Avelumab In Patients With Previously Treated Advanced Stage Classical Hodgkin's Lymphoma (JAVELIN HODGKINS)

Phase 1TerminatedNCT02603419

Pfizer34 enrolled

Overview

This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an expansion phase. The lead-in phase is a multiple-dose, randomized, parallel-arm, pharmacokinetic and pharmacodynamic study of avelumab as a single agent in adult patients with cHL. Patients enrolled in the lead-in phase of this study are required to have relapsed following a prior autologous or allogeneic HSCT, or to be ineligible for HSCT. Based on the preliminary TO, safety, and efficacy results from the lead-in phase, the expansion phase will evaluate the anti-tumor activity and safety of single-agent avelumab utilizing an intra-patient dose escalation paradigm based on two of the dosing regimens studied in the lead-in phase in 40 cHL patients in whom an allogeneic HSCT has failed.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Hodgkins Lymphoma

Interventions

Anti-PD-L1 antibody at X1 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression.

AvelumabDRUG

Anti-PD-L1 antibody at X2 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression.

AvelumabDRUG

Anti-PD-L1 antibody at X3 mg IV every 3 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression

AvelumabDRUG

Anti-PD-L1 antibody at X3 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression

AvelumabDRUG

Anti-PD-L1 antibody at X mg IV every 2 weeks. Treatment with avelumab will continue until disease progression

AvelumabDRUG

Anti-PD-L1 antibody at X1 mg IV every 2 weeks which can be escalated to X4 mg every 2 weeks based on safety and efficacy. Treatment with avelumab will continue until disease progression.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

KEY INCLUSION CRITERIA * Histological confirmation of classical Hodgkin's Lymphoma (cHL) with relapsed or refractory disease who, for the lead-in phase, either have had a prior autologous or allogeneic HSCT or are not eligible for HSCT, and , for the expansion phase, have had a prior allogeneic HSCT. In the expansion phase there must be a documented CD3+ donor chimerism of ≥20%. * Patients must be off previous cHL therapy for at least 28 days prior to randomization in the lead-in phase/first dose of study treatment in the expansion phase. * At least 1 fluorodeoxyglucose (FDG) PET avid (Deauville 4/5) measurable lesion \>1.5 cm on PET-CT scan as defined by the Response Criteria for Malignant Lymphoma (for the lead-in phase) and the Lugano Classification (for the expansion phase) that has not previously been irradiated. * Expansion phase: Required "de novo" or "archival" tumor biopsy, as well as required on treatment biopsy * Estern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 KEY EXCLUSION CRITERIA * Patients with prior allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) who have had: 1. Lead-in phase: allo HSCT performed \<12 months prior to randomization. Expansion phase: allo-HSCT performed ≤4 months prior to the first dose of study treatment. NOTE: Patients who have had allo-HSCT performed \>4 months prior to the first dose of study treatment must have discontinued all immunosuppressive therapy, and must have no clinical evidence of GVHD; or 2. Immunosuppressive treatment for acute or chronic GVHD within 3 months prior to randomization for the lead-in phase or prior to the first dose of study treatment for the expansion phase (with the exception of those patients who required 15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral prednisone or equivalent must have discontinued it within 7 days prior to first dose of study treatment; or 3. Acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the modified Seattle Glucksberg criteria (Consensus Conference on Acute GVHD Grading Criteria); or 4. Prior chronic GVHD (as defined by the NIH Consensus Development Project) that persisted for \>6 months and required systemic immunosuppression (with the exception of those patients who required 15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral prednisone or equivalent must have discontinued it within 7 days prior to the first dose of study treatment; or 5. A donor lymphocyte infusion (DLI) within 3 months prior to randomization for the lead-in phase or first dose of study treatment for the expansion phase. * Prior therapy with an anti PD 1 or anti PD L1 mAb. 1. Lead-in Phase: May be enrolled if patient stopped prior anti PD1 or anti-PD-L1 therapy more than one year prior to randomization and had a documented prior response. 2. Expansion Phase: Prior therapy with an anti-PD-1 or anti-PD-L1 agent following allo-HSCT is prohibited unless the therapy was stopped more than one year prior to the first dose of study treatment, and the patient had a documented prior response. NOTE: Prior therapy with an anti-PD-1 or anti-PD-L1 agent prior to allo-HSCT is permitted with no time limits and irrespective of a documented response. 3. Patients with a history of ≥Grade 3 anti-PD-1 or anti-PD-L1-related immune toxicity are not eligible.

