Trial Outcomes & Findings for A Study of Palbociclib in Combination With Bazedoxifene in Hormone Receptor Positive Breast Cancer (NCT NCT02448771)

NCT ID: NCT02448771

Last Updated: 2022-10-24

Results Overview

Clinical Benefit Rate is the percentage of participants who achieve clinical benefit from the study treatment. Clinical benefit is defined as at least 24 weeks of confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD). SD or better is achieved if the following are true: Target Lesions: -At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Non-target Lesions: * No progression. * No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Bone Lesions: * \< 25% increase in lesions. * No new lesions.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 36 participants
• Primary outcome timeframe: Assessed for response for up to 34 months
• Results posted on: 2022-10-24

Participant Flow

Patients were enrolled between 7/9/2015 and 7/19/2017

Participant milestones

Measure	Palbociclib in Combination With Bazedoxifene Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Overall Study STARTED	36
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	36

Reasons for withdrawal

Measure	Palbociclib in Combination With Bazedoxifene Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Overall Study Disease Progression	30
Overall Study Unacceptable Toxicity	1
Overall Study Physician Decision	3
Overall Study Started new therapy	2

Baseline Characteristics

A Study of Palbociclib in Combination With Bazedoxifene in Hormone Receptor Positive Breast Cancer

Baseline characteristics by cohort

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Age, Continuous	59.5 years n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	31 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 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	32 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants
ECOG Performance Status 00 - Fully Active	33 Participants n=5 Participants
ECOG Performance Status 01 - Restricted	3 Participants n=5 Participants
Estrogen Receptor Status Unknown	1 Participants n=5 Participants
Estrogen Receptor Status Low Positive	1 Participants n=5 Participants
Estrogen Receptor Status Positive (>10% cell staining)	34 Participants n=5 Participants
Progesterone Receptor Status Unknown	1 Participants n=5 Participants
Progesterone Receptor Status Low Positive	1 Participants n=5 Participants
Progesterone Receptor Status Positive (>10% cell staining)	22 Participants n=5 Participants
Progesterone Receptor Status Negative (<=10% cell staining)	12 Participants n=5 Participants
Human Epidermal Growth Factor Receptor 2 Amplification Negative	36 Participants n=5 Participants
Human Epidermal Growth Factor Receptor 2 Amplification Positive	0 Participants n=5 Participants
Site of Metastatic Disease Lung and Pleural	12 Participants n=5 Participants
Site of Metastatic Disease Breast and Chest	14 Participants n=5 Participants
Site of Metastatic Disease Lymph Node	13 Participants n=5 Participants
Site of Metastatic Disease Liver	23 Participants n=5 Participants
Site of Metastatic Disease Bone	26 Participants n=5 Participants
Site of Metastatic Disease Others	7 Participants n=5 Participants
Site of Metastatic Disease: Bone Only Yes	2 Participants n=5 Participants
Site of Metastatic Disease: Bone Only No	34 Participants n=5 Participants
Site of Metastatic Disease: Visceral Disease Yes	29 Participants n=5 Participants
Site of Metastatic Disease: Visceral Disease No	7 Participants n=5 Participants
Prior Hormonal Therapy for Metastatic Breast Cancer Zero	6 Participants n=5 Participants
Prior Hormonal Therapy for Metastatic Breast Cancer One	14 Participants n=5 Participants
Prior Hormonal Therapy for Metastatic Breast Cancer Two	8 Participants n=5 Participants
Prior Hormonal Therapy for Metastatic Breast Cancer Three	6 Participants n=5 Participants
Prior Hormonal Therapy for Metastatic Breast Cancer Four	2 Participants n=5 Participants
Prior Chemotherapy for Metastatic Breast Cancer Zero	17 Participants n=5 Participants
Prior Chemotherapy for Metastatic Breast Cancer One	16 Participants n=5 Participants
Prior Chemotherapy for Metastatic Breast Cancer Two	3 Participants n=5 Participants
Everolimus for Metastatic Breast Cancer Yes	4 Participants n=5 Participants
Everolimus for Metastatic Breast Cancer No	32 Participants n=5 Participants
Prior Hormonal Therapy for Primary Cancer Yes	25 Participants n=5 Participants
Prior Hormonal Therapy for Primary Cancer No	11 Participants n=5 Participants
Prior Tamoxifen for Primary or Metastatic Breast Cancer Yes	26 Participants n=5 Participants
Prior Tamoxifen for Primary or Metastatic Breast Cancer No	10 Participants n=5 Participants

PRIMARY outcome

Timeframe: Assessed for response for up to 34 months

Clinical Benefit Rate is the percentage of participants who achieve clinical benefit from the study treatment. Clinical benefit is defined as at least 24 weeks of confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD).

