Skip Navigation

Coronavirus (COVID-19) information for Dana-Farber patients & families Learn more

A Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Patients with Richter’s Syndrome

Enrolling

Trial ID:NCT03534323

View complete trial on ClinicalTrials.gov

Protocol #:18-089

877-DF-TRIAL (877-338-7425)

DiseasesLymphoid Leukemia

Phase:I/II

Principal Investigator:Davids, Matthew, S

Site Investigator(s):Arnason, Jon,
Soumerai, Jacob,

Research Nurse(s):Babcock, Elise,
Brennan, Lisa,
Bright, Susan,
Burke, Candace,
Davis, Jaynie,
Kilcommons, Marykate,
Knudsen, Elisabeth,
Marzullo, Tess, V.
McDermott, Kathleen,
Normilus, Samantha,
Nutter, Meredith, Elise
Patterson, Victoria,
Plummer, Sean, F.
Smith, Caitlin,
Tichon, Jennifer,

Trial Description:
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 best rate of complete response (CR) or complete response with incomplete count recovery (CRi) of duvelisib in combination with the MTD of venetoclax as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for CLL/SLL or Lugano 2014 criteria for Richter's syndrome (RS). (Phase II)

SECONDARY OBJECTIVES:
I. Evaluate pharmacokinetics of both duvelisib and venetoclax in CLL/SLL and RS. (Phase I)
II. Evaluate preliminary efficacy, including the best 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, and rate of best MRD-negative CR/CRi in the bone marrow. (Phase II)
IV. Determine the association of fluorescence in situ hybridization (FISH) abnormalities, TP53, NOTCH1, or SF3B1 mutations, and IGHV mutational status with ORR and CR rate. (Phase II)

EXPLORATORY OBJECTIVES:
I. Use both standard (performed prior to initiation of therapy and following one week of duvelisib monotherapy) and dynamic BH3 profiling 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 every 3 or 6 months up to 1 year, then indefinitely afterwards.

Eligibility Requirements:
Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma requiring therapy, per International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) 2008 requiring therapy based on the at least one of the following criteria, as listed below: * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 11.0 g/L) and/or thrombocytopenia (platelets < 100 x 10^9/L) * Massive (>= 6 cm below the left costal margin), OR progressive, OR symptomatic splenomegaly * Massive nodes (at least 10 cm longest diameter), OR progressive, OR symptomatic * Lymphadenopathy * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of < 6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy * Documented constitutional symptoms, defined as 1 or more of the following disease related symptoms or signs: ** Evidence of infection ** Night sweats for more than 1 month prior to screening without evidence of infection OR ** Biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter’s syndrome

Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy (CLL/SLL patients only): * If Richter’s syndrome, this criterion is not applicable

Age greater than or equal to 18 years

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 local upper limit of normal (ULN)

Bilirubin =< 1.5 x local ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)

Serum creatinine =< 1.5 times the local 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 for the duration of study participation, and for 3 months after the last dose of duvelisib. Male subjects must also refrain from donating sperm during their participation during the study and for 3 months after the last dose of duvelisib. Effective methods of contraception include: * True abstinence: When this is in line with the preferred and usual lifestyle of the subject. ** Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), and withdrawal are not effective methods of contraception * Sterilization ** Female subject or female partner of male subject: When a woman of childbearing potential has had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to starting treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment would they be eligible to begin treatment ** Male subject or male partner of female subject: (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate) * Placement of an intrauterine device (IUD) or intrauterine system (IUS) * Hormonal methods of contraception associated with inhibition of ovulation: oral, implantable, injectable, intravaginal, or transdermal contraception

Negative serum human chorionic gonadotropin (hCG) pregnancy test within 7 days before first dose of study intervention if the subject is a woman of childbearing potential

Ability to understand and the willingness to sign a written informed consent document

Previous treatment with venetoclax or duvelisib (prior venetoclax allowed for RS patients and for CLL/SLL patients if they have been off venetoclax therapy for at least one year prior to enrollment)

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

Administration of live or live attenuated vaccine within 6 weeks of initiation of therapy

Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV) at screening

Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine)

Active malignancy other than CLL/SLL or RS requiring therapy with the exception of hormonal therapy, non-melanoma skin cancer or carcinoma in situ of the cervix, bladder cancer, or prostate cancer not requiring treatment. Subjects with previous malignancies are eligible if they have been disease-free for 2 years or more

Any active systemic infection requiring intravenous (IV) antibiotics or uncontrolled, active infections

Active human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) * Subjects with a positive hepatitis B surface antigen [HBsAg] or hepatitis C antibody [HCV Ab] will be excluded * Subjects with a positive hepatitis B core antibody (HBcAb) must have negative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) to be eligible, must receive prophylaxis with entecavir (or equivalent) concomitant with duvelisib treatment, and must be periodically monitored for HBV reactivation by institutional guidelines * Investigators who believe that a positive HBcAb is false due to passive immunization from previous immunoglobulin infusion therapy should consider the risk-benefit for the patient given the potential for reactivation

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, acute coronary syndrome, stroke, or sustained ventricular arrhythmia within 6 months of first dose of study drug

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

History of chronic liver disease or veno-occlusive disease/sinusoidal obstruction syndrome

Active abuse of alcohol or illicit drug use

History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function

Known hypersensitivity to duvelisib and/or its excipients

History of tuberculosis treatment within the 2 years prior to initiation of therapy

Protocol #: 18-089

Questions & Enrollment
877-DF-TRIAL
(877-338-7425)