Trial Outcomes & Findings for Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma (NCT NCT00633594)

Last Updated: 2017-01-31

Results Overview

Determination of the maximum tolerated dose (MTD) of lenalidomide combined with bortezomib and rituximab, defined as the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity according to the NCI CTCAE v. 4.03. MTD of Lenalidomide was tested, included with 1.3 mg/m2 subcutaneous (D1, 4, 8, 11) bortezomib, 375 mg/m2 (D1, 8, 15 of Cycle 1, D1 on subsequent cycles) rituximab. Three dose limiting toxicities were reported in two patients (grade 4 neutropenia and grade 3 neuropathy, grade 3 rash)

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

39 participants

Primary outcome timeframe

Collected from day of first dose to the end of the first treatment cycle, up to 21 days

Results posted on

2017-01-31

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I - Lenalidomide 15mg PO QD Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 15 mg PO daily on Days 1-14.	Phase I - Lenalidomide 10mg PO QD Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.	Phase II - Lenalidomide 10mg PO QD Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Overall Study STARTED	5	8	26
Overall Study COMPLETED	5	3	16
Overall Study NOT COMPLETED	0	5	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I - Lenalidomide 10mg PO QD Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.	Phase II - Lenalidomide 10mg PO QD Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Overall Study Adverse Event	4	7
Overall Study Death	1	2
Overall Study Disease Progression	0	1

Baseline Characteristics

Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I - Lenalidomide 15mg PO QD n=5 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 15 mg PO daily on Days 1 14. .	Phase I - Lenalidomide 10mg PO QD n=8 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1 14.	Phase II - Lenalidomide 10mg PO QD n=26 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1 14.	Total n=39 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	12 Participants n=4 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	6 Participants n=7 Participants	19 Participants n=5 Participants	27 Participants n=4 Participants
Age, Continuous	60 years n=5 Participants	69 years n=7 Participants	69 years n=5 Participants	69 years n=4 Participants
Age, Customized Previously Treated : <= 18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Customized Previously Treated : Between 18 and 65 years	3 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Age, Customized Previously Treated : >= 65 years	1 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants	7 Participants n=4 Participants
Age, Customized Previously Untreated : <= 18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Customized Previously Untreated : Between 18 and 65 years	0 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	9 Participants n=4 Participants
Age, Customized Previously Untreated : >= 65 years	1 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants	20 Participants n=4 Participants
Sex/Gender, Customized Previously Treated : Female	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Sex/Gender, Customized Previously Treated : Male	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants
Sex/Gender, Customized Previously Untreated : Female	0 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants	6 Participants n=4 Participants
Sex/Gender, Customized Previously Untreated : Male	1 Participants n=5 Participants	6 Participants n=7 Participants	16 Participants n=5 Participants	23 Participants n=4 Participants
Gender Female	1 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	10 Participants n=4 Participants
Gender Male	4 Participants n=5 Participants	6 Participants n=7 Participants	19 Participants n=5 Participants	29 Participants n=4 Participants
Region of Enrollment United States	5 participants n=5 Participants	8 participants n=7 Participants	26 participants n=5 Participants	39 participants n=4 Participants
Previous Treatment for Mantle Cell Lymphoma (MCL) Previously Untreated	1 participants n=5 Participants	7 participants n=7 Participants	21 participants n=5 Participants	29 participants n=4 Participants
Previous Treatment for Mantle Cell Lymphoma (MCL) Previously Treated	4 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants	10 participants n=4 Participants

PRIMARY outcome

Timeframe: Collected from day of first dose to the end of the first treatment cycle, up to 21 days

Population: Includes patients that were enrolled in both lenalidomide dose levels (10 mg PO daily, 15 mg PO daily) in the Phase I portion of the study

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=13 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Maximum Tolerated Dose of Lenalidomide Combined With Bortezomib and Rituximab in Phase I Participants	10 mg lenalidomide, orally, daily, day 1-14	—

PRIMARY outcome

Timeframe: Collected from day of first dose to 30 days after the last dose of study medication, a maximum of 18 weeks and 30 days after last study treatment

Population: Includes patients that were enrolled in the Phase II section of the study

A count of affected participants with non-serious adverse events (regardless of relationship to study treatments) occurring in \>= 15% of treated patients enrolled in the Phase II section of the study. Lenalidomide DL-1 dose (10 mg orally, once daily (PO QD)) Day 1-14 followed by 7 days of rest, Rituximab 375 mg/m2 IV Days 1, 8, and 15 of Cycle 1; Cycles 2-6: 375 mg/m2 IV Day 1, Bortezomib 1.3 mg/m2 subcutaneous Days 1, 4, 8, and 11 for Cycles 1-6