SD or better is achieved if the following are true:

Target Lesions:

-At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Non-target Lesions:

• No progression.
• No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Bone Lesions:

• < 25% increase in lesions.
• No new lesions.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Clinical Benefit Rate	33 percentage of participants Interval 9.8 to 56.4

PRIMARY outcome

Timeframe: Assessed for response for up to 34 months

Population: Total number analyzed is the sum of both categories (mutant and wild type).

Clinical Benefit Rate is the percentage of participants who achieve clinical benefit from the study treatment. Clinical benefit is defined as at least 24 weeks of confirmed CR, PR, SD.

SD or better is achieved if the following are true:

Target Lesions:

-At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Non-target Lesions:

• No progression.
• No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Bone Lesions:

• < 25% increase in lesions.
• No new lesions.

ESR1 genotype determined using established methods

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=28 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Clinical Benefit Rate by ESR1 Genotype Wild Type	31 percentage of participants Interval 11.0 to 58.67
Clinical Benefit Rate by ESR1 Genotype Mutant	43 percentage of participants Interval 9.9 to 81.6

PRIMARY outcome

Timeframe: Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months.

Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 regardless of whether the event is related or unrelated to treatment. Neutrophil counts are evaluated using established methods.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Percent of Participants With All Grade Neutrophil Count Decrease	61.1 percentage of participants Interval 45.0 to 77.0

SECONDARY outcome

Timeframe: Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months.

Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 regardless of whether the event is related or unrelated to treatment. Neutrophil counts are evaluated using established methods.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Number of Participants With All Grade Neutrophil Count Decrease	22 Participants

SECONDARY outcome

Timeframe: Assessed for response for up to 34 months

The objective response rate is the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria.

PR or better is achieved if the following are true:

Target Lesions:

-At least a 30% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Non-target Lesions:

• No progression.
• No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Bone Lesions:

->50% increase in lesions.

-No new lesions.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Objective Response Rate	11.1 percentage of participants Interval 3.1 to 26.4

SECONDARY outcome

Timeframe: Up to 42 months

Population: Rows are representative of subgroups of study population.

Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Median Progression-Free Survival	3.58 months Interval 1.97 to 7.24

SECONDARY outcome

Timeframe: Up to 42 months

Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=36 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Median Overall Survival	26.5 months Interval 1.5 to 41.5

SECONDARY outcome

Timeframe: Up to 24 months

Population: Total number analyzed is the sum of both categories (mutant and wild type).

Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. ESR1 genotype is determined using established methods. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=27 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Median Progression-Free Survival for Patients by ESR1 Genotype Mutant	2.0 months Interval 1.5 to 9.3
Median Progression-Free Survival for Patients by ESR1 Genotype Wild Type	3.6 months Interval 1.9 to 5.7

SECONDARY outcome

Timeframe: Up to 42 months

Population: Total number analyzed is the sum of both categories (mutant and wild type).

Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. ESR1 genotype determined by established methods.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=23 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Overall Survival by ESR1 Genotype Wild Type	21.1 probability of survival Interval 13.2 to Follow-up is not long enough/data is not mature to provide upper bound confidence interval.
Overall Survival by ESR1 Genotype Mutant	26.5 probability of survival Interval 1.5 to Follow-up is not long enough/data is not mature to provide upper bound confidence interval.

SECONDARY outcome

Timeframe: Up to 34 months

Population: Total number analyzed is the sum of both categories (mutant and wild type).

The objective response rate is the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria.

PR or better is achieved if the following are true:

Target Lesions:

-At least a 30% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Non-target Lesions:

No progression. No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Bone Lesions:

->50% increase in lesions.

-No new lesions.

ESR1 genotype determined by established methods.

