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Avelumab In Combination Regimens That Include An Immune Agonist, Epigenetic Modulator, CD20 Antagonist and/or Conventional Chemotherapy in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL) (Javelin DLBCL)

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ClinicalTrials.gov Identifier: NCT02951156
Recruitment Status : Active, not recruiting
First Posted : November 1, 2016
Last Update Posted : January 29, 2019
Sponsor:
Collaborator:
EMD Serono
Information provided by (Responsible Party):
Pfizer

Brief Summary:
Study B9991011 is a multi-center, international, randomized, open label, 2 component (Phase 1b followed by Phase 3), parallel-arm study of avelumab in combination with various agents for the treatment of Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).

Condition or disease Intervention/treatment Phase
Diffuse Large B-Cell Lymphoma Biological: Avelumab Biological: Utomilumab Biological: Rituximab Other: Azacitidine Drug: Bendamustine Drug: Gemcitabine Drug: Oxaliplatin Phase 3

Detailed Description:
The target study population of this Phase 1b/3 registrational study is patients with R/R DLBCL who have completed at least 2 (but not more than 4) lines of prior rituximab-containing multi-agent chemotherapy, and/or in whom autologous stem cell transplant (ASCT) has failed, or who are not candidates for ASCT or who are not eligible for intensive chemotherapy. Patients who are ineligible for intensive second line chemotherapy must have received at least one prior rituximab-containing combination chemotherapy regimen. The study will assess the safety, efficacy, pharmacokinetics (PK), immunogenicity of the 3 avelumab-based combination regimens tested, and collect patient reported outcome (PRO) data.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PHASE 1B/PHASE 3 MULTICENTER STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION REGIMENS THAT INCLUDE AN IMMUNE AGONIST, EPIGENETIC MODULATOR, CD20 ANTAGONIST AND/OR CONVENTIONAL CHEMOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) JAVELIN DLBCL
Actual Study Start Date : December 16, 2016
Estimated Primary Completion Date : March 20, 2020
Estimated Study Completion Date : May 29, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Phase 1b Arm A
avelumab/utomilumab/rituximab
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Name: MSB0010718C

Biological: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist
Other Name: PF-05082566

Biological: Rituximab
CD20-directed cytolytic antibody
Other Name: Rituxan

Experimental: Phase 1b Arm B
avelumab/utomilumab/azacitidine
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Name: MSB0010718C

Biological: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist
Other Name: PF-05082566

Other: Azacitidine
Antimetabolite antineoplastic agent and demethylation agent.
Other Name: Vidaza

Experimental: Phase 1b Arm C
avelumab/rituximab/bendamustine
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Name: MSB0010718C

Biological: Rituximab
CD20-directed cytolytic antibody
Other Name: Rituxan

Drug: Bendamustine
Alkylating drug
Other Name: Treanda

Experimental: Phase 3 Arm D (selected from Phase 1b)
Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Name: MSB0010718C

Biological: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist
Other Name: PF-05082566

Biological: Rituximab
CD20-directed cytolytic antibody
Other Name: Rituxan

Other: Azacitidine
Antimetabolite antineoplastic agent and demethylation agent.
Other Name: Vidaza

Drug: Bendamustine
Alkylating drug
Other Name: Treanda

Active Comparator: Phase 3 Arm E
Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
Biological: Rituximab
CD20-directed cytolytic antibody
Other Name: Rituxan

Drug: Bendamustine
Alkylating drug
Other Name: Treanda

Drug: Gemcitabine
Nucleoside analogue
Other Name: Gemzar

Drug: Oxaliplatin
Platinum-based drug
Other Name: Eloxatin




Primary Outcome Measures :
  1. Phase 1b: Dose Limiting Toxicity (DLT) [ Time Frame: The first cycle (28 days) observation for 4-weeks ]
  2. Phase 1b: Objective Response (OR) [ Time Frame: From date of randomization until the date of first documented disease progression or date of death due to any cause, whichever comes first assessed up to 120 months ]
    Per Lugano Response Classification Criteria

  3. Phase 3: Progression Free Survival (PFS) [ Time Frame: From the date of randomization until the date of the first documentation of objective Progressive Disease (PD) or date of death due to any cause, whichever occurs first assessed up to 120 months. ]
    Determined by Blinded Independent Central Review (BICR) per Lugano Response Classification Criteria


Secondary Outcome Measures :
  1. Phase 1b: Duration of Response (DR) [ Time Frame: From the date of first documentation of objective response (CR or PR) to the date of first documentation of objective progression of disease (PD) or death due to any cause assessed up to 120 months ]
  2. Phase 1b: Time to Tumor Response (TTR) [ Time Frame: From the date of randomization to the first documentation of objective response (CR or PR) assessed up to 120 months ]
  3. Phase 1b: Disease Control (DC) [ Time Frame: From the date of randomization to the date of PD, death or start of new anti-cancer therapy, whichever comes first, assessed up to 120 months ]
  4. Phase 1b: Progression-Free Survival (PFS) [ Time Frame: From the date of randomization until the date of the first documentation of PD or death due to any cause, whichever occurs first, assessed up to 120 months ]
    By Investigator assessment

