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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02951156




Registration number
NCT02951156
Ethics application status
Date submitted
19/10/2016
Date registered
1/11/2016
Date last updated
29/01/2019

Titles & IDs
Public title
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)
Scientific 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
Secondary ID [1] 0 0
2016-002904-15
Secondary ID [2] 0 0
B9991011
Universal Trial Number (UTN)
Trial acronym
Javelin DLBCL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diffuse Large B-Cell Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Avelumab
Other interventions - Utomilumab
Other interventions - Rituximab
Other interventions - Azacitidine
Treatment: Drugs - Bendamustine
Treatment: Drugs - Gemcitabine
Treatment: Drugs - Oxaliplatin

Experimental: Phase 1b Arm A - avelumab/utomilumab/rituximab

Experimental: Phase 1b Arm B - avelumab/utomilumab/azacitidine

Experimental: Phase 1b Arm C - avelumab/rituximab/bendamustine

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

Active Comparator: Phase 3 Arm E - Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin


Other interventions: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody

Other interventions: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist

Other interventions: Rituximab
CD20-directed cytolytic antibody

Other interventions: Azacitidine
Antimetabolite antineoplastic agent and demethylation agent.

Treatment: Drugs: Bendamustine
Alkylating drug

Treatment: Drugs: Gemcitabine
Nucleoside analogue

Treatment: Drugs: Oxaliplatin
Platinum-based drug

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1b: Dose Limiting Toxicity (DLT)
Timepoint [1] 0 0
The first cycle (28 days) observation for 4-weeks
Primary outcome [2] 0 0
Phase 1b: Objective Response (OR) - Per Lugano Response Classification Criteria
Timepoint [2] 0 0
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
Primary outcome [3] 0 0
Phase 3: Progression Free Survival (PFS) - Determined by Blinded Independent Central Review (BICR) per Lugano Response Classification Criteria
Timepoint [3] 0 0
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.
Secondary outcome [1] 0 0
Phase 1b: Duration of Response (DR)
Timepoint [1] 0 0
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
Secondary outcome [2] 0 0
Phase 1b: Time to Tumor Response (TTR)
Timepoint [2] 0 0
From the date of randomization to the first documentation of objective response (CR or PR) assessed up to 120 months
Secondary outcome [3] 0 0
Phase 1b: Disease Control (DC)
Timepoint [3] 0 0
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
Secondary outcome [4] 0 0
Phase 1b: Progression-Free Survival (PFS) - By Investigator assessment
Timepoint [4] 0 0
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
Secondary outcome [5] 0 0
Phase 1b: Overall Survival (OS)
Timepoint [5] 0 0
From the date of randomization to the date of death due to any cause, whichever comes first assessed up to 120 months
Secondary outcome [6] 0 0
Phase 1b: Minimal Residual Disease (MRD) burden
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
Phase 3: Overall Survival (OS)
Timepoint [7] 0 0
From the date of randomization to the date of death due to any cause, whichever comes first assessed up to 120 months
Secondary outcome [8] 0 0
Phase 3: Progression Free Survival (PFS) - By Investigator assessment
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
Phase 3: Objective Response (OR) - BICR and Investigator assessment
Timepoint [9] 0 0
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
Secondary outcome [10] 0 0
Phase 3: Time to Tumor Response (TTR) - BICR and Investigator assessment
Timepoint [10] 0 0
From the date of randomization to the first documentation of objective response (CR or PR) assessed up to 120 months
Secondary outcome [11] 0 0
Phase 3: Duration of Response (DR) - BICR and Investigator assessment
Timepoint [11] 0 0
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
Secondary outcome [12] 0 0
Phase 3: Disease Control (DC). - BICR and Investigator assessment
Timepoint [12] 0 0
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
Secondary outcome [13] 0 0
Phase 3:Change from baseline in Brief Fatigue Inventory (BFI) questionnaire
Timepoint [13] 0 0
The first day of the first study visit and every 28 days thereafter up to 120 months
Secondary outcome [14] 0 0
Phase 3: Minimal residual disease (MRD) burden
Timepoint [14] 0 0
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.
Secondary outcome [15] 0 0
Phase 1b: Phase 1b: AUC(0-t) [Area under the serum concentration time profile from time zero to the next dose (after single dose)]
Timepoint [15] 0 0
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.
Secondary outcome [16] 0 0
Phase 1b: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against avelumab
Timepoint [16] 0 0
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
Secondary outcome [17] 0 0
Phase 1b: PD L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline
Timepoint [17] 0 0
Baseline
Secondary outcome [18] 0 0
Phase 3: Change from baseline in the NCCN-FACT FLymSI-18 questionnaire
Timepoint [18] 0 0
First day of the first visit, and every 28 days. through the 90-day follow-up visit after EOT.
Secondary outcome [19] 0 0
Phase 3: Change from baseline in the EQ-5D-5L questionnaire
Timepoint [19] 0 0
First day of the first visit, and every 7 days. through the 90-day follow-up visit after EOT.
Secondary outcome [20] 0 0
Phase 3: AUC(0-t) [Area under the serum concentration time profile from time zero to the next dose (after single dose)
Timepoint [20] 0 0
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.
Secondary outcome [21] 0 0
Phase 3: Cmax [(Maximum observed serum concentration (after single dose)]
Timepoint [21] 0 0
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. ]
Secondary outcome [22] 0 0
Phase 3: PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline
Timepoint [22] 0 0
Baseline
Secondary outcome [23] 0 0
Phase 1b: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against rituximab
Timepoint [23] 0 0
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
Secondary outcome [24] 0 0
Phase 1b: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against utomilumab
Timepoint [24] 0 0
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.
Secondary outcome [25] 0 0
Phase 3: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against avelumab
Timepoint [25] 0 0
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.
Secondary outcome [26] 0 0
Phase 3: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against rituximab
Timepoint [26] 0 0
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
Secondary outcome [27] 0 0
Phase 3: Anti-Drug Antibody (ADA); neutralizing antibodies (Nab) against utomilumab
Timepoint [27] 0 0
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
Secondary outcome [28] 0 0
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)
Timepoint [28] 0 0
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.
Secondary outcome [29] 0 0
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]
Timepoint [29] 0 0
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.
Secondary outcome [30] 0 0
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]
Timepoint [30] 0 0
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.
Secondary outcome [31] 0 0
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]
Timepoint [31] 0 0
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.
Secondary outcome [32] 0 0
Phase 1b: Maximum observed serum concentration (after single dose)
Timepoint [32] 0 0
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.
Secondary outcome [33] 0 0
Phase 1b: Maximum observed serum concentration (after single dose)
Timepoint [33] 0 0
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.
Secondary outcome [34] 0 0
Phase 1b: Maximum observed serum concentration (after single dose)
Timepoint [34] 0 0
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.
Secondary outcome [35] 0 0
Phase 1b: Maximum observed plasma concentration (after single dose and at steady state)
Timepoint [35] 0 0
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.
Secondary outcome [36] 0 0
Phase 1b: Maximum observed plasma concentration (after single dose and at steady state)
Timepoint [36] 0 0
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.

Eligibility
Key inclusion criteria
Key

-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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Nuclear Medicine Department - Kogarah
Recruitment hospital [2] 0 0
Pharmacy Department - Kogarah
Recruitment hospital [3] 0 0
Radiology Department - Kogarah
Recruitment hospital [4] 0 0
St. George Hospital - Kogarah
Recruitment hospital [5] 0 0
Clinical Trials Pharmacy Monash Health - Clayton
Recruitment hospital [6] 0 0
Monash Health - Clayton
Recruitment hospital [7] 0 0
Monash Imaging - Clayton
Recruitment hospital [8] 0 0
Cancer Clinical Trials Centre, Austin Health, Level 4 - Heidelberg
Recruitment hospital [9] 0 0
Department of Pharmacy - Heidelberg
Recruitment hospital [10] 0 0
Nuclear Medicine - Heidelberg
Recruitment hospital [11] 0 0
Radiology Department - Heidelberg
Recruitment postcode(s) [1] 0 0
2217 - Kogarah
Recruitment postcode(s) [2] 0 0
3168 - Clayton
Recruitment postcode(s) [3] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Kentucky
Country [3] 0 0
United States of America
State/province [3] 0 0
Louisiana
Country [4] 0 0
United States of America
State/province [4] 0 0
Michigan
Country [5] 0 0
United States of America
State/province [5] 0 0
Minnesota
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
Belgium
State/province [7] 0 0
Gent
Country [8] 0 0
Belgium
State/province [8] 0 0
Leuven
Country [9] 0 0
Italy
State/province [9] 0 0
MI
Country [10] 0 0
Korea, Republic of
State/province [10] 0 0
Seoul
Country [11] 0 0
Poland
State/province [11] 0 0
Lubelskie
Country [12] 0 0
Poland
State/province [12] 0 0
Malopolskie
Country [13] 0 0
Poland
State/province [13] 0 0
Krakow
Country [14] 0 0
Poland
State/province [14] 0 0
Zamosc
Country [15] 0 0
Spain
State/province [15] 0 0
Caceres
Country [16] 0 0
Spain
State/province [16] 0 0
Cáceres
Country [17] 0 0
Spain
State/province [17] 0 0
Málaga
Country [18] 0 0
United Kingdom
State/province [18] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Pfizer
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
EMD Serono
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT02951156
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Pfizer CT.gov Call Center
Address 0 0
Pfizer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications