The Combination of Venetoclax and Obinutuzumab in Patients with Chronic Lymphocytic Leukemia (CLL)
This phase II trial studies the effect of venetoclax and obinutuzumab in treating patients with chronic lymphocytic leukemia who have not received a previous treatment. Venetoclax blocks Bcl-2, a protein in cancer cells that helps those cells survive and resist the effects of cancer treatments. By blocking Bcl-2, venetoclax may kill cancer cells and/or make them more vulnerable to the effects of other treatments. Obinutuzumab targets a protein called CD20, which is found on the surface of B cells, the white blood cells that are affected by CLL. When obinutuzumab attaches to CD20, it both destroys the B cells and makes them more visible to the immune system. The immune system then attacks and destroys the cancerous B cells. Combining venetoclax and obinutuzumab has provided an alternative to chemotherapy for people with CLL. Researchers have found that combining venetoclax and obinutuzumab increases the drugs’ ability to fight cancer cells, and the drugs in combination may be more effective than the drugs on their own.
Inclusion Criteria
- Signed informed consent form
- Ability and willingness to comply with the requirements of the study protocol
- Age >= 18 years
- Have documented previously untreated chronic lymphocytic leukemia according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) / World Health Organization (WHO) criteria
- Require treatment of CLL per iwCLL guidelines
- Cumulative Illness Rating Scale (CIRS) score =< 6 (patient’s CLL diagnosis is not included in CIRS score)
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Hemoglobin >= 8 g/dL without transfusion support, unless anemia is due to marrow involvement of CLL
- Absolute neutrophil count >= 1.0 x 10^9/L
- Platelet count >= 30 x 10^9/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be >= 10 x 10^9/L if there is bone marrow involvement
- Modified Cockcroft-Gault equation (estimated creatinine clearance [eCCR]; with the use of ideal body mass [IBM] instead of mass) of > 50 mL/min
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
- Total bilirubin =< 1.5 x ULN (or =< 5 x ULN for patients with documented Gilbert syndrome)
- 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 obinutuzumab, whichever is longer * Women must refrain from donating eggs during this same period * A woman is considered to be of childbearing potential if she is postmenarchal, 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) * 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 * 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
- 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 90 days after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer. Men must refrain from donating sperm during this same period * With pregnant female partners, men must remain abstinent or use a condom for the duration of the pregnancy 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 CLL-directed therapy. Patients may have received a brief (=< 7 days) course of systemic steroids prior to initiation of study therapy for control of lymphoma-related symptoms
- Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (Richter’s transformation or prolymphocytic leukemia)
- Known hypersensitivity to any of the study drugs
- History of prior malignancy, except for conditions as listed below if patients have recovered from the acute side effects incurred as a result of previous therapy: * Malignancies treated with curative intent and with no known active disease within 2 years * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease (no time constraint) * Adequately treated cervical carcinoma in situ without evidence of disease (no time constraint) * Surgically/adequately treated low grade, early stage, localized prostate cancer without evidence of disease (no time constraint)
- 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 4 weeks prior to cycle 1 day 1
- Requires the use of warfarin (because of potential drug-drug interactions that may potentially increase the exposure of warfarin)
- Received the following agents within 7 days prior to the first dose of venetoclax: * Strong and moderate CYP3A inhibitors * Strong and moderate CYP3A inducers * Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax
- Clinically significant history of liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
- Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody * Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation * Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV deoxyribonucleic acid (DNA) is undetectable. These patients must be willing to undergo monthly DNA testing and should consider antiviral prophylaxis as per institutional standards
- Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1)
- 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
- Pregnant or lactating, or intending to become pregnant during the study * Women of childbearing potential must have a negative serum pregnancy test result within 21 days prior to initiation of study drug per institutional standards
- Recent major surgery (within 4 weeks prior to the start of cycle 1, day 1) other than for diagnosis
- Inability to swallow a large number of tablets
- Malabsorption syndrome or other condition that precludes enteral route of administration. This is subject to investigator discretion
- Known allergy to both xanthine oxidase inhibitors and rasburicase
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04447768.
PRIMARY OBJECTIVE:
I. To estimate the 36-month progression free survival (PFS) for fit patients treated with 9-24 cycles of venetoclax and obinutuzumab (duration dependent on minimal residual disease [MRD] status at cycle 7 day 1/cycle 9 day 1 or cycle 12 day 1) in the front-line setting.
SECONDARY OBJECTIVES:
I. To evaluate best overall response rate (ORR), best complete response (CR) rate, overall survival (OS), and event-free survival for fit patients treated with venetoclax and obinutuzumab in the front-line setting.
II. To evaluate rate of undetectable minimal residual disease (U-MRD) in peripheral blood by next generation sequencing (NGS) at sequential time points during therapy and following completion of therapy.
III. To evaluate toxicity profile for venetoclax-obinutuzumab therapy in the front-line setting.
IV. To evaluate incidence of tumor lysis syndrome (TLS) for patients undergoing venetoclax dose escalation in the outpatient setting, regardless of TLS risk per Food and Drug Administration (FDA) label.
V. To evaluate change in TLS risk from baseline to completion of obinutuzumab monotherapy in cycle 1, prior to venetoclax initiation.
VI. To evaluate treatment free remission defined as time from study treatment discontinuation to next-line therapy (line of therapy 2, LOT2).
VII. To evaluate time from MRD positivity to clinical progression and MRD positivity to initiation of LOT2.
VIII. To evaluate adverse events (AEs), ORR, PFS, and OS for LOT2 following venetoclax-obinutuzumab therapy.
EXPLORATORY OBJECTIVES:
I. To evaluate association between difference in ribonucleic acid (RNA) sequencing (RNA Seq) profile before and after treatment with venetoclax and obinutuzumab and PFS at 36 months.
II. To evaluate association between baseline fecal microbiota characteristics (alpha diversity, presence of dominant species) and response to therapy and PFS at 36 months.
III. To evaluate the impact of venetoclax + obinutuzumab on the T-cell repertoire and immune function of patients with CLL analyzing patient samples collected pre-treatment, during treatment and post-treatment.
OUTLINE:
Patients receive obinutuzumab intravenously (IV) over 3-4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax orally (PO) daily on days 22-28 of cycle 1 and on days 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 9 cycles (up to 12-24 cycles for patients who remain MRD positive) in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow biopsy and aspiration, and computed tomography (CT) scan or magnetic resonance imaging (MRI) scans throughout study.
After completion of study treatment, patients are followed up every 3 months for up to 5 years from last patient enrollment.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorMeghan Caitlin Thompson
- Primary ID20-044
- Secondary IDsNCI-2020-13240
- ClinicalTrials.gov IDNCT04447768