  5. Phase 1b: Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death due to any cause, whichever comes first assessed up to 120 months ]
  6. Phase 1b: Minimal Residual Disease (MRD) burden [ Time Frame: From the date of randomization, 3, 6, 9, 12 months and after 12-months, every 6 months until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 120 months. ]
  7. Phase 3: Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death due to any cause, whichever comes first assessed up to 120 months ]
  8. Phase 3: Progression Free Survival (PFS) [ Time Frame: From the date of randomization until the date of the first documentation of PD or death due to any cause, whichever occurs first, assessed up to 120 months ]
    By Investigator assessment

  9. Phase 3: Objective Response (OR) [ Time Frame: From date of randomization until the date of first documented disease progression or date of death due to any cause, whichever comes first assessed up to 120 months ]
    BICR and Investigator assessment

  10. Phase 3: Time to Tumor Response (TTR) [ Time Frame: From the date of randomization to the first documentation of objective response (CR or PR) assessed up to 120 months ]
    BICR and Investigator assessment

  11. Phase 3: Duration of Response (DR) [ Time Frame: From the date of first documentation of objective response (CR or PR) to the date of first documentation of objective progression of disease (PD) or death due to any cause assessed up to 120 months ]
    BICR and Investigator assessment

  12. Phase 3: Disease Control (DC). [ Time Frame: From the date of randomization to the date of PD, death or start of new anti-cancer therapy, whichever comes first, assessed up to 120 months ]
    BICR and Investigator assessment

  13. Phase 3:Change from baseline in Brief Fatigue Inventory (BFI) questionnaire [ Time Frame: The first day of the first study visit and every 28 days thereafter up to 120 months ]
  14. Phase 3: Minimal residual disease (MRD) burden [ Time Frame: From the date of randomization, 3, 6, 9, 12 months and after 12-months, every 6 months until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 120 months. ]
  15. Phase 1b: Phase 1b: AUC(0-τ) [Area under the serum concentration time profile from time zero to the next dose (after single dose)] [ Time Frame: avelumab: pre-dose and 1 hour (at the end of infusion) following the first dose on Day 2 of Cycle 1, then on Day 8 and 16 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  16. Phase 1b: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against avelumab [ Time Frame: Pre-dose on Day 2 of Cycle 1 and pre-dose on Day 1 of Cycles 4 and 6. Additional samples for ADAs will be collected at 30 days after the end of therapy ]
  17. Phase 1b: PD L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline [ Time Frame: Baseline ]
  18. Phase 3: Change from baseline in the NCCN-FACT FLymSI-18 questionnaire [ Time Frame: First day of the first visit, and every 28 days. through the 90-day follow-up visit after EOT. ]
  19. Phase 3: Change from baseline in the EQ-5D-5L questionnaire [ Time Frame: First day of the first visit, and every 7 days. through the 90-day follow-up visit after EOT. ]
  20. Phase 3: AUC(0-τ) [Area under the serum concentration time profile from time zero to the next dose (after single dose) [ Time Frame: for avelumab: pre-dose and 1 hour (at the end of infusion) then on Day 8 and 16 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  21. Phase 3: Cmax [(Maximum observed serum concentration (after single dose)] [ Time Frame: for avelumab: pre-dose and 1 hour (at the end of infusion) following the first dose of avelumab on Day 2 of Cycle 1, then on Day 8 and 16 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ] ]
  22. Phase 3: PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline [ Time Frame: Baseline ]
  23. Phase 1b: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against rituximab [ Time Frame: Pre-dose on Day 1 of Cycle 1 and pre-dose on Day 1 of Cycles 4 and 6. Additional samples for ADAs will be collected at 30 days after the end of therapy for rituximab ]
  24. Phase 1b: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against utomilumab [ Time Frame: Pre-dose on Day 2 of Cycle 1 and pre-dose on Day 1 of Cycles 4 and 6. Additional samples for ADAs will be collected 30 days after the end of therapy for utomilumab. ]
  25. Phase 3: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against avelumab [ Time Frame: Pre-dose on Day 2 of Cycle 1 and pre-dose on Day 1 of Cycles 4 and 6. Additional samples for ADAs will be collected at 30 days after the end of therapy. ]
  26. Phase 3: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against rituximab [ Time Frame: Pre-dose on Day 1 of Cycle 1 and pre-dose on Day 1 of Cycles 4 and 6. Additional samples for ADAs will be collected at 30 days after the end of therapy for rituximab ]
  27. Phase 3: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against utomilumab [ Time Frame: Pre-dose on Day 2 of Cycle 1 and pre-dose on Day 1 of Cycles 4 and 6. Additional samples for ADAs will be collected 30 days after the end of therapy for utomilumab ]
  28. Phase 1b: AUC(0-t) [Area under the serum concentration time profile from time zero to the time of the last quantifiable concentration (C last) (after single dose) [ Time Frame: rituximab: pre-dose and at the end of infusion on Day 1 of Cycle 1, then on Days 7, 15 and 22 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  29. Phase 1b: AUC(0-t) Area under the serum concentration time profile from time zero to the time of the last quantifiable concentration (C last) [after single dose] [ Time Frame: utomilumab: pre-dose, and 1 hour (at the end of infusion) following the first dose on Day 2 of the first cycle in the study, and then on Day 16 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  30. Phase 1b: AUC(0-t) Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (C last) [after single dose and steady state] [ Time Frame: azacitidine: pre-dose, 0.5, 1, 2, and 4 hours on Day 1 and 5 of Cycle 1. Samples pre-dose and at 0.5 hour will also be collected on Day 1 of Cycles 4 and 6. ]
  31. Phase 1b: AUC(0-t) Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (C last) [after single dose] [ Time Frame: bendamustine (and M3 metabolite) pre-dose and at 1 hour (at the end of infusion), 2, and 4 hours following the first dose in the first cycle. Samples at pre-dose and 1 hour will also be collected following the first dose of Cycles 4 and 6. ]
  32. Phase 1b: Maximum observed serum concentration (after single dose) [ Time Frame: for avelumab: pre-dose and 1 hour (at the end of infusion) following the first dose on the Day 2 of Cycle 1, and additional samples will be collected on Day 8 and 16 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  33. Phase 1b: Maximum observed serum concentration (after single dose) [ Time Frame: rituximab: pre-dose and at the end of infusion on Day 1 in Cycle 1, and then on Days 7, 15 and 22 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  34. Phase 1b: Maximum observed serum concentration (after single dose) [ Time Frame: utomilumab: pre-dose, and 1 hour (at the end of infusion) following the first dose on Day 2 of the first cycle in the study, and then on Day 16 of Cycle 1. Pre-dose samples will also be collected on Day 1 of Cycles 4 and 6. ]
  35. Phase 1b: Maximum observed plasma concentration (after single dose and at steady state) [ Time Frame: azacitidine: pre-dose, 0.5, 1, 2, and 4 hours on Day 1 and 5 of Cycle 1. Samples pre-dose and at 0.5 hour will also be collected on Day 1 of Cycles 4 and 6. ]
  36. Phase 1b: Maximum observed plasma concentration (after single dose and at steady state) [ Time Frame: bendamustine (and M3 metabolite) pre-dose and at 1 hour (at the end of infusion), 2, and 4 hours following the first dose in the first cycle. Samples at pre-dose and 1 hour will also be collected following the first dose of Cycles 4 and 6. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

