A Phase II Study of Venetoclax (ABT-199) added to Ibrutinib in Patients with High-Risk CLL
Philip A. Thompson
The goal of this clinical research study is to learn if giving the drug venetoclax with ibrutinib can help to control the disease in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The safety of this combination treatment will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Ibrutinib,Venetoclax
Treatment Location: Only at MDACC
Primary Objective 1. To estimate the therapeutic efficacy of venetoclax consolidation in patients who have detectable CLL/SLL after receiving ibrutinib monotherapy for at least 12 months and who have high risk CLL. High risk is defined as the presence of del(11q) del(17p) mutated TP53, BTK, or PLCG2 complex metaphase karyotype and/or patients who have not normalized their serum â2-microglobulin (B2M) after 12 months on ibrutinib. Patients who have developed mutations in BTK and/or PLCG2, will be eligible if they have no clinical or laboratory evidence of progressive disease. The primary endpoint will be CR/CRi rate after 12 cycles of combination therapy, for those patients who are not in CR/CRi. For patients in CR/CRi, the primary endpoint will be MRD level <0.01% in bone marrow after 12 cycles of combination therapy. One cycle is 4 weeks of treatment. Secondary Objectives 1. Determine CR/CRi rate after 6, 9, 18 and 24 cycles of combination therapy and to estimate the time to best response with this combination. 2. 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. 3. Determine the safety of combined ibrutinib and venetoclax. 4. Determine the progression-free and overall survival.
IRB Review and Approval Date: 06/16/2017
Recruitment Status: Open
Projected Accrual: N/A
1) Patients must have a diagnosis of CLL/CLL and EITHER Have high-risk
cytogenetic features or molecular features, defined as: del(17p),
del(11q), mutated TP53, complex metaphase karyotype (defined as >/=3
unrelated chromosomal abnormalities, present in at least 2 metaphases on
conventional, stimulated cytogenetic analysis) OR Have developed a BTK
or PLCG2 mutation, detected by sequencing and have not developed disease
progression during ibrutinib therapy as defined by IWCLL criteria
(Appendix 1) OR B2M has not normalized after at least 1 yr on ibrutinib
therapy *** Note: some patients treated with ibrutinib may no longer
have detectable 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 within the 3 months prior to starting ibrutinib or at some time
during their ibrutinib therapy and analyzed at a CLIA-accredited laboratory.
2) 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 - Measurable lymph nodes with at least one node >1.5 cm in diameter on CT; OR - Bone marrow with >/= 30% lymphocytes on aspirate differential; OR - Detectable CLL cells using a standardized flow cytometry assay for minimal residual disease
3) Age 18 years or older.
4) Eastern Cooperative Oncology Group (ECOG) Performance Status </=2.
5) Patients must have adequate renal and hepatic function: i) Serum bilirubin </=1.5 x upper limit of normal (ULN) or </=3 x ULN for patients with Gilbert’s disease ii) Serum creatinine clearance of >/= 50ml/min (calculated or measured) iv) ALT and AST </=3.0 x ULN, unless clearly due to disease involvement.
6) Adequate bone marrow function: i) Platelet count of greater than 20,000/µl, with no platelet transfusion in prior 2 weeks ii) ANC >/=500/µl in the absence of growth factor support unless due to compromised bone marrow production from CLL, indicated by >/=80% CLL in marrow. iii) Hemoglobin >/=8mg/dL.
7) INR <1.5
8) Adequate cardiac function, as assessed by: - Absence of uncontrolled cardiac arrhythmia. - Echocardiogram demonstrating LVEF >/=35%. - NYHA functional class </=2.
9) Ability to provide informed consent and adhere to the required follow-up.
10) Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 7 days prior to the first dose of study drugs and must agree to use use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (eg., 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.
11) Patients or their legally authorized representative must provide written informed consent.
1) Richter transformation.
2) 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.
3) Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 3 weeks prior to the first dose of the study drug.
4) Grade 3 or 4 hemorrhage within the past 3 weeks.
5) Uncontrolled active infections (viral, bacterial, and fungal).
6) Females who are pregnant or lactating.
7) Known positive serology for human immunodeficiency virus (HIV).
8) Active hepatitis B infection (defined as the presence of detectable HBV DNA or HBe antigen). Patients who are HBsAg negative/HBsAb positive but HBcAb positive are eligible, provided HBV DNA is negative. These patients must have monthly monitoring of HBV DNA for the duration of the study.
9) Active hepatitis C, defined by the detection of hepatitis C RNA in plasma by PCR.
10) Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy >20mg prednisone daily or equivalent, within 7 days of starting venetoclax.
11) Received other investigational therapeutic agent for CLL/SLL within 21 days of starting venetoclax.
12) Concurrent use of warfarin.
13) Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting venetoclax.
14) Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting venetoclax.
15) Prior treatment with venetoclax or other Bcl-2 inhibitor.
16) Malabsorption syndrome or other condition that precludes enteral route of administration.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
Philip A. Thompson
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