Clinical trial NCT02951156: 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)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Diffuse Large B-Cell Lymphoma
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: EMD Serono
First posted: 2016-11-01
Enrollment: 29
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: 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).

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.

Eligibility 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).

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Day 1 Cycle 1 up to 4 Weeks
measure: Objective Response Rate (ORR) as Assessed by Investigator Per Lugano Response Classification Criteria
timeFrame: Randomization until date of PD, start of new anticancer therapy, discontinuation from study or death due to any cause, whichever occurred first (maximum up to 36 months)
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Greater Than or Equal to (>=) Grade 3, As Per National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE), Version 4.03
timeFrame: From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)
measure: Number of Participants With Laboratory Abnormalities As Per National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03
timeFrame: From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities
timeFrame: From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)
measure: Duration of Response (DOR) as Assessed by Investigator Per Lugano Response Classification Criteria
timeFrame: First response (CR or PR) to date of PD, start of new anti-cancer therapy, discontinuation from the study, censoring date or death due to any cause, whichever occurred first (maximum up to 36 months)
measure: Time to Tumor Response (TTR) as Assessed by Investigator Per Lugano Response Classification Criteria
timeFrame: From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to 36 months)
measure: Disease Control Rate as Assessed by the Investigator Per Lugano Response Classification Criteria
timeFrame: From the date of randomization to the first documentation of PD, study discontinuation, start of new anti-cancer therapy or death due to any cause, whichever occurred first (maximum up to 36 months)
measure: Progression-Free Survival (PFS) as Assessed by the Investigator Per Lugano Response Classification Criteria
timeFrame: From the date of randomization to progression of disease, study discontinuation, censoring date or death due to any cause, whichever occurred first (up to 36 months)
measure: Overall Survival
timeFrame: From the date of randomization to discontinuation from the study or death, whichever occurred first (maximum up to 36 months)
measure: Concentration Verses Time Summary of Avelumab
timeFrame: 1 hour Post dose Day 2 Cycle 1, 144 hour Post dose Day 8 of Cycle 1, 0 hour Post dose Day 16 of Cycle 1, Day 1 of Cycle 4 and Cycle 6
measure: Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status
timeFrame: Baseline: 2 hours pre-dose of first dose of avelumab, Post baseline: post first dose up to up to 30 Days after the end of treatment (maximum up to 36 months)
measure: Number of Participants With Anti-Drug Antibodies (ADA) Against Rituximab by Never and Ever Positive Status
timeFrame: From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
measure: Number of Participants With Anti-Drug Antibodies (ADA) Against Utomilumab by Never and Ever Positive Status
timeFrame: From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
measure: Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status
timeFrame: From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
measure: Number of Participants With Neutralizing Antibodies (nAb) Against Rituximab by Never and Ever Positive Status
timeFrame: From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
measure: Number of Participants With Neutralizing Antibodies (nAb) Against Utomilumab by Never and Ever Positive Status
timeFrame: From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
measure: Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline
timeFrame: Screening (prior to first dose of study treatment)
measure: Number of Participants With Minimal Residual Disease Burden (MRD) Positive, Negative and Not Evaluable (NE) Status
timeFrame: Baseline, Day 1 of Cycle 3, 6, 9, 12 and 18
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Louisville
country: United States
facility: Norton Diagnostic Center - Dupont
state: Kentucky
city: Louisville
country: United States
facility: Norton Women's and Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Billerica
country: United States
facility: Parexel International
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: East Setauket
country: United States
facility: North Shore Hematology Oncology Associates
state: New York
city: Kogarah
country: Australia
facility: St. George Hospital
state: New South Wales
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Heidelberg
country: Australia
facility: Cancer Clinical Trials Centre, Austin Health, Level 4
state: Victoria
city: Heidelberg
country: Australia
facility: Genesis Care
state: Victoria
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Rozzano
country: Italy
facility: Farmacia Studi Clinici
state: MI
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center Clinical Trial Pharmacy
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli
state: Lubelskie
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne S.C.
state: Malopolskie
city: Krakow
country: Poland
facility: Nzoz McD Voxel Osrodek Pet-Tk-Nmr
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli Oddzial Hematologiczny
city: Zamosc
country: Poland
facility: NU-MED Centrum Diagnostyki i Terapii Onkologicznej Zamosc Sp. z o.o.
city: Caceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Málaga
country: Spain
facility: Centro de Investigación Medicina Especializada Sanitaria (CIMES)
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie Pathology Partnership
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Hawkes EA, Phillips T, Budde LE, Santoro A, Saba NS, Roncolato F, Gregory GP, Verhoef G, Offner F, Quero C, Radford J, Giannopoulos K, Stevens D, Thall A, Huang B, Laird AD, Sandner R, Ansell SM. Avelumab in Combination Regimens for Relapsed/Refractory DLBCL: Results from the Phase Ib JAVELIN DLBCL Study. Target Oncol. 2021 Nov;16(6):761-771. doi: 10.1007/s11523-021-00849-8. Epub 2021 Oct 23.