Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL

Study Overview
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Brief Summary
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This is an open-label non-randomized two-center phase 2 study evaluating the safety and efficacy of concurrent therapy with ibrutinib and venetoclax in subjects with relapsed or refractory CLL/SLL.

Detailed Description
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The primary objective of this study is to evaluate the efficacy of concurrent therapy with ibrutinib and venetoclax in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). The secondary objectives of this study are to define the safety, tolerability, and dose-limiting toxicity (DLT) within 28 days of completion of dose-escalation.

Official Title
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An Open Label Phase 2 Trial of Venetoclax With Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Conditions
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Recurrent Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must voluntarily sign and date an informed consent approved by the Institutional Review Board prior to initiation of any study specific procedures Subject must have a diagnosis of CLL that meets International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute (NCI)-Working Group (WG) criteria Subject must have relapsed/refractory disease with an indication for treatment according to the 2008 IWCLL/NCI WG criteria Measurable nodal disease by computed tomography (CT) Absolute neutrophil count > 750 cells/mm^3 (0.75 x 10^9/L) Platelet count > 30,000 cells/mm^3 (30 x 10^9/L) Hemoglobin > 8.0 g/dL Serum aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x upper limit of normal (ULN) Estimated creatinine clearance >= 30 mL/min (Cockcroft-Gault) Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) Prothrombin time/international normalized ratio (PT/INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 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 Male and female subjects must agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug Exclusion Criteria: Subject has previously received either venetoclax or ibrutinib Subject has received a live virus vaccine within 28 days prior to the initiation of study treatment Subject has undergone an allogeneic stem cell transplant in the past 1 year and must not have active chronic graft versus host disease (cGVHD) if over 1 year post allogeneic transplant Subject has developed Richter's transformation confirmed by biopsy Chemotherapy =< 21 days prior to first administration of study treatment and/or monoclonal antibody =< 6 weeks prior to first administration of study treatment History of other malignancies, except: 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 treating physician Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc, or chronic administration [> 14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version [v]4), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia Known bleeding disorders (eg, von Willebrand's disease) or hemophilia History of stroke or intracranial hemorrhage within 6 months prior to enrollment Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded Any uncontrolled active systemic infection Major surgery within 4 weeks 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 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 randomization 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 Concomitant use of warfarin or other vitamin K antagonists Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor Lactating or pregnant Unwilling or unable to participate in all required study evaluations and procedures 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ibrutinib, venetoclax)<br>Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1.<br>* Other names: PCI-32765;Drug: Venetoclax<br>* Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).<br>* Other names: Venclexta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) | Complete Response (CR) will be assessed as the number of participants who, based on investigator assessment based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, achieve a complete remission. IWCLL complete remission is defined as follows. Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. The outcome is reported as the number of participants who achieve CR, a number without dispersion. | 62 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) | Duration of response (DoR) refers to a participant maintaining clinical response after achieving either complete response (CR) or partial response (PR). The outcome is reported as the number of subjects who have maintained clinical response through 117 weeks. Response defined as the following. CR. Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. PR. Lymphadenopathy: decrease ≥ 50% Blood lymphocytes: decrease ≥ 50% Hepatomegaly: decrease ≥ 50% Splenomegaly: decrease ≥ 50% Bone marrow: not considered. | 117 weeks | 
| Minimal Residual Disease (MRD) | Minimal residual disease (MRD) refers to the small numbers of leukemic cells that can remain in the participant after treatment, and may not be associated with any symptoms (remission). Although the participant may feel healthy, the MRD is a major cause of eventual leukemic relapse. MRD-negative is the ideal treatment outcome. MRD negativity was defined as less than one leukemic cell per 10,000 leukocytes as assessed by bone marrow-based flow cytometry. The outcome is reported as the number of participants who were positive for MRD, or negative. | 117 weeks | 
| Overall Response (OR) | Overall response (OR) is the overall number of subjects that begin treatment and achieve a complete response (CR); partial response (PR); or Stable Disease (SD) 62 weeks after the beginning of treatment, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. IWCLL CR is defined as follows. The outcome is reported as the number of participants who achieve CR, PR, or SD, and number without dispersion. CR: Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. PR: Lymphadenopathy: decrease ≥ 50% Blood lymphocytes: decrease ≥ 50% Hepatomegaly: decrease ≥ 50% Splenomegaly: decrease ≥ 50% Bone marrow: not considered. SD: Lymphadenopathy: change of ± 49% Blood lymphocytes: change of ± 49% Hepatomegaly: change of ± 49% Splenomegaly: change of ± 49% Bone marrow: not considered. | 62 weeks | 
| Overall Survival (OS) | Overall survival (OS) represents the amount of time the participants remain alive after treatment. The outcome is reported as the number of participants remaining alive at 117 weeks (about 2 years and 3 months) after the start of treatment, a number without dispersion. | Through 117 weeks | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) is a term that means to remain alive with progressive disease (PD). PD is defined as Lymphadenopathy: Increase ≥ 50% Blood lymphocytes: Increase ≥ 50% Hepatomegaly: Increase ≥ 50% Splenomegaly: Increase ≥ 50% Bone marrow: not considered. The outcome is reported as the number of participants who remained alive without PD 117 weeks after the beginning of treatment. | 117 weeks | 
| Time-to-progression (TTP) | Time-to-progression (TTP) is a measure of the length of time from the beginning of treatment until progressive disease (PD). PD is defined as Lymphadenopathy: Increase ≥ 50% Blood lymphocytes: Increase ≥ 50% Hepatomegaly: Increase ≥ 50% Splenomegaly: Increase ≥ 50% Bone marrow: not considered. The outcome will be reported as the median TTP as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI). | Through 117 weeks |