Duvelisib and Venetoclax in Treating Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Status: Active

Description

This phase I / II trial studies the side effects and best dose of venetoclax when given together with duvelisib and to see how well they work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that has come back or does not respond to treatment. Duvelisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax targets a protein called BCL-2, which helps cancer cells survive. Combining duvelisib and venetoclax may be able to prevent tumor from growing.

Eligibility Criteria

Inclusion Criteria

  • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma requiring therapy, as per IW-CLL 2008 criteria
  • Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 500 cells/mm^3 (0.5 x 10^9/L). Growth factor is allowed in order to achieve this (patients must meet this criteria at screening, unless they have significant bone marrow involvement of CLL confirmed on biopsy)
  • Platelet count >= 25,000 cells/mm^3 (25 x 10^9/L) independent of transfusion within 7 days of screening (patients must meet this criteria at screening, unless they have significant bone marrow involvement of CLL confirmed on biopsy)
  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 x upper limit of normal (ULN)
  • Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
  • Serum creatinine =< 1.5 times the upper limit of normal or creatinine clearance >= 50 mL/min using a 24-hour urine collection
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal, barrier method or abstinence) prior to study entry and for the duration of study participation
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Previous treatment with venetoclax or duvelisib
  • Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, surgery within 2 weeks of cycle 1/day 1 with the following exceptions: * For patients on targeted therapies, a washout of least five half lives is required * Patients who experience clinical deterioration may start therapy after a shorter washout period with prior approval by the principal investigator (PI) * Corticosteroid therapy (prednisone or equivalent =< 20 mg daily) is allowed
  • Confirmed central nervous system involvement
  • Allogeneic hematologic stem cell transplant within 6 months of starting study treatment or active graft versus (vs.) host disease (GVHD) requiring treatment or prophylaxis
  • History of active malignancy requiring therapy with the exception of hormonal therapy
  • Any active systemic infection requiring intravenous (IV) antibiotics or uncontrolled, active infections
  • Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV)
  • Major surgery within 4 weeks of first dose of study drug
  • Currently active gastrointestinal disease, including colitis, inflammatory bowel disease and diarrhea requiring therapy
  • 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 of initial dosing on study
  • 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
  • Use of Coumadin for anticoagulation (other anticoagulants permitted)
  • Lactating or pregnant
  • Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A. The concomitant use of drugs or foods that are strong or moderate inhibitors or inducers of CYP3A are not allowed beginning 1 week prior to the first dose of duvelisib
  • Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications
  • Unable to swallow capsules 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 resulting in malabsorption or chronic diarrhea
  • Active abuse of alcohol

Locations & Contacts

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: Active
Contact: Jon E. Arnason
Email: Jarnason@bidmc.harvard.edu
Brigham and Women's Hospital
Status: Active
Contact: Matthew Steven Davids
Email: matthew_davids@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Matthew Steven Davids
Email: matthew_davids@dfci.harvard.edu
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Jacob D. Soumerai
Email: Jsoumerai@mgh.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD) as well as the recommended phase II dose and safety profile for this combination regimen of duvelisib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). (Phase I)

II. Determine the rate of complete response (CR) of duvelisib in combination with the MTD of venetoclax as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate pharmacokinetics of both duvelisib and venetoclax. (Phase I)

II. Evaluate preliminary efficacy, including objective response rate (ORR), duration of response (DOR) among patients who have achieved a partial response (PR) or CR, progression free survival (PFS), and overall survival (OS) in patients treated with combined duvelisib and venetoclax. (Phase II)

III. Determine the rate of minimal residual disease (MRD-negative CR) in the bone marrow at six months, one year and two years, or every three months if MRD negativity is achieved in the blood. (Phase II)

IV. Determine the association of fluorescence in situ hybridization (FISH) abnormalities, TP53, NOTCH1, or SF3B1 mutations, ZAP70 expression, and IGHV mutational status with ORR and CR rate. (Phase II)

EXPLORATORY OBJECTIVES:

I. Use both standard and dynamic BH3 profiling (performed prior to initiation of therapy and following one week of duvelisib monotherapy) to determine whether duvelisib therapy enhances mitochondrial priming and how this correlates with response.

II. Use BH3 profiling (performed prior to initiation of therapy, following one week of duvelisib monotherapy, and after three and six months of combination therapy) to determine whether BCL-2 dependency predicts response to therapy or risk of tumor lysis syndrome. Alternatively, will determine whether dependency of anti-apoptotic proteins other than BCL-2 (i.e., MCL-1 and BCL-XL) predicts resistance to therapy.

III. Use cytometry by time of flight (CyTOF) to identify how duvelisib monotherapy and duvelisib and venetoclax combination therapy impacts immune cell subtypes, in particular the ratio of regulatory to conventional T cells.

IV. Determine change in lymph node size following one week of duvelisib monotherapy.

V. Determine change in quality of life score using quality of life survey after one week of duvelisib monotherapy.

OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

Patients receive duvelisib orally (PO) twice daily (BID). Treatment repeats every 28 days (up to 49 days for cycle 1) for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO daily. Cycles repeat every 28 days (up to 42 days for cycle 1) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Matthew Steven Davids

Trial IDs

Primary ID 18-089
Secondary IDs NCI-2018-02317
Clinicaltrials.gov ID NCT03534323