Outcome measures

Measure	Palbociclib in Combination With Bazedoxifene n=28 Participants Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Objective Response Rate by ESR1 Genotype Wild Type · Complete Response	0 Participants
Objective Response Rate by ESR1 Genotype Wild Type · Partial Response	0 Participants
Objective Response Rate by ESR1 Genotype Wild Type · Stable Disease	13 Participants
Objective Response Rate by ESR1 Genotype Wild Type · Progressive Disease	5 Participants
Objective Response Rate by ESR1 Genotype Wild Type · Not Evaluable	1 Participants
Objective Response Rate by ESR1 Genotype Mutant · Complete Response	0 Participants
Objective Response Rate by ESR1 Genotype Mutant · Partial Response	0 Participants
Objective Response Rate by ESR1 Genotype Mutant · Stable Disease	3 Participants
Objective Response Rate by ESR1 Genotype Mutant · Progressive Disease	5 Participants
Objective Response Rate by ESR1 Genotype Mutant · Not Evaluable	1 Participants

Adverse Events

Palbociclib in Combination With Bazedoxifene

Serious events: 17 serious events

Other events: 34 other events

Deaths: 17 deaths

Serious adverse events

Measure	Palbociclib in Combination With Bazedoxifene n=36 participants at risk Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Blood and lymphatic system disorders Anemia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Bladder infection	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Bronchial infection	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Neutrophil count decreased	41.7% 15/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Platelet count decreased	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations White blood cell decreased	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Vascular disorders Thromboembolic event	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.

Other adverse events

Measure	Palbociclib in Combination With Bazedoxifene n=36 participants at risk Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle One cycle is 28 days.
Blood and lymphatic system disorders Anemia	16.7% 6/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Blood and lymphatic system disorders Blood and lymphatic system disorders - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Cardiac disorders Ventricular arrhythmia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Cardiac disorders Ventricular tachycardia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Ear and labyrinth disorders Tinnitus	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Ear and labyrinth disorders Vertigo	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Eye disorders Blurred vision	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Abdominal pain	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Ascites	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Bloating	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Constipation	19.4% 7/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Diarrhea	19.4% 7/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Dry mouth	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Dyspepsia	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Gastritis	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Gastroesophageal reflux disease	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Mucositis oral	19.4% 7/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Nausea	33.3% 12/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Obstruction gastric	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Stomach pain	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Vomiting	13.9% 5/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Edema limbs	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Fatigue	61.1% 22/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Fever	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Flu like symptoms	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Gait disturbance	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Non-cardiac chest pain	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
General disorders Pain	13.9% 5/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Lung infection	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Papulopustular rash	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Rhinitis infective	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Upper respiratory infection	8.3% 3/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Infections and infestations Infections and infestations - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Injury, poisoning and procedural complications Fracture	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Alanine aminotransferase increased	11.1% 4/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Aspartate aminotransferase increased	13.9% 5/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Electrocardiogram QT corrected interval prolonged	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Lymphocyte count decreased	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Neutrophil count decreased	58.3% 21/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Platelet count decreased	22.2% 8/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Weight gain	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations White blood cell decreased	8.3% 3/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Investigations Investigations - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Anorexia	11.1% 4/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Hypercalcemia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Hyperglycemia	8.3% 3/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Hypocalcemia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Hypokalemia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Hyponatremia	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Metabolism and nutrition disorders Hypophosphatemia	11.1% 4/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Arthralgia	8.3% 3/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Back pain	8.3% 3/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Bone pain	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Myalgia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Neck pain	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Pain in extremity	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Dysgeusia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Facial nerve disorder	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Headache	13.9% 5/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Movements involuntary	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Peripheral motor neuropathy	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Tremor	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Vasovagal reaction	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Nervous system disorders Nervous system disorders - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Psychiatric disorders Anxiety	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Psychiatric disorders Delirium	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Psychiatric disorders Hallucinations	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Psychiatric disorders Insomnia	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Psychiatric disorders Psychiatric disorders - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Renal and urinary disorders Hematuria	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Renal and urinary disorders Proteinuria	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Renal and urinary disorders Urinary frequency	8.3% 3/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Renal and urinary disorders Urinary urgency	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Renal and urinary disorders Renal and urinary disorders - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Reproductive system and breast disorders Vaginal dryness	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 4/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Dyspnea	19.4% 7/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Epistaxis	11.1% 4/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Postnasal drip	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Productive cough	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Sore throat	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Alopecia	19.4% 7/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Dry skin	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Pruritus	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Rash acneiform	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Rash maculo-papular	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Scalp pain	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	5.6% 2/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Vascular disorders Hot flashes	16.7% 6/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Vascular disorders Superficial thrombophlebitis	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Vascular disorders Thromboembolic event	2.8% 1/36 • Baseline, until resolution or for 30 days after the subject's last study visit, up to 43 months. Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.

Additional Information

Rinath Jeselsohn

Dana-Farber Cancer Institute

Phone: 617.632.6887

Email: rinath_jeselsohn@dfci.harvard.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place