-Any of the following as defined by the WHO, 2016 lymphoid neoplasm classifications and histologically confirmed:

  • Diffuse large B-cell lymphoma (DLBCL), Not Otherwise Specified (NOS): Germinal center B-cell type (GCB), Activated B-cell type (ABC)
  • High-grade B-cell lymphoma (HGBCL) NOS
  • HGBCL with MYC and BCL2 and/or BCL6 rearrangements
  • T-cell histocyte-rich large B-cell lymphoma
  • EBV+ DLBCL, NOS
  • HHV8+ DLBCL, NOS

Relapsed or refractory disease following at least 2 lines (and a maximum of 4 lines) of prior rituximab containing multi-agent chemotherapy which may include an autologous stem cell transplantation unless patients are not considered suitable for intensive second-line chemotherapy or autologous stem cell transplantation. Patients who are ineligible for intensive second line chemotherapy,must have received at least one prior rituximab-containing combination chemotherapy regimen. Patients who are ineligible for intensive second line chemotherapy, must have received at least one prior rituximab-containing combination chemotherapy regimen.

  • Baseline measurable disease with at least 1 bi dimensional lesion with longest diameter (LDi) >1.5cm on CT scan which is FDG avid on PET scan.
  • A biopsy (archived or Screening/recent) will be collected at Screening.
  • At least 18years of age (or ≥20 years in Japan).
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

Key Exclusion Criteria:

  • Active central nervous system (CNS) lymphoma.
  • Prior organ transplantation including prior allogeneic SCT.
  • Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody, or drug specifically targeting T cell co stimulatory or immune checkpoint pathways).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02951156


  Show 38 Study Locations
Sponsors and Collaborators
Pfizer
EMD Serono
Investigators
Layout table for investigator information
Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02951156     History of Changes
Other Study ID Numbers: B9991011
2016-002904-15 ( EudraCT Number )
First Posted: November 1, 2016    Key Record Dates
Last Update Posted: January 29, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Gemcitabine
Azacitidine
Rituximab
Oxaliplatin
Bendamustine Hydrochloride
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents