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

NCT02603419 | Terminated Phase 1 Results

• 4 other identifiers: B99910072015-002636-41JAVELIN HODGKINSJAVELIN HODGKIN'S
• Study Type: interventional
• Target: 34
• Locations: 3 countries
• Sites: 13

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.

Conditions

Hodgkins Lymphoma

Keywords

classical Hodgkins Lymphoma (relapsed/refractory); post-allogeneic HSCT; anti PD-L1; Phase 1; PK; Receptor occupancy; Immunophenotypic biomarkers

Outcome Measures

Primary Outcomes (18)

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

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

  Day 2 of Cycle 1

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

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

  Day 1 of Cycle 2

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

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

  Day 2 of Cycle 1

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

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

  Day 1 of Cycle 2

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

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

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

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

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

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

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

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

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

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

  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

  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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary Outcomes (35)

• 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

Study Arms (6)

Lead-in phase-Cohort A

EXPERIMENTAL

X1 mg IV every 2 weeks

Drug: Avelumab

Lead-in phase-Cohort B

EXPERIMENTAL

X2 mg IV every 2 weeks

Drug: Avelumab

Lead-in phase-Cohort C

EXPERIMENTAL

X3 mg IV every 3 weeks

Drug: Avelumab

Lead-in phase-Cohort D

EXPERIMENTAL

X4 mg IV every 2 weeks

Drug: Avelumab

Lead-in phase-Cohort E

EXPERIMENTAL

X5 mg IV every 2 weeks

Drug: Avelumab

Expansion phase

EXPERIMENTAL

X1 mg IV every 2 weeks followed by X1 or X4 mg every 2 weeks

Drug: Avelumab

Interventions

Avelumab DRUG

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

Lead-in phase-Cohort A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Patients with prior allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) who have had:
• 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
• 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
• 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
• 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
• 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.
• 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.
• 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.
• Patients with a history of ≥Grade 3 anti-PD-1 or anti-PD-L1-related immune toxicity are not eligible.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (13)

City of Hope

Duarte, California, 91010, United States

Location

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

Bologna, BO, 40138, Italy

Location

Istituto Clinico Humanitas U.O. Oncologia ed Ematologia

Rozzano, Milano, 20089, Italy

Location

Q2 Solutions

Rosebank, Livingston, EH54 7EG, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust

Headington, OX3 7LE, United Kingdom

Location

Leeds Teaching Hospital NHS Trust

Leeds, LS9 7TF, United Kingdom

Location

St James's University Hospital

Leeds, LS97TF, United Kingdom

Location

University Hospitals of Leicester NHS Trust

Leicester, LE1 5WW, United Kingdom

Location

University Hospitals of Leicester NHS Trust

Leicester, LE2 7LG, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, N7 9NH, United Kingdom

Location

UCLH Clinical Research Facility

London, WIT 7HA, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Plymouth Hospitals NHS Trust, Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34477818 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Hodgkin Disease; Recurrence

Interventions

avelumab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Results for PK parameters(AUC0-inf and Tlast after Multiple Dose) in Lead-in phase and (AUC0-inf, Cmax,AUC0-tau, t1/2, Tmax, Ctrough and Tlast after single and multiple doses) in expansion phase not reported, as data for these OMs were not collected.

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2015
• First Posted: November 11, 2015
• Study Start: March 10, 2016
• Primary Completion: December 1, 2018
• Study Completion: April 11, 2019
• Last Updated: April 24, 2020
• Results First Posted: March 18, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2); GB (10); US (1)