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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Ibrutinib; Drug: Venetoclax

