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

Phase 1

Terminated

Conditions: Hodgkins Lymphoma

Interventions: Drug: Avelumab

Registration Number: NCT02603419

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 34

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lead-in phase-Cohort A	Avelumab	X1 mg IV every 2 weeks
Lead-in phase-Cohort B	Avelumab	X2 mg IV every 2 weeks
Lead-in phase-Cohort D	Avelumab	X4 mg IV every 2 weeks
Lead-in phase-Cohort C	Avelumab	X3 mg IV every 3 weeks
Lead-in phase-Cohort E	Avelumab	X5 mg IV every 2 weeks
Expansion phase	Avelumab	X1 mg IV every 2 weeks followed by X1 or X4 mg every 2 weeks

Primary Outcome Measures

Name	Time	Method
Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1	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.
Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 1 of Cycle 2	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.
Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 2 of Cycle 1	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.
Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 1 of Cycle 2	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.
Expansion Phase: Percentage of Participants With Objective Response as Assessed by Blinded Independent Central Review (BICR)	From treatment start in expansion phase until progressive disease or death due to any cause (maximum duration of 14 months)	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.
Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Single Dose	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1	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.
Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Multiple Dose	pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2	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.
Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single Dose	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	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	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1	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.
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	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2	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.
Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single Dose	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after single dose.
Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Multiple Dose	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after multiple dose.
Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single Dose	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1	Time to reach maximum observed plasma concentration of avelumab, after single dose.
Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Multiple Dose	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2	Time to reach maximum observed plasma concentration of avelumab, after multiple dose.
Lead-in Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Multiple Dose	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	pre-dose, 1, 6, 24, 144, 312 and 527 hours post-dose on Day 1 of Cycle 1	The last time point of the last quantifiable concentration (Tlast) of avelumab, after single dose.
Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Multiple Dose	pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2	The last time point of the last quantifiable concentration (tlast) of avelumab, after multiple dose.

Secondary Outcome Measures

Name	Time	Method
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	From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)	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.
Lead-in Phase: Number of Participants With Laboratory Abnormalities Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03	From first dose of study drug up to 90 days after the last administration of the study drug (maximum duration of 32 months)	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.
Lead-in Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status	Day 1 up to Month 29	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.
Expansion Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status	Day 1 up to Month 14	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.
Lead-in Phase: Number of Participants With Neutralizing Antibodies (nAb) Status	Day 1 up to Month 29	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.
Expansion Phase: Number of Participants With Neutralizing Antibodies (nAb) Status	Day 1 up to Month 14	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.
Lead-in Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab	Day 1 up to Month 29	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.
Expansion Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab	Day 1 up to Month 14	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.
Lead-in Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab	Day 1 up to Month 29	Serum samples were assayed for nAb using a validated analytical method. Number of nAb ever positive participants for serum nAb titer (1) is reported.
Expansion Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab	Day 1 up to Month 14	Serum samples were assayed for nAb using a validated analytical method.
Lead-in Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy	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	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	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	From randomization until disease progression or death due to any cause (maximum duration of 32 months)	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.
Lead-in Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator	From randomization to PD, death or start of new anti-cancer therapy (maximum duration of 32 months)	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).
Lead-in Phase: Time to Tumor Response (TTR) as Assessed by Investigator	From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of 32 months)	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.
Lead-in Phase: Duration of Response (DR) as Assessed by Investigator	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)	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).
Lead-in Phase: Progression-Free Survival (PFS) as Assessed by Investigator	From randomization to the date of progression of disease or death due to any cause, whichever occurs first (maximum duration of 32 months)	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.
Expansion Phase: Percentage of Participants With Objective Response as Assessed by Investigator	From treatment start in expansion phase until disease progression or death due to any cause (maximum duration of 14 months)	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).
Expansion Phase: Time to Tumor Response (TTR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)	From treatment start in expansion phase to first documentation of objective response (CR or PR) (maximum duration of 14 months)	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.
Expansion Phase: Duration of Response (DR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)	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)	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.
Expansion Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator and by Blinded Independent Central Review (BICR)	From treatment start in expansion phase to PD, death or start of new anti-cancer therapy (maximum duration of 14 months)	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.
Expansion Phase: Progression-Free Survival (PFS) as Assessed by Investigator and by Blinded Independent Central Review (BICR)	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)	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.
Expansion Phase: Number of Participants With Laboratory Abnormalities of Grade 3 Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03	From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)	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.
Expansion Phase: Number of Participants With Acute and Chronic Graft Versus Host Disease (GVHD)	From treatment start in expansion phase up to 90 days after last administration of study drug (maximum duration of 14 months)	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.
Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf), After Single and Multiple Dose	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3	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.
Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single and Multiple Dose	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
Expansion Phase: Overall Survival	From treatment start in expansion phase until death (maximum duration of 14 months)	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.
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	From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)	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.
Expansion Phase: 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	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3	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.
Expansion Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single and Multiple Dose	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.
Expansion Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single and Multiple Dose	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
Expansion Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Single and Multiple Dose	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
Expansion Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single and Multiple Dose	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3	The last time point of the last quantifiable concentration (tlast), after single and multiple dose.
Expansion Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy	Pre-treatment tumor biopsy for baseline and on-treatment biopsy at Day 7 of Cycle 3

Trial Locations

Locations (12): Az. Ospedaliera-Univers. di Bologna Policlinico S.Orsola-Malpighi
🇮🇹
Bologna, BO, Italy
City of Hope
🇺🇸
Duarte, California, United States
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 College London Hospitals NHS Foundation Trust
🇬🇧
London, United Kingdom
University Hospitals of Leicester NHS Trust
🇬🇧
Leicester, United Kingdom
Plymouth Hospitals NHS Trust, Derriford Hospital
🇬🇧
Plymouth, United Kingdom
The Christie NHS Foundation Trust
🇬🇧
Manchester, United Kingdom
UCLH Clinical Research Facility
🇬🇧
London, United Kingdom