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

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)

Population: Data for this outcome measure (OM) was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: Data for this outcome measure was not collected due to early termination of study.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The TO analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The Target Occupancy (TO) analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose.

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

Population: The TO analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The TO analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: Data for this outcome measure was not collected due to early termination of study.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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 and multiple dose.

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

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.

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

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)

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

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

Population: Analysis was performed on participants who had received at least one dose of study drug and who had ADA ever-positive results.

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

Time frame: Day 1 up to Month 14

Population: Analysis was performed on participants who had received at least one dose of study drug and who had nAb ever-positive results. Here 0 in overall number of participants analyzed signifies that there were no nAb ever-positive participants in the specified group.

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)

Population: FAS included all randomized participants.

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

Population: The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one ADA sample collected for avelumab.

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)

Population: Safety analysis set included all participants who receive at least one dose of study drug.

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 14

Population: The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one nAb sample collected for avelumab.

Time frame: Pre-treatment tumor biopsy for baseline and on-treatment biopsy at Day 7 of Cycle 3

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

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)

Population: Safety analysis set included all participants who receive at least one dose of study drug.

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)

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

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)

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

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)

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

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)

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

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

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

Time frame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Population: Data for this outcome measure was not collected due to early termination of study.

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)

Population: Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

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)

Population: The FAS included all randomized participants. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

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

Population: Analysis was performed on participants who had received at least one dose of study drug and who had ADA ever-positive results. Here 0 in overall number of participants analyzed signifies that there were no ADA ever-positive participants in that specified group.

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

Population: Analysis was performed on participants who had received at least one dose of study drug and who had nAb ever-positive results. Here 0 in overall number of participants analyzed signifies that there were no nAb ever-positive participants in that specified group.

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

Population: The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one ADA sample collected for avelumab.

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)

Population: Data for this outcome measure was not collected and analyzed due to lack of availability of tumor biopsy tissue for analysis.

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)

Population: Safety analysis set included all participants who receive at least one dose of study drug. Here, 'Number analyzed' ('n') = Participants evaluable for this outcome measure for each specified category.

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

Population: The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one nAb sample collected for avelumab.

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)

Population: Data for this outcome measure was not collected and analyzed due to lack of availability of tumor biopsy tissue for analysis.

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

Population: Data for this outcome measure was not collected and analyzed, as the assay (which was planned for this parameter) could not be used due to quality issues.

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)

Population: Safety analysis set included all participants who receive at least one dose of study drug.

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)

Population: FAS included all randomized participants.

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)

Population: The FAS included all randomized participants.

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)

Population: The FAS included all randomized participants.

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)

Population: The FAS included all randomized participants. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.