Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) MedDRA version: 19.1 Level: PT Classification code 10012822 Term: Diffuse large B-cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Pfizer Inc, 235 East 42nd Street, New York, NY 10017
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed DLBCL. 2. Documentation that the disease is relapsed or refractory 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. 3. Patients previously treated with bendamustine must have experienced a response duration =6 months. 4. Documentation of baseline measurable disease with at least 1 bi-dimensional lesion >1.5 cm on CT scan which is fluorodeoxyglucose (FDG) avid on PET scan. 5. A biopsy (archived or Screening/recent) will be collected at Screening. 6. Estimated life expectancy =3 months. 7. At least 18 years of age (or =20 years in Japan). 8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 9. All adverse events must have resolved to NCI CTCAE v.4.03 Grade =1 (with the exception of alopecia and other Grade =2 AEs not considered medically relevant in the judgment of the Investigator). 10. Patients must have an adequate bone marrow function, including: a. Absolute neutrophil count (ANC) =1.5 x 10(9)/L; b. Platelet count =100 x 10(9)/L; c. Hemoglobin =8 g/dL. 11. Patients must have adequate liver function, including: a. Total bilirubin level =1.5 × upper limit of normal (ULN); b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.5 x ULN. 12. Patients must have an adequate renal function as evidenced by a creatinine clearance =40 mL/min as calculated using the Cockcroft-Gault equation. 13. Serum or urine pregnancy test (for females of childbearing potential) must be negative. 14. Female patients of non-childbearing potential must meet at least 1 of the following criteria: Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state; Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 152 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 152
Exclusion criteria
Exclusion criteria: 1. Transformed lymphoma or Burkitt’s Lymphoma. 2. Active/symptomatic central nervous system (CNS) lymphoma based on clinical evaluation. 3. Prior organ transplantation including prior allogeneic SCT. 4. 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). 5. Use of any standard or experimental anti-cancer therapy within 2 weeks prior to randomization, including cytoreductive therapy and radiotherapy, immunotherapy, or cytokine therapy (except for erythropoietin). 6. Use of any non-drug anti-cancer therapy including chimeric antigen receptor (CAR) T-Cell (CAR-T-Cell) therapy. 7. Major surgery within 28 days prior to first dose of study treatment. 8. Diagnosis of any other malignancy =3 years prior to first dose of study treatment, with the exception of: (i) adequately treated basal cell or squamous cell skin cancer, (ii) carcinoma in situ of the breast or cervix, or (iii) low-grade (Gleason =6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration). 9. Known history of testing positive for human immunodeficiency virus ( HIV) or known acquired immunodeficiency syndrome. 10. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen, positive HBV core antibody or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive). 11. Active infection requiring systemic therapy. 12. Vaccination within 4 weeks prior to randomization and while on trial is prohibited except for administration of inactivated vaccines. 13. Peripheral neuropathy with functional impairment (for the Phase 3 component only due to oxaliplatin). 14. Current use of immunosuppressive medication, EXCEPT for the following: a.) intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular injection); b.) Systemic corticosteroids at physiologic doses =10 mg/day of prednisone or equivalent; c.) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 15. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 16. Known anaphylaxis or severe hypersensitivity to rituximab or other monoclonal antibodies, mannitol, or any of the compounds used in this study or to compounds with a similar chemical or biological composition.72 17. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke/transient ischemic attack [TIA]/symptomatic pulmonary embolism (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (=New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, other severe acute or chronic medical (including coliti
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1b Primary Objective: To asses safety, efficacy, and potentially select the most active treatment regimen among 3 treatment arms to advance to the Phase 3 component of the study. Phase 3 Primary Objective: To demonstrate superiority in PFS as assessed by the Blinded Independent Central Review (BICR) of the selected Phase 1b avelumab-based combination regimen over Investigator’s Choice chemotherapy. ; Secondary Objective: Ph1b: evaluate PK & assess immunogenicity of treatments; evaluate PD-L1 expression levels in tumor cells and cells of the tumor microenvironment with their relationship to clinical response parameters; evaluate relationship between minimal residual disease burden as assessed using serial blood samples with clinical response parameters Ph3: compare overall survival between the selected Ph1b avelumab combination regimen to Investigator’s Choice chemotherapy; evaluate efficacy & safety profile of treatments; evaluate PK & assess immunogenicity of Ph1b avelumab combination regimen; evaluate reported outcomes in Ph1b avelumab combination regimen vs Investigator’s Choice chemotherapy; evaluate PD-L1 expression levels in tumor cells and cells of the tumor microenvironment with their relation to clinical response parameters; evaluate relationship between minimal residual disease burden as assessed using serial blood samples with clinical response parameters ; Primary end point(s): Phase 1b Primary Endpoint: Dose Limiting Toxicity (DLT); Objective Response (OR) as assessed by the Investigator per Lugano Response Classification Criteria. Phase 3 - Primary Endpoint: Progression-Free Survival (PFS) as determined by Blinded Independent Central Review (BICR) per Lugano Response Classification Criteria. ; Timepoint(s) of evaluation of this end point: Phase 1b: 18F-fluorodeoxyglucose (18F-FDG) Po | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b Secondary Endpoints: Safety: AEs and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology -Critera for Adverse Events (CTCAE) v.4.03; vital signs (blood pressure, heart rate); electrocardiograms (ECGs); -Duration of Response (DR), Time to Tumor Response (TTR), Disease Control (DC); Progression-Free Survival (PFS), as assessed by the Investigator per Lugano Response Classification Criteria and Overall Survival (OS); -Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine and bendamustine as data permit: maximum plasma concentration C(max), time to maximum plasma concentration T(max), area under the plasma concentration time curve from time 0 to T hours post dose apparent plasma clearance (CL/F), and apparent volume of distribution (V/F) of each analyte following single and multiple dosing. - Immunogenicity: Anti-drug antibodies (ADA); neutralizing antibodies (Nab) against avelumab, rituximab, and utomilumab. -PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline. - Minimal residual disease burden (MRD) as assessed using serial blood samples. Phase 3 - Secondary Endpoints: - Overall Survival (OS). - PFS by Investigator assessment. - Objective Response (OR), Time to Tumor Response (TTR), Duration of Response (DR), and Disease Control (DC) by BICR and Investigator assessment. - Safety: AEs and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology Critera for Adverse Events (CTCAE) v.4.03; vital signs (blood pressure, heart rate); electrocardiogram (ECG). - Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine, and bendamustine (depending on the treatment being tested in Phase 3) will be determined as data permit: maximum pl | — |
Countries
Australia, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Trials.gov Call Centre
Pfizer Inc.
Outcome results
None listed