Details

Details

Title A Phase 2 Study to Evaluate the Efficacy and Tolerability of Debio 1562 in Combination with Rituximab in Patients with Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma and Other Forms of Non-Hodgkin’s Lymphoma

IRB DBPI1415

CC 16-672

Hospital Main Campus

Phase Phase 2

Disease Lymphoma - Diffuse Large B Cell, Lymphoma - Non - Hodgkin

Drug Debio 1562, Rituximab

Description

Description

Primary Objective
  • Characterize the safety and tolerability of Debio 1562 in combination with rituximab when administered IV every three weeks to adult patients with relapsed and/or refractory NHL
  • Determine the anti-tumor activity of IMGN529 in combination with rituximab when administered IV every three weeks to adult patients with relapsed and/or refractory NHL
Secondary Objectives
  • Characterize the PK of Debio 1562 and rituximab
  • Determine time to event outcomes [progression-free survival (PFS), time to response, duration of response (DOR), and overall survival (OS)]
  • Assess the immunogenicity of IMGN529 (anti-drug antibodies, ADA)
Exploratory Objectives
  • Correlate the extent of CD37 and CD20 antigen expression in tumor samples with anti-tumor activity of the Debio 1562 and rituximab combination.
  • Explore potential predictive and prognostic biomarkers including, but not limited to, cell of origin; MYC and BCL2 expression; gene expression profiling and genomic analysis of relevant genes
  • Determine the FcyRIIIA and/or FcyRIIA genotype.
Inclusion Criteria

Inclusion Criteria

  1. Patients must have histopathologically confirmed diagnosis of relapsed and/or refractory (R/R) DLBCL, FL, MZL/MALT, MCL, or other Sponsor approved NHL subtypes according to the World Health Organization (WHO) classification 2008 for which standard measures do not exist or are no longer effective.
  2. Must have received at least one but no more than six prior treatment regimens. Prior treatment with an anti-CD20 agent, either alone or in combination, is allowed.
  3. Patients must be ≥ 18 years.
  4. Patients must have ECOG Performance Status 0 - 2.
  5. Patients must meet the following laboratory criteria:
    • Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/mm3)
    • Platelet count ≥ 50 x 109/L (50,000/mm3; must not have been transfused within previous 10 days)
    • Patients receiving therapeutic anticoagulation are eligible provided their anticoagulation parameters are within range (e.g. INR 2-3 on Coumadin if applicable) and they have no history of ≥ Grade 2 bleeding while on anticoagulation therapy.
    • For patients receiving therapeutic doses of anticoagulation: Platelet count ≥ 100 x 109/L (100,000/mm3; must not have been transfused within previous 10 days)
    • Hemoglobin ≥ 8.0 g/dL (may have been transfused),
    • Serum creatinine ≤ 2.0 x upper limit of normal (ULN) or 24-hour creatinine clearance of ≥ 60 mL/minute,
    • AST ≤ 2.5 x ULN; ALT ≤ 2.5 x ULN and
    • Total bilirubin ≤ 1.5 x ULN; patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin ≤ 3.0 x ULN.

    Note: Patients with confirmed bone marrow infiltration may enroll with lower counts only with Sponsor approval

  6. Patients must have evaluable or measurable disease in accordance with the International Working Group Guidelines for Lymphoma (Cheson 2007).
  7. Patients who have FDG-avid disease must be able to be followed by PET-CT from baseline through the end of study.
  8. Patients who are HBsAg + (must be PCR negative) who are taking antivirals are allowed to enroll.
  9. Male patients and female patients of child bearing potential participating in this study must agree to use two highly effective methods of contraception throughout this study and for at least 12 weeks after the last dose of IMGN529 and 12 months after the last dose of rituximab. Examples of acceptable birth control methods include but are not limited to the following methods: (e.g., oral, parenteral, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; partner�s latex condom or vasectomy).
  10. Patients must be willing to provide informed consent and be willing to comply with the study protocol.
  11. Patients must be willing to provide a fresh or archived tumor biopsy. If archived tissue is provided, it must have been obtained within one year of the screening period and the patient must not have transformed during that time. If transformation occurred within one year from starting study treatment, the most recent tumor biopsy must be from after the latest transformation; otherwise a fresh biopsy must be collected.
Exclusion Criteria

Exclusion Criteria

  1. Patients with a diagnosis of CLL or small lymphocytic lymphoma (SLL).
  2. The following exclusions, with regard to prior therapy apply:
    • Not recovered from prior chemotherapy or radiation.
    • Anti-CD20 monoclonal antibody therapy within 14 days of starting study treatment.
    • Prior therapy with other anti-CD37-targeting antibody drug conjugate.
    • Radioimmunotherapy within two months prior to starting study treatment.
    • Small molecule anti-cancer therapeutic agent, and all investigational agents within 5 x t1/2 or 14 days whichever is shorter.
    • Allogeneic stem cell transplantation in the safety run-in period

      Note: In the phase 2 portion of the study patients who have had an allogeneic stem cell transplant maybe eligible if their GVHD is controlled, after investigator/sponsor discussion.

    • Chronic, systemic treatment with corticosteroids unless the dose has been stable for >7 days and is equivalent to ≤ 10 mg of prednisone per day.

      Note: Patients receiving replacement for adrenal insufficiency will be allowed on the study.

    • Patients who have not recovered from prior surgery. Patients must have recovered or stabilized from the side effects of any major or minor surgical procedures prior to study treatment.
  3. Dose Expansion Phase Only - Patients with primary refractory disease, which is defined as achieving less than a PR in their first therapy or relapsing from a response to their first line of therapy within six months. Patients with primary refractory disease will be allowed to enroll in the Safety Run-in phase of the study.
  4. Patients who have had a prior anaphylactic or other severe infusion reaction such that the patient is unable to tolerate antibody administration.
  5. Patients who have known central nervous system, meningeal, or epidural disease including brain metastases.
  6. Patients who have received or are to receive vaccination with live viruses within 30 days of Cycle 1 Day1.
  7. Impaired cardiac function or clinically significant cardiac disease such as:
    • New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, or cardiomyopathy;
    • Unstable angina pectoris ≤ 6 months prior to starting study treatment;
    • Acute myocardial infarction ≤ 6 months prior to starting study treatment; or
    • Other clinically significant heart disease e.g., ≥ grade 3 hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen.
  8. Patients with ≥ Grade 2 peripheral neuropathy.
  9. Patients with active hepatitis A, B or C infection.
  10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, psychiatric illness that would limit compliance with study requirements, active autoimmune disease requiring immunosuppressive therapy, severe immune deficiency.
  11. Known diagnosis of human immunodeficiency virus (HIV) infection.
  12. Patients with a concurrent primary malignancy that requires treatment or that would confound the disease response interpretation for the disease under study.
  13. WCBP who are pregnant or breast feeding.