Venetoclax and Ibrutinib in Treating Patients With High-Risk Chronic Lymphocytic Leukemia
Study Details
Study Description
Brief Summary
This phase II trial studies how well venetoclax and ibrutinib work in treating patients with high-risk chronic lymphocytic leukemia. Drugs used in chemotherapy, such as 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. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and ibrutinib may work better in treating patients with chronic lymphocytic leukemia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To estimate the therapeutic efficacy of venetoclax consolidation in patients who have detectable chronic lymphocytic leukemia (CLL) after receiving ibrutinib monotherapy for at least 12 months and who have high risk CLL.
SECONDARY OBJECTIVES:
-
Determine complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate after 6, 12, 18 and 24 cycles of combination therapy in patients who were not in CR/Cri at study initiation and estimate the time to best response with this combination.
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Determine the cumulative rate of bone marrow minimal residual disease (MRD)-free complete responders by an assay method with at least 0.01% sensitivity and median time to MRD-negativity.
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Determine the safety of combined ibrutinib and venetoclax. IV. Determine the progression-free and overall survival.
OUTLINE: This is a dose-escalation study of venetoclax.
Patients receive venetoclax orally (PO) once daily (QD) and ibrutinib PO QD. Treatment repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, patients are followed up every 6-12 months.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (venetoclax, ibrutinib) Patients receive venetoclax PO QD and ibrutinib PO QD. Treatment repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unaccepted toxicity. |
Drug: Ibrutinib
Given PO
Other Names:
Drug: Venetoclax
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- The primary endpoint will be the rate of MRD-negativity in the bone marrow, using an assay method with at least 0.01% sensitivity after 12 cycles of combination therapy. One cycle is 4 weeks of treatment. [through study completion, an average of 1 year]
One cycle is 4 weeks of treatment. (each cycle 28 days)
Secondary Outcome Measures
- Determine complete remission CR/complete remission with incomplete hematologic recovery CRi rate of combination therapy in patients who were not in CR/Cri at study initiation and estimate the time to best response with this combination. [through study completion, an average of 1 year]
after 6, 12, 18 and 24 cycles (each cycle 28 days)
- Determine the cumulative rate of bone marrow minimal residual disease (MRD)-free complete responders by an assay method with at least 0.01% sensitivity and median time to MRD-negativity. [through study completion, an average of 1 year]
- Determine the safety of combined ibrutinib and venetoclax. [through study completion, an average of 1 year]
Safety data will be summarized by category, severity and frequency. The proportion of patients with AEs will be estimated, along with the Bayesian 95% credible interval. The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever possible.
- Determine the progression-free survival [through study completion, an average of 1 year]
- Determine the overall survival. [through study completion, an average of 1 year]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
• Patients must have a diagnosis of CLL/CLL and have high-risk cytogenetic features or molecular features, defined as: del(17p), mutated TP53, * Note: some patients treated with ibrutinib may no longer have detectable fluorescence in situ hybridization (FISH), karyotypic or molecular abnormalities after 12 months of therapy. These patients will be eligible if they fulfill the above criteria on a bone marrow biopsy or peripheral blood specimen taken either prior to starting ibrutinib, provided they did not receive treatment for their CLL between the date of the lab test and starting ibrutinib or at some time during their ibrutinib therapy and analyzed at a Clinical Laboratory Improvement Act (CLIA)-accredited laboratory
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Patients must have received at least 12 months of ibrutinib therapy and have measurable CLL by at least one of the following:
-
Absolute monoclonal lymphocyte count > 4000/microL; OR
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Measurable lymph nodes with at least one node > 1.5 cm in diameter on computed tomography (CT); OR
-
Bone marrow with >= 30% lymphocytes on aspirate differential OR
-
Detectable CLL cells using a standardized flow cytometry assay for minimal residual disease
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Eastern Cooperative Oncology Group (ECOG) performance status =< 2
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Serum bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert's disease
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Serum creatinine clearance of >= 50 ml/min (calculated or measured)
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Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN, unless clearly due to disease involvement
-
Platelet count of greater than 50,000/ul, with no platelet transfusion in prior 2 weeks
-
Absolute neutrophil count (ANC) >= 1000/ul in the absence of growth factor support unless due to compromised bone marrow production from CLL, indicated by >= 80% CLL in marrow
-
Hemoglobin >= 8 mg/dL
-
International normalized ratio (INR) < 1.5
-
Absence of uncontrolled cardiac arrhythmia
-
Echocardiogram demonstrating left ventricular ejection fraction (LVEF) >= 35%
-
New York Heart Association (NYHA) functional class =< 2
-
Ability to provide informed consent and adhere to the required follow-up
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Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-human chorionic gonadotropin [hCG]) pregnancy test result within 7 days prior to the first dose of study drugs and must agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the period of therapy and for 30 days after the last dose of study drug. Women of non- childbearing potential are those who are postmenopausal (defined as absence of menses for >= 1 year) or who have had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing potential must agree to use effective contraception, defined above, during the study and for 30 days following the last dose of study drug
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Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject
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Patients or their legally authorized representative must provide written informed consent
Exclusion Criteria:
-
Richter transformation
-
Active malignancy requiring systemic therapy, other than CLL, with the exception of: adequately treated in situ carcinoma of the cervix uteri; adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
-
Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 3 weeks prior to the first dose of the study drug
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Grade 3 or 4 hemorrhage within the past 3 weeks
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Uncontrolled active infections (viral, bacterial, and fungal)
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Females who are pregnant or lactating
-
Known positive serology for human immunodeficiency virus (HIV)
-
Active hepatitis B infection (defined as the presence of detectable hepatitis B virus [HBV] deoxyribonucleic acid [DNA] or hemoglobin E [HBe] antigen). Patients who are hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive are eligible, provided HBV DNA is negative. These patients will have monthly monitoring of HBV DNA for the duration of the study, if clinically indicated. Please note that patients who have received intravenous immunoglobulin (IVIG) may have false positive HBcAb results. In such patients, if HBV DNA and HBsAg are negative, serial HBV DNA monitoring is not necessary
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Active hepatitis C, defined by the detection of hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR)
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Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy > 20 mg prednisone daily or equivalent, within 7 days of starting venetoclax
-
Received other investigational therapeutic agent for CLL/SLL within 21 days of starting venetoclax
-
Concurrent use of warfarin
-
Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting venetoclax
-
Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting venetoclax
-
Prior treatment with venetoclax or other Bcl-2 inhibitor
-
Malabsorption syndrome or other condition that precludes enteral route of administration
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- M.D. Anderson Cancer Center
Investigators
- Principal Investigator: Philip A Thompson, M.D. Anderson Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 2016-0785
- NCI-2018-01182
- 2016-0785