Bendamustine Hydrochloride, Rituximab, Ibrutinib, and Venetoclax in Treating Patients with Relapsed or Refractory Mantle Cell Lymphoma

Status: Active

Description

This phase I trial studies the side effects and best dose of venetoclax when giving together with bendamustine hydrochloride, rituximab, and ibrutinib in treating patients with mantle cell lymphoma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as bendamustine hydrochloride and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving bendamustine hydrochloride, rituximab, ibrutinib, and venetoclax may work better in treating patients with mantle cell lymphoma.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed mantle cell lymphoma (MCL)
  • Relapse, refractory or progressive disease following at least 1 line of systemic therapy for mantle cell lymphoma
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Patients must have completed anticancer treatment with chemotherapy, small molecule inhibitors, immune modulator drugs, biologics, and/or treatment with other anticancer agents at least 3 weeks prior treatment, or 2 weeks if progressing, and recovered from clinically significant toxicity associated with treatment
  • Palliative radiotherapy must have been discontinued at least 1 week prior to treatment in this study
  • Short-course corticosteroids for disease control, improvement of performance status or non-cancer indication are allowed (=< 10 days) and must be discontinued prior to study treatment start cycle 1, day 1 * Ongoing administration of a stable dose of corticosteroid therapy (equivalent to =< 30 mg prednisone daily and previously received for >= 30 days) is permissible provided there is evidence of measurable disease and there will be no increase in steroid dose during the clinical trial
  • Patients who have been previously treated with bendamustine plus rituximab (BR) or bendamustine alone are eligible, provided they did not progress during treatment or within 6 months of completing BR or bendamustine (B) treatment
  • Patients who have been previously treated with ibrutinib or acalabrutinib (or any alternate BTK-inhibitor) are eligible, provided they had evidence of response (at least stable disease [SD], PR, or CR) and did not progress within 6 months of treatment initiation
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 2 weeks prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • A positive serum pregnancy test due to fertility preservation will not be an exclusion after physician review
  • Absolute neutrophil count > 1,000 cells/mm^3 (1.0 x 10^9/L), if neutropenia is due to bone marrow involvement absolute neutrophil count must be >= 500 cells/mm^3 (0.5 x 10^9/L)
  • Platelet count > 75,000 cells/mm^3 (75 x 10^9/L), unless thrombocytopenia is due to bone marrow involvement platelet count must be greater than 25,000 cells/mm^3
  • Hemoglobin > 8.0 g/dL
  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x upper limit of normal (ULN)
  • Estimated creatinine clearance (Cockcroft-Gault) >= 40 mL/min; if creatinine clearance is < 40mL/min, but the serum creatinine is within institutional normal limits, the patient will be eligible
  • Bilirubin < 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax or 18 months after the last dose of rituximab, whichever is longer * Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices * A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus)
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: * With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of rituximab; men must refrain from donating sperm during this same period * With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of rituximab to avoid exposing the embryo * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria

  • Prior therapy with venetoclax or alternate BCL-2 inhibitor
  • Any life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject's safety or put the study outcomes at undue risk
  • Unable to swallow capsules or tablets, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction or other condition that precludes enteral route of administration
  • Cerebral/meningeal disease related to the underlying malignancy; patients with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior central nervous system disease has been definitively treated with no evidence of disease or requirement for steroids
  • Active human immunodeficiency virus (HIV) or hepatitis B or C with positive viral load, requiring anti-viral therapy
  • Bleeding diathesis or use of warfarin or other vitamin K antagonist
  • Prior history of infusion reactions or hypersensitivity to any of the study drugs
  • Active concurrent malignancy requiring active therapy
  • Pregnant or lactating females
  • Prior autologous stem cell transplant within 90 days of study start
  • Prior allogeneic stem cell transplant within 12 months of study start * Patients with active graft-versus-host-disease are not eligible * Patients receiving immunosuppressive therapy for prevention of graft-versus-host disease are not eligible
  • Patients who require treatment with a potent cytochrome P450 (CYP) 3A inhibitor or inducer
  • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 2 weeks prior to cycle 1, day 1
  • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
  • Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment

Locations & Contacts

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Anita Kumar
Phone: 212-639-2668
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Anita Kumar
Phone: 212-639-2668
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Anita Kumar
Phone: 212-639-2688

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Anita Kumar
Phone: 212-639-2668
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Anita Kumar
Phone: 212-639-2668
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Anita Kumar
Phone: 212-639-2668
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Anita Kumar
Phone: 212-639-2668

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of venetoclax (VEN) in combination with bendamustine hydrochloride (bendamustine), rituximab, and ibrutinib (BR-I) and determine the maximum tolerated dose (MTD) of VEN in combination with BR-I.

SECONDARY OBJECTIVES:

I. To preliminarily explore the therapeutic efficacy of BR-I-VEN, including overall response rate (ORR), complete response rate (CR), partial response rate (PR), the duration of response (DOR), progression free survival (PFS), and event free survival (EFS).

EXPLORATORY OBJECTIVES:

I. Collect baseline tumor biopsies (tissue block or 15-20 unstained slides) for banking for future correlative studies, such as genomic analyses.

II. Collect serum and peripheral blood mononuclear cells for banking for future correlative studies.

OUTLINE: This is a dose-escalation study of venetoclax.

Patients receive bendamustine hydrochloride intravenously (IV) over 10 minutes on days 1 and 2, rituximab IV on day 1, and ibrutinib orally (PO) once daily (QD) on days 1-28. Patients also receive venetoclax PO QD on day 1-28 of course 1 and on days 1-5, 1-7, or 1-10 day of subsequent courses. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unaccepted toxicity. Patient with complete response may continue receive ibrutinib PO QD until disease progression or intolerance at the discretion of the treating physician.

After completion of study treatment, patients are followed up every 3 and 6 months for 1 year and then periodically thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Anita Kumar

Trial IDs

Primary ID 17-216
Secondary IDs NCI-2017-01874
Clinicaltrials.gov ID NCT03295240