Phase II study of the combination of ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma
William G. Wierda
There are 2 cohorts (parts) to this study: Minimal residual disease (MRD) Cohort and Fixed Duration Cohort. This consent form is for the MRD Cohort only. Enrollment for this cohort has been completed. The goal of this clinical research study is to compare ibrutinib and venetoclax to ibrutinib and placebo in order to learn if the study drugs can help to control chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in patients who have not received previous treatment. Researchers also want to learn if certain blood tests can be used to learn how effective the study drug will be for you, how your cancer cells respond to the study drug, how long the study drugs stay in the body, and to find out the side effects of the study drugs. The safety of the study drugs will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Ibrutinib,Venetoclax
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Pharmacyclics, LLC
MRD COHORT Pre-randomization Phase Subjects will receive single-agent ibrutinib for 3 cycles (1 cycle = 28 days) followed by ibrutinib + venetoclax combination treatment for at least 12 cycles. Primary Objective: To determine the minimum residual disease (MRD)-negative response rate of the combination of ibrutinib + venetoclax. Secondary Objectives: To evaluate: Safety, tolerability, and determination of the recommended doses for the combination Overall response rate Complete response rate Progression free survival Hematological improvement as measured by hemoglobin and platelet counts Overall survival Pharmacokinetics of ibrutinib and venetoclax when dosed in combination Randomization Phase Subjects who achieve response and a confirmed MRD-negative response after 12 cycles of the ibrutinib + venetoclax combination will be randomized to continued-ibrutinib (venetoclax discontinued) vs placebo (ibrutinib and venetoclax discontinued). Subjects who do not achieve a confirmed MRD-negative response (MRD-positive) after 12 cycles of the ibrutinib + venetoclax combination will be randomized to continued ibrutinib + venetoclax vs ibrutinib alone )venetoclax discontinued). Primary Objective: To evaluate if discontinuing ibrutinib, in the setting of a confirmed MRD-negative response with the combination of ibrutinib + venetoclax, allows for a treatment holiday as assessed by 1-year diseasefree survival. One-year disease-free survival is defined as a continued MRD-negative response without progression or death at least 1 year after randomization. Secondary Objectives: MRD-negative response (in MRD-positive randomized subjects) Safety and tolerability Exploratory Objectives: Progression free survival Overall survival Outcome of ibrutinib reintroduction after MRD-positive relapse or disease progression (PD) Identification of potential predictive and/or prognostic, genetic and molecular biomarkers. FIXED DURATION COHORT Subjects will receive single-agent ibrutinib for 3 cycles (1 cycle = 28 days) followed by ibrutinib + venetoclax combination treatment for 12 cycles. Primary Objective: To evaluate the depth of response with the combination of ibrutinib + venetoclax administered for a fixed duration of therapy by assessment of complete response rate. Secondary Objectives: To evaluate: Duration of Response (DOR) MRD status in subjects with CR MRD-negative rate Overall response rate (ORR) Progression free survival (PFS) Hematological improvement as measured by hemoglobin and platelet counts Overall survival (OS) Safety and tolerability
IRB Review and Approval Date: 05/25/2017
Recruitment Status: Open
Projected Accrual: 289
1) Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008).
2) Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring treatment: (a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia; (b) Massive, progressive, or symptomatic splenomegaly; (c) Massive nodes or progressive or symptomatic lymphadenopathy; (d) Progressive lymphocytosis; (e) Constitutional symptoms
3) Measurable nodal disease by computed tomography (CT).
4) Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening, (with the exception of pegylated G-CSF ([pegfilgrastim]) and darbopoeitin which require at least 14 days) prior to screening laboratory assessment defined as: (a) Absolute neutrophil count (ANC) >750/µL (750 cells/mm3 or 0.75 x 109/L); (b) Platelet count >30,000/µL (30,000 cells/mm3 or 30 x 109/L); (c) Hemoglobin >8.0 g/dL
5) Adequate hepatic and renal function defined as: (a) Serum aspartate transaminase (AST) or alanine transaminase (ALT) </=3.0 x upper limit of normal (ULN); (b) Estimated Creatinine Clearance (CrCl) >/=60 mL/min (eg. as estimated by Cockcroft-Gault); (c) Bilirubin </=1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin).
6) Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder).
7) Men and women >/= 18 and </=70 years of age.
8) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
9) Female subjects who are of non-reproductive potential (ie, post- menopausal by history - no menses for =1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
10) Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence1, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation until 90 days after the last dose of study drug.
1) Any prior therapy (including but not limited to chemotherapy,
targeted therapy, immunomodulating therapy, radiotherapy, and/or
monoclonal antibody) used for treatment of CLL or SLL.
2) History of other malignancies, except: (a) Malignancy treated with curative intent and with no known active disease present for >/= 3 years before the first dose of study drug and felt to be at low risk for recurrence by the treating physician; (b) Adequately treated non-melanoma skin cancer or lentigo maligna without current evidence of disease; (c) Adequately treated carcinoma in situ without current evidence of disease.
3) Known or suspected history of Richter’s transformation.
4) Concurrent administration of >20 mg/day of prednisone within 7 days of initiation of study drug unless indicated for prophylaxis or management of allergic reactions (eg, contrast).
5) Known hypersensitivity to one or more study drugs.
6) Known allergy to xanthine oxidase inhibitors and/or rasburicase. Subjects who are allergic to xanthine oxidase inhibitors and cannot receive rasburicase will be excluded.
7) Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
8) Recent infection requiring systemic treatment that is ongoing or was completed </= 14 days before the first dose of study drug, or any uncontrolled active systemic infection.
9) Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
10) History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
11) Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
12) Major surgery within 4 weeks of first dose of study drug.
13) 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.
14) 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 prior to enrollment.
15) Unable to swallow capsules/tablets 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.
16) Concomitant use of warfarin or other vitamin K antagonists.
17) Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
18) Currently active, clinically significant hepatic impairment Child-Pugh Class B or C according to the Child Pugh classification.
19) Lactating or pregnant.
20) Unwilling or unable to participate in all required study evaluations and procedures.
21) Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
22) Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as those subjects with a declining hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study drug, or the need for daily prednisone >/=20 mg daily (or corticosteroid equivalent) to treat or control the autoimmune disease.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
William G. Wierda
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