23.5% 20/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Blood and lymphatic system disorders Leukocytosis	21.2% 18/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Upper respiratory infection	21.2% 18/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Vomiting	21.2% 18/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Alanine aminotransferase increased	20.0% 17/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders and administration site conditions Fever	20.0% 17/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hyperkalemia	20.0% 17/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Psychiatric disorders Insomnia	20.0% 17/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Blood bilirubin increased	18.8% 16/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Gastroesophageal reflux disease	17.6% 15/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypokalemia	17.6% 15/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Respiratory, thoracic and mediastinal disorders Nasal congestion	17.6% 15/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypophosphatemia	16.5% 14/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Back pain	15.3% 13/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Skin and subcutaneous tissue disorders Dry skin	15.3% 13/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypoglycemia	15.3% 13/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypomagnesemia	15.3% 13/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Psychiatric disorders Anxiety	14.1% 12/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Nervous system disorders Dizziness	14.1% 12/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders and administration site conditions Edema limbs	14.1% 12/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Cardiac disorders Palpitations	14.1% 12/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Bone pain	12.9% 11/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Skin and subcutaneous tissue disorders Rash maculo-papular	12.9% 11/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Alkaline phosphatase increased	11.8% 10/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Dyspepsia	11.8% 10/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Skin and subcutaneous tissue disorders Pruritus	11.8% 10/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Creatinine increased	10.6% 9/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypoalbuminemia	10.6% 9/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Lung infection	10.6% 9/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	10.6% 9/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders and administration site conditions Pain	10.6% 9/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Abdominal pain	9.4% 8/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Anorexia	9.4% 8/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Respiratory, thoracic and mediastinal disorders Dyspnea	9.4% 8/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Blood and lymphatic system disorders Febrile neutropenia	9.4% 8/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders and administration site conditions Chills	8.2% 7/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	8.2% 7/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	8.2% 7/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.1% 6/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Vascular disorders Hot flashes	7.1% 6/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Vascular disorders Hypertension	7.1% 6/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Nervous system disorders Peripheral sensory neuropathy	7.1% 6/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Infections and infestations Sinusitis	7.1% 6/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Respiratory, thoracic and mediastinal disorders Sore throat	7.1% 6/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Cardiac disorders Atrial fibrillation	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Psychiatric disorders Depression	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Dry mouth	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Flank pain	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Skin and subcutaneous tissue disorders Hyperhidrosis	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Hypernatremia	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders and administration site conditions Infusion related reaction	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Investigations Investigations - Other, specify	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
General disorders and administration site conditions Localized edema	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, specify	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Gastrointestinal disorders Mucositis oral	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.
Musculoskeletal and connective tissue disorders Neck pain	5.9% 5/85 • Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email. Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.

Additional Information

Matthew Davids, MD

Dana-Farber Cancer Institute

Phone: 617-632-6331

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place