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=26 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Rash	19 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Fatigue	18 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Thrombocytopenia	16 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Leukopenia	13 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Nausea	12 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Diarrhea	11 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Edema	11 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hyperglycemia	11 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Peripheral Neuropathy	10 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Neutropenia	10 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hypoalbuminemia	10 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Constipation	9 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hypocalcemia	9 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Pain in Extremity	9 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Anemia	8 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Cough	8 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Fever	8 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Dehydration	7 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Pruritus	7 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Dyspnea	7 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hyponatremia	7 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Insomnia	6 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Abdominal Pain	6 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Dizziness	6 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hypokalemia	6 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Weight Loss	6 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Anorexia	5 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Erythema	5 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hypomagnesemia	5 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Allergic Reaction	5 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Chills	5 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hyperhidrosis	5 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Myalgia	4 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Headache	4 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Mucositis	4 participants	—
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II Hypoglycemia	4 participants	—

SECONDARY outcome

Timeframe: Every 6 weeks until treatment discontinuation then every 3 months thereafter, projected average 24 months

Population: The efficacy evaluable population (all participants who have received any study treatment)

Response to treatment (Complete Response (CR) or Partial Response (PR)) determined using Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses, no increase in the size of other nodes, liver or spleen, no new sites of disease, patients who achieve CR but have persistent morphologic bone marrow involvement; Stable Disease (SD): failing to attain PR or CR, but not fulfilling criteria for progressive disease; Progressive Disease (PD)/Relapse: appearance of new lesions more than 1.5 cm in any axis, 50% or greater increase from nadir SPD of any previously involved sites, 50% or greater increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in short axis.

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=13 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=26 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Overall Response Rate (ORR) of Phase I and Phase II Participants	12 Participants	21 Participants

SECONDARY outcome

Timeframe: Every 6 weeks until treatment discontinuation then every 3 months thereafter, projected average 24 months

Population: The efficacy evaluable population (all participants who have received any study treatment)

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=10 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=29 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Overall Response Rate (ORR) of Previously Treated and Previously Untreated Participants	8 Participants	25 Participants

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years

Population: All participants that received study treatment that were evaluable for a response assessment (one participant in Phase I and two participants in Phase II were considered unevaluable, discontinuing prior to first post-baseline response assessment)

Measured from the time of study entry to the documented beginning of response (CR or PR). This is measured in responders per Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase in size of other nodes, liver or spleen, no new disease sites, patients with CR and persistent morphologic bone marrow involvement. Time to Best Response will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=12 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=24 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Time to Best Response of Phase I and Phase II Participants	63.50 days Interval 59.0 to 169.0	71.50 days Interval 47.0 to 523.0

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years

Population: All patients that received study treatment that were evaluable for a response assessment (2 previously untreated participants and 1 previously treated participant were considered unevaluable, discontinuing prior to first post-baseline response assessment)

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=10 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=29 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Time to Best Response of Previously Treated and Previously Untreated Participants	2.04 months Interval 1.5441 to 4.271	2.37 months Interval 2.037 to 4.2053

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression

Population: All participants that received study treatment that were responders (achieved a PR or better)

Measured from the documented beginning of response (CR or PR) to the time of relapse. This is measured in responders per Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase in size of other nodes, liver or spleen, no new disease sites, patients with CR and persistent morphologic bone marrow involvement. Duration of Response will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=12 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=21 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Duration of Response (DoR) of Phase I and Phase II Participants	25.72 months Interval 5.3224 to 52.665	17.81 months Interval 4.6982 to 21.092

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression

Population: All participants that received study treatment that were responders (achieved a PR or better)

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=8 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=25 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Duration of Response (DoR) of Previously Treated and Previously Untreated Participants	17.94 months Interval 2.8583 to 46.982	21.09 months Interval 5.6509 to 52.665

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression

Population: All participants that received study treatment

Defined as the time from entry onto study until lymphoma progression or death from any cause. Progression Free Survival will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=13 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=26 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Progression Free Survival (PFS) of Phase I and Phase II Participants	27.70 months Interval 7.2608 to 55.097	19.35 months Interval 7.5236 to 25.298

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression

Population: All participants that received study treatment

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=10 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=29 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Progression Free Survival (PFS) of Previously Treated and Previously Untreated Participants	12.4517 months Interval 0.4271 to 27.6632	25.2649 months Interval 7.4908 to 60.4189

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression

Population: all participants that received study treatment

Defined as the date of study entry to the date of death. Overall Survival will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=13 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=26 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Overall Survival of Phase I and Phase II Participants	51.45 months Interval 21.52 to 71.294	35.35 months Interval 22.374 to Not applicable (N/A) was reported as the maximum of the 95% confidence interval due to having insufficient data to provide the upper confidence limit estimate

SECONDARY outcome

Timeframe: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression

Population: all participants that received study treatment

Outcome measures

Outcome measures
Measure	Phase I Participants (10 mg/15 mg Lenalidomide) n=10 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 or 15 mg PO daily on Days 1-14. Includes participants tested on two separate dose levels, 15 mg by mouth (PO) daily (5 participants) or 10 mg PO daily (8 participants)	Phase II Participants (10 mg Lenalidomide) n=29 Participants Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1-14.
Overall Survival of Previously Treated and Previously Untreated Participants	28.4189 months Interval 0.4271 to 51.4168	71.2608 months Interval 35.3183 to 71.2608

Adverse Events

Phase I - Lenalidomide 15mg PO QD

Serious events: 2 serious events

Other events: 5 other events

Deaths: 0 deaths

Phase I - Lenalidomide 10mg PO QD

Serious events: 6 serious events

Other events: 8 other events

Deaths: 0 deaths

Phase II - Lenalidomide 10mg PO QD

Serious events: 13 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Ian Flinn, MD

Sarah Cannon Research Institute

Phone: 1-877-691-7274

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor can review/embargo results communications prior to public release for a period that is \>60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.
Publication restrictions are in place

Restriction type: OTHER

Measure	Phase I - Lenalidomide 15mg PO QD n=5 participants at risk Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 15 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 15 mg PO daily on Days 1 14.	Phase I - Lenalidomide 10mg PO QD n=8 participants at risk Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1 14.	Phase II - Lenalidomide 10mg PO QD n=26 participants at risk Cycle 1: rituximab 375 mg/m2 intravenously (IV) on Days 1, 8, and 15; bortezomib 1.3 mg/ m2 subcutaneously (SC) on Days 1, 4, 8, and 11; and lenalidomide 10 mg by mouth (PO) daily on Days 1-14. Cycles 2 - 6: rituximab 375 mg/m2 IV on Day 1; bortezomib 1.3 mg/ m2 SC on Days 1, 4, 8, and 11; and lenalidomide 10 mg PO daily on Days 1 14.
Renal and urinary disorders Acute Kidney Injury	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Renal and urinary disorders Acute Renal Failure	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Cardiac disorders Cardiac Ischemia/Infarction	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Infections and infestations Clostridium Difficile	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Gastrointestinal disorders Colitis	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
General disorders Death	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Gastrointestinal disorders Diarrhea	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	7.7% 2/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Nervous system disorders Encephalopathy	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Gastrointestinal disorders Esophagitis	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Blood and lymphatic system disorders Febrile Neutropenia	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
General disorders Fever	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	7.7% 2/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Gastrointestinal disorders Gastrointestinal- Intussusception	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Vascular disorders Hypotension	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Infections and infestations Infection- Lung (Pneumonia)	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	7.7% 2/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Infections and infestations Infection- Pyelonephritis	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Infections and infestations Infection- Septic Shock	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Infections and infestations Infection- Varicella	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	7.7% 2/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Infections and infestations Infection- Viral Syndrome	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Psychiatric disorders Mental Status Change	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
General disorders Opioid Withdrawal	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
General disorders Pain- Non Cardiac Chest	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
General disorders Pain- NOS	20.0% 1/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Gastrointestinal disorders Pancreatitis	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Blood and lymphatic system disorders Platelet Count Decreased	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Skin and subcutaneous tissue disorders Rash	20.0% 1/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Secondary Malignancy- Squamous Cell Carcinoma	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	12.5% 1/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Nervous system disorders Syncope	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval
Metabolism and nutrition disorders Tumor Lysis Syndrome	0.00% 0/5 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	0.00% 0/8 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval	3.8% 1/26 • 8 years Time frame from the initiation of study treatment for the first patient enrolled until all patients off-treatment into the survival follow-up interval