Locations (13)

City of Hope

Duarte, California, United States

Az. Ospedaliera-Univers. di Bologna Policlinico S.Orsola-Malpighi

Bologna, BO, Italy

Istituto Clinico Humanitas U.O. Oncologia ed Ematologia

Rozzano, Milano, Italy

Q2 Solutions

Rosebank, Livingston, United Kingdom

Oxford University Hospitals NHS Foundation Trust

Headington, United Kingdom

Leeds Teaching Hospital NHS Trust

Leeds, United Kingdom

St James's University Hospital

Leeds, United Kingdom

University Hospitals of Leicester NHS Trust

Leicester, United Kingdom

University Hospitals of Leicester NHS Trust

Leicester, United Kingdom

University College London Hospitals NHS Foundation Trust

London, United Kingdom

...and 3 more locations

Outcomes

Primary Outcomes

Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1

Target occupancy on peripheral blood CD14+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

Time frame: Day 2 of Cycle 1

Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 1 of Cycle 2

Target occupancy on peripheral blood CD14+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

Time frame: Day 1 of Cycle 2

Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 2 of Cycle 1

Target occupancy on peripheral blood CD3+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

Time frame: Day 2 of Cycle 1

Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 1 of Cycle 2

Target occupancy on peripheral blood CD3+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

Time frame: Day 1 of Cycle 2

Expansion Phase: Percentage of Participants With Objective Response as Assessed by Blinded Independent Central Review (BICR)

Objective response: complete response (CR) or partial response (PR) according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression (Disease progression: \>= 20% and \>= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease) or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in sum of products of greatest diameters. PR was defined \>= 50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD.

Time frame: From treatment start in expansion phase until progressive disease or death due to any cause (maximum duration of 14 months)

Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Single Dose

AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to extrapolated infinity AUC(0-inf), after single dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Multiple Dose

AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to extrapolated infinity AUC(0-inf), after multiple dose.

Time frame: pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2

Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single Dose

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Multiple Dose

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab After Single Dose

AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after single dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab After Multiple Dose

AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after multiple dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single Dose

Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after single dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Multiple Dose

Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after multiple dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single Dose

Time to reach maximum observed plasma concentration of avelumab, after single dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Multiple Dose

Time to reach maximum observed plasma concentration of avelumab, after multiple dose.

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Lead-in Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Multiple Dose

Time frame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single Dose

The last time point of the last quantifiable concentration (Tlast) of avelumab, after single dose.

Time frame: pre-dose, 1, 6, 24, 144, 312 and 527 hours post-dose on Day 1 of Cycle 1

Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Multiple Dose

The last time point of the last quantifiable concentration (tlast) of avelumab, after multiple dose.

Time frame: pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2

Secondary Outcomes

Lead-in Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related TEAEs and TEAEs Graded >=3 as Per National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03: Grade 3: severe or medically significant but not immediately life-threatening, or prolongation of existing hospitalization indicated; Grade 4: life-threatening consequence; Grade 5: death related to AE. SAE was an AE resulting in any of following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or congenital anomaly. A TEAEs: an event that emerged during treatment period (From first dose of study drug until end of open label phase \[From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)\] that was absent before treatment,or worsened during treatment period relative to pre-treatment state. AE was considered related to study drug if event was assessed by investigator as probably or possibly related.

Time frame: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)

Lead-in Phase: Number of Participants With Laboratory Abnormalities Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Hematology: Anemia (Grade)G3: Hg \<8.0 grams/deciliter (g/dL); lymphocyte count decreased G3: \<0.5-0.2\*10\^9/L, G4: \<0.2\*10\^9/L; neutrophil count decreased: G3: \<1.0-0.5\*10\^9/L, G4: \<0.5\*10\^9/L; platelet count decreased: G3:\<50.0-25.0\*10\^9/L, G4: \<25.0\*10\^9/L; white blood cell (WBC) decreased: G3: \<0.2\*10\^9/L, G4: \<1.0\*10\^9/L. Chemistry: \[ALT, ALP increased and AST G3: \>5.0-20.0\*ULN, G4: \>20.0\*ULN\]. blood bilirubin increased: G3: \>3.0-10.0\*ULN, G4: \>10.0 \*ULN. \[cholesterol high: G3: \>10.34 - 12.92, G4: \>12.92; hypokalemia G3: \<3.0-2.5, G4: \<2.5\]mmol/L, creatine phosphokinase (Cpk) increased: G3: \>5\*ULN-10\*ULN, G4: \>10\*ULN; gamma-glutamyl transferase (Ggt) increased: G3: \>5.0-20.0\*ULN, G4: \>20.0\*ULN; \[hypertriglyceridemia G3: \>500-1000, G4: \>1000; hypermagnesemia, G3: \>3.0-8.0, G 4: \>8.0\]mg/dL, Lipase increased: G3: \>2.0 - 5.0\*ULN, G4: \>5.0\*ULN, Serum amylase increased: G3: \>2.0 - 5.0\*ULN, G4: \>5.0\*ULN. Only those category in which at least one participant had data were reported.

Time frame: From first dose of study drug up to 90 days after the last administration of the study drug (maximum duration of 32 months)

Data from ClinicalTrials.gov

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Lead-in Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status

ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. ADA never-positive participants were those who had no positive (titer less than cutpoint \[22.5 percentage (%) inhibition\]) ADA results at any time point. ADA ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint \[22.5% inhibition\]) ADA result at any time point.

Time frame: Day 1 up to Month 29

Expansion Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status

ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. ADA never-positive participants were those who had no positive (titer less than cutpoint \[22.5% inhibition\]) ADA results at any time point. ADA ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint \[22.5% inhibition\]) ADA result at any time point.

Time frame: Day 1 up to Month 14

Lead-in Phase: Number of Participants With Neutralizing Antibodies (nAb) Status

nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive participants. nAb never-positive participants were those who had no positive (titer less than cutpoint \[0.71\]) nAb results at any time point. nAb ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint \[0.71\]) nAb result at any time point.

Time frame: Day 1 up to Month 29

Expansion Phase: Number of Participants With Neutralizing Antibodies (nAb) Status

Time frame: Day 1 up to Month 14

Lead-in Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab

Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum ADA titer (180, 4860, 43740 and 131220) are reported.

Time frame: Day 1 up to Month 29

Expansion Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab

Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum ADA titer (180, 4860, 43740 and 131220) are reported.

Time frame: Day 1 up to Month 14

Lead-in Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab

Serum samples were assayed for nAb using a validated analytical method. Number of nAb ever positive participants for serum nAb titer (1) is reported.

Time frame: Day 1 up to Month 29

Expansion Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab

Serum samples were assayed for nAb using a validated analytical method.

Time frame: Day 1 up to Month 14

Lead-in Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy

Time frame: Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of Cycle 3, 5, 7; and at End of Treatment (EOT) (maximum duration of 29 months)

Lead-in Phase: Number of Participants With Gene Expression of Transcripts Associated With Immune Activation and Regulation

Time frame: Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of Cycle 3, 5, 7; and at End of Treatment (maximum duration of 29 months)

Lead-in Phase: Number of Participants With T Cell Immunophenotype

Time frame: Day 1 of Cycles 1, 2, 3, 4, 7, 10 and at End of Treatment (maximum duration of 29 months)

Lead-in Phase: Percentage of Participants With Objective Response as Assessed by Investigator

Objective response: complete response (CR) or partial response (PR) according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression (Disease progression: \>= 20% and \>= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease) or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in sum of products of greatest diameters. PR was defined \>= 50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD.

Time frame: From randomization until disease progression or death due to any cause (maximum duration of 32 months)

Lead-in Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator

DC: best overall response of CR, PR, or stable disease (SD). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75% in sum of the products of greatest diameters. PR was defined \>=50% decreased in SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in SPD and SD was defined as \< PR but not progressive disease. To qualify as a best overall response of SD, at least one SD assessment must be observed \>=6 weeks after start date and before disease progression. (Disease progression: \>= 20% and \>= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).

Time frame: From randomization to PD, death or start of new anti-cancer therapy (maximum duration of 32 months)

Lead-in Phase: Time to Tumor Response (TTR) as Assessed by Investigator

TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined \>=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD.

Time frame: From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of 32 months)

Lead-in Phase: Duration of Response (DR) as Assessed by Investigator

DR is defined, for participants with an objective response, as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective PD or to death due to any cause, whichever occurs first. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined \>=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD.(PD: \>= 20% and \>= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).

Time frame: From first documentation of objective response to date of first documentation of objective PD or death due to any cause (maximum duration of 32 months)

Lead-in Phase: Progression-Free Survival (PFS) as Assessed by Investigator

PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression as per RECIST 1.1, was defined as at least a 20% increase in the sum of 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 have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered as progression of disease.

Time frame: From randomization to the date of progression of disease or death due to any cause, whichever occurs first (maximum duration of 32 months)

Expansion Phase: Percentage of Participants With Objective Response as Assessed by Investigator

Objective response was defined as CR or PR according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined \>=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD. (PD: \>= 20% and \>= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).

Time frame: From treatment start in expansion phase until disease progression or death due to any cause (maximum duration of 14 months)

Expansion Phase: Time to Tumor Response (TTR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)

Time to Tumor Response (TTR) was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined \>=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD.

Time frame: From treatment start in expansion phase to first documentation of objective response (CR or PR) (maximum duration of 14 months)

Expansion Phase: Duration of Response (DR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)

Duration of Response (DR) is defined, for participants with an objective response, as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective progression of disease (PD) or to death due to any cause, whichever occurs first. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined \>=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD.

Time frame: From first documentation of objective response in expansion phase to date of first documentation of objective PD or death due to any cause (maximum duration of 14 months)

Expansion Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator and by Blinded Independent Central Review (BICR)

Disease Control (DC) was defined as the best overall response of CR, PR, or SD. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if \>1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined \>=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by \>=50% in the SPD and Stable Disease was defined as less than a PR but not progressive disease. To qualify as a best overall response of SD, at least one SD assessment must be observed \>=6 weeks after start date and before disease progression.

Time frame: From treatment start in expansion phase to PD, death or start of new anti-cancer therapy (maximum duration of 14 months)

Expansion Phase: Progression-Free Survival (PFS) as Assessed by Investigator and by Blinded Independent Central Review (BICR)

PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of 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 have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using a Cox's Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.

Time frame: From treatment start in expansion phase to date of first documentation of objective Progressive Disease (PD) or death due to any cause, whichever occurs first (maximum duration of 14 months)

Expansion Phase: Overall Survival

Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.

Time frame: From treatment start in expansion phase until death (maximum duration of 14 months)

Expansion Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related TEAEs and TEAEs Graded >=3 Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03: Grade 3: severe or medically significant but not immediately life-threatening, or prolongation of existing hospitalization indicated; Grade 4: life-threatening consequence; Grade 5: death related to AE. SAE was an AE resulting in any of following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or congenital anomaly. TEAEs: an event that emerged during treatment period (From first dose of study drug until end of expansion phase \[From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)\] that was absent before treatment, or worsened during treatment period relative to pre-treatment state. AE was considered related to study drug if event was assessed by investigator as probably or possibly related.

Time frame: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)

Expansion Phase: Number of Participants With Laboratory Abnormalities of Grade 3 Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

As per NCI-CTCAE v 4.03, Grade \>= 3 criteria were; Alanine aminotransferase: 0 LLN, 0.58 ULN microkat/L (microkatal /L); GGT: 0 LLN, 0.63 ULN microkat/L, Glucose: 4.11 LLN, 5.88 ULN mmol/L, LOW Sodium: 136 LLN, 146 ULN mmol/L; Prothrombin intl. normalized ratio: 0.9 LLN, 1.2 ULN; LOW lymphocytes (10\^9/L); 1.5 LLN, 4.0 ULN; Platelets (10\^9/L): 130 LLN, 400 ULN. Only those category in which at least one participant had data were reported.

Time frame: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)

Expansion Phase: Number of Participants With Acute and Chronic Graft Versus Host Disease (GVHD)

Acute GvHD is a reaction of donor immune cells against host tissues. The three main tissues that acute GvHD affects are the skin, liver and gastrointestinal tract. Chronic GvHD is a syndrome of variable clinical features resembling autoimmune and other immunologic disorders. Manifestations of chronic GvHD may be restricted to a single organ or site or may be widespread, with profound impact on quality of life.

Time frame: From treatment start in expansion phase up to 90 days after last administration of study drug (maximum duration of 14 months)

Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf), After Single and Multiple Dose

AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to infinity AUC(0-inf), after single and multiple dose.