Clinical trial NCT02603419: Avelumab In Patients With Previously Treated Advanced Stage Classical Hodgkin's Lymphoma (JAVELIN HODGKINS)
Official title: A PHASE 1 PHARMACOKINETIC-PHARMACODYNAMIC STUDY OF AVELUMAB (MSB0010718C) IN PATIENTS WITH PREVIOUSLY TREATED ADVANCED STAGE CLASSICAL HODGKIN'S LYMPHOMA
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hodgkins Lymphoma
Keywords: classical Hodgkins Lymphoma (relapsed/refractory)
post-allogeneic HSCT
anti PD-L1
Phase 1
PK
Receptor occupancy
Immunophenotypic biomarkers
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2015-11-11
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1
timeFrame: Day 2 of Cycle 1
measure: Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 1 of Cycle 2
timeFrame: Day 1 of Cycle 2
measure: Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 2 of Cycle 1
timeFrame: Day 2 of Cycle 1
measure: Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 1 of Cycle 2
timeFrame: Day 1 of Cycle 2
measure: Expansion Phase: Percentage of Participants With Objective Response as Assessed by Blinded Independent Central Review (BICR)
timeFrame: From treatment start in expansion phase until progressive disease or death due to any cause (maximum duration of 14 months)
measure: Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Single Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1
measure: Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Multiple Dose
timeFrame: pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2
measure: Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1
measure: Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Multiple Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2
measure: 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
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1
measure: 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
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2
measure: Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1
measure: Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Multiple Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2
measure: Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1
measure: Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Multiple Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2
measure: Lead-in Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Multiple Dose
timeFrame: pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2
measure: Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single Dose
timeFrame: pre-dose, 1, 6, 24, 144, 312 and 527 hours post-dose on Day 1 of Cycle 1
measure: Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Multiple Dose
timeFrame: pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2
Secondary outcomes:
measure: 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
timeFrame: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)
measure: Lead-in Phase: Number of Participants With Laboratory Abnormalities Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
timeFrame: From first dose of study drug up to 90 days after the last administration of the study drug (maximum duration of 32 months)
measure: Lead-in Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status
timeFrame: Day 1 up to Month 29
measure: Expansion Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status
timeFrame: Day 1 up to Month 14
measure: Lead-in Phase: Number of Participants With Neutralizing Antibodies (nAb) Status
timeFrame: Day 1 up to Month 29
measure: Expansion Phase: Number of Participants With Neutralizing Antibodies (nAb) Status
timeFrame: Day 1 up to Month 14
measure: Lead-in Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab
timeFrame: Day 1 up to Month 29
measure: Expansion Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab
timeFrame: Day 1 up to Month 14
measure: Lead-in Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab
timeFrame: Day 1 up to Month 29
measure: Expansion Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab
timeFrame: Day 1 up to Month 14
measure: Lead-in Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy
timeFrame: 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)
measure: Lead-in Phase: Number of Participants With Gene Expression of Transcripts Associated With Immune Activation and Regulation
timeFrame: 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)
measure: Lead-in Phase: Number of Participants With T Cell Immunophenotype
timeFrame: Day 1 of Cycles 1, 2, 3, 4, 7, 10 and at End of Treatment (maximum duration of 29 months)
measure: Lead-in Phase: Percentage of Participants With Objective Response as Assessed by Investigator
timeFrame: From randomization until disease progression or death due to any cause (maximum duration of 32 months)
measure: Lead-in Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator
timeFrame: From randomization to PD, death or start of new anti-cancer therapy (maximum duration of 32 months)
measure: Lead-in Phase: Time to Tumor Response (TTR) as Assessed by Investigator
timeFrame: From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of 32 months)
measure: Lead-in Phase: Duration of Response (DR) as Assessed by Investigator
timeFrame: 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)
measure: Lead-in Phase: Progression-Free Survival (PFS) as Assessed by Investigator
timeFrame: From randomization to the date of progression of disease or death due to any cause, whichever occurs first (maximum duration of 32 months)
measure: Expansion Phase: Percentage of Participants With Objective Response as Assessed by Investigator
timeFrame: From treatment start in expansion phase until disease progression or death due to any cause (maximum duration of 14 months)
measure: Expansion Phase: Time to Tumor Response (TTR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
timeFrame: From treatment start in expansion phase to first documentation of objective response (CR or PR) (maximum duration of 14 months)
measure: Expansion Phase: Duration of Response (DR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
timeFrame: 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)
measure: Expansion Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
timeFrame: From treatment start in expansion phase to PD, death or start of new anti-cancer therapy (maximum duration of 14 months)
measure: Expansion Phase: Progression-Free Survival (PFS) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
timeFrame: 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)
measure: Expansion Phase: Overall Survival
timeFrame: From treatment start in expansion phase until death (maximum duration of 14 months)
measure: 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
timeFrame: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)
measure: Expansion Phase: Number of Participants With Laboratory Abnormalities of Grade 3 Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
timeFrame: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)
measure: Expansion Phase: Number of Participants With Acute and Chronic Graft Versus Host Disease (GVHD)
timeFrame: From treatment start in expansion phase up to 90 days after last administration of study drug (maximum duration of 14 months)
measure: Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf), After Single and Multiple Dose
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single and Multiple Dose
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: 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
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: Expansion Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single and Multiple Dose
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: Expansion Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single and Multiple Dose
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: Expansion Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Single and Multiple Dose
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: Expansion Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single and Multiple Dose
timeFrame: pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3
measure: Expansion Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy
timeFrame: Pre-treatment tumor biopsy for baseline and on-treatment biopsy at Day 7 of Cycle 3
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Bologna
country: Italy
facility: Az. Ospedaliera-Univers. di Bologna Policlinico S.Orsola-Malpighi
state: BO
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas U.O. Oncologia ed Ematologia
state: Milano
city: Rosebank
country: United Kingdom
facility: Q2 Solutions
state: Livingston
city: Headington
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospital NHS Trust
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: UCLH Clinical Research Facility
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust, Derriford Hospital
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Herrera AF, Burton C, Radford J, Miall F, Townsend W, Santoro A, Zinzani PL, Lewis D, Fowst C, Brar S, Huang B, Thall A, Collins GP. Avelumab in relapsed/refractory classical Hodgkin lymphoma: phase 1b results from the JAVELIN Hodgkins trial. Blood Adv. 2021 Sep 14;5(17):3387-3396. doi: 10.1182/bloodadvances.2021004511.