A PHASE 1 PHARMACOKINETIC-PHARMACODYNAMIC STUDY OF AVELUMAB (MSB0010718C) IN PATIENTS WITH PREVIOUSLY TREATED ADVANCED STAGE CLASSICAL HODGKIN'S LYMPHOMA
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Pfizer
- Enrollment
- 34
- Locations
- 12
- Primary Endpoint
- Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Lead-in phase-Cohort A
X1 mg IV every 2 weeks
Intervention: Avelumab (Drug)
Lead-in phase-Cohort B
X2 mg IV every 2 weeks
Intervention: Avelumab (Drug)
Lead-in phase-Cohort C
X3 mg IV every 3 weeks
Intervention: Avelumab (Drug)
Lead-in phase-Cohort D
X4 mg IV every 2 weeks
Intervention: Avelumab (Drug)
Lead-in phase-Cohort E
X5 mg IV every 2 weeks
Intervention: Avelumab (Drug)
Expansion phase
X1 mg IV every 2 weeks followed by X1 or X4 mg every 2 weeks
Intervention: Avelumab (Drug)
Outcomes
Primary Outcomes
Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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)
Time Frame: 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
Time Frame: 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
Time Frame: 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
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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
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
Time Frame: 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
Time Frame: 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 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(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(From first dose of study drug up to 90 days after the last administration of the study drug (maximum duration of 32 months))
- Lead-in Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status(Day 1 up to Month 29)
- Expansion Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status(Day 1 up to Month 14)
- Lead-in Phase: Number of Participants With Neutralizing Antibodies (nAb) Status(Day 1 up to Month 29)
- Expansion Phase: Number of Participants With Neutralizing Antibodies (nAb) Status(Day 1 up to Month 14)
- Lead-in Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab(Day 1 up to Month 29)
- Expansion Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab(Day 1 up to Month 14)
- Lead-in Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab(Day 1 up to Month 29)
- Expansion Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab(Day 1 up to Month 14)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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)
- 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))
- 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))
- 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)
- 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)
- 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)
- 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)