Clinical Trials /

Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

NCT02956382

Description:

This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma
  • Official Title: Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2016-0014
  • NCT ID: NCT02956382

Conditions

  • Refractory Follicular Lymphoma
  • Relapsed Follicular Lymphoma

Interventions

DrugSynonymsArms
IbrutinibPCI-32765Phase I - Dose Level 0
VenetoclaxABT-199Phase I - Dose Level 0

Purpose

This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.

Detailed Description

      In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy
      in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated
      synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines.
      The investigators theorize that the combination of ibrutinib and venetoclax will provide
      dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in
      both significant efficacy and less nonspecific toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I - Dose Level 0ExperimentalIbrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long.
  • Ibrutinib
  • Venetoclax
Phase I - Dose Level 1ExperimentalIbrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long.
  • Ibrutinib
  • Venetoclax
Phase I - Dose Level 2ExperimentalIbrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg Each medication is taken daily. Treatment cycles are 28 days long.
  • Ibrutinib
  • Venetoclax
Phase I - Dose Level 3ExperimentalIbrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg Each medication is taken daily. Treatment cycles are 28 days long.
  • Ibrutinib
  • Venetoclax
Phase II DoseExperimentalThe Phase II dose will be the maximum tolerated dose as determined in the Phase I portion.
  • Ibrutinib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          1. Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or
             IIIa which requires therapy defined by at least one of the following:

               -  Constitutional symptoms

               -  Cytopenias

          2. High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic splenomegaly,
             organ compression or compromise, ascites, pleural effusion)Must have received at least
             two prior systemic therapies

          3. All risk by FLIPI 0-5 factors (Appendix I)

          4. Measurable disease Measurable disease must be present either on physical examination
             or imaging studies; non-measurable disease alone is not acceptable. Any tumor mass >
             1.5 cm is acceptable.

             Lesions that are considered non-measurable include the following:

               -  Bone lesions (lesions if present should be noted)

               -  Ascites

               -  Pleural/pericardial effusion

               -  Lymphangitis cutis/pulmonis

               -  Bone marrow (involvement by lymphoma should be noted)

          5. Adequate hematologic function independent of transfusion and growth factor support for
             at least 3 weeks prior to screening unless attributable to disease. Defined as:

               -  Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L). ANC > 500
                  cells/mm3 is permissible if due to disease.

               -  Platelet count >50,000 cells/mm3 (50 x 109/L) unless attributable to disease.
                  Platelet count > 20,000 cells/mm3 is permissible if due to disease.

               -  Hemoglobin >8.0 g/dL.

          6. Adequate hepatic and renal function defined as:

               -  Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper
                  limit of normal (ULN) Serum aspartate transaminase (AST) or alanine transaminase
                  (ALT) ≤ 5 is permissible if due to disease.

               -  Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
                  non-hepatic origin) Bilirubin ≤3 x ULN is permissible if due to disease.

               -  Estimated Creatinine Clearance ≥50 ml/min (Cockcroft-Gault based on actual
                  weight)

          7. Prothrombin time (PT)/International normalized ratio (INR) <1.5 x ULN and PTT (aPTT)
             <1.5 x ULN.

          8. Men and women ≥ 18 years of age.

          9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II)

         10. Female subjects who are of non-reproductive potential (i.e., post-menopausal by
             history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral
             tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing
             potential must have a negative serum pregnancy test upon study entry.

         11. Male and female subjects who agree to use highly effective methods of birth control
             (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine
             devices (IUDs), sexual abstinence, or sterilized partner) during the period of therapy
             and for 30 days after the last dose of study drug

        Exclusion Criteria:

          1. Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or
             equal 21 days prior to first administration of study treatment

          2. Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (BCL-2)
             inhibitor.

          3. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to ibrutinib or venetoclax.

          4. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk
             for tumor lysis syndrome.

          5. History of other malignancies, except:

               -  Malignancy treated with curative intent and with no known active disease present
                  for ≥ 3 years before the first dose of study drug and felt to be at low risk for
                  recurrence by treating physician.

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               -  Adequately treated carcinoma in situ without evidence of disease.

          6. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc.,
             or chronic administration [>14 days] of > 20 mg/day of prednisone) within 28 days of
             the first dose of study drug.

          7. Undergone an allogeneic stem cell transplant within the past 1 year.

          8. Current or history of graft versus host disease

          9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

         10. Recent infection requiring systemic treatment that was completed ≤14 days before the
             first dose of study drug.

         11. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
             to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade ≤1, or
             to the levels dictated in the inclusion/exclusion criteria with the exception of
             alopecia.

         12. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.

         13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

         14. Known HIV infection

         15. Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).

             • Subjects who are positive for hepatitis B core antibody, hepatitis B surface
             antigen, hepatitis C antibody, must have a negative polymerase chain reaction (PCR)
             result for the respective disease before enrollment. Those who are PCR positive will
             be excluded.

         16. Any uncontrolled active systemic infection.

         17. Major surgery within 4 weeks of first dose of study drug.

         18. Any life-threatening illness, medical condition, or organ system dysfunction that, in
             the investigator's opinion, could compromise the subject's safety or put the study
             outcomes at undue risk.

         19. Currently active, clinically significant cardiovascular disease, such as uncontrolled
             arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
             Association Functional Classification; or a history of myocardial infarction, unstable
             angina, or acute coronary syndrome within 6 months prior to randomization.

         20. Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly
             affecting gastrointestinal function, or resection of the stomach or small bowel,
             symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete
             bowel obstruction.

         21. Concomitant use of warfarin or other Vitamin K antagonists.

         22. Requires treatment with a strong cytochrome P450 CYP3A4/5 inhibitor. (Appendix V)

         23. Richter's transformation confirmed by biopsy.

         24. Malabsorption syndrome or other condition precluding enteral route of administration.

         25. Known Central nervous system (CNS) involvement by lymphoma

         26. Erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome

         27. Lactating or pregnant.

         28. Unwilling or unable to participate in all required study evaluations and procedures.

         29. Unable to understand the purpose and risks of the study and to provide a signed and
             dated informed consent form (ICF) and authorization to use protected health
             information (in accordance with national and local subject privacy regulations).

         30. Currently active, clinically significant hepatic impairment (greater than or equal
             moderate hepatic impairment according to the Child Pugh classification (see Appendix
             IX)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 dose
Time Frame:18 months
Safety Issue:
Description:The maximum tolerated dose of Ibrutinib and Venetoclax

Secondary Outcome Measures

Measure:Pharmacokinetics of Ibrutinib
Time Frame:18 months
Safety Issue:
Description:Steady-state plasma concentrations of ibrutinib
Measure:Pharmacokinetics of Venetoclax
Time Frame:18 months
Safety Issue:
Description:Steady-state plasma concentrations of venetoclax
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:36 months
Safety Issue:
Description:Toxicity (attribute and grade) will be summarized for each dose level for all patients who receive at least one dose of study treatment

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Georgetown University

Trial Keywords

  • Ibrutinib
  • Venetoclax
  • Follicular
  • Refractory
  • Relapsed
  • Lymphoma

Last Updated

February 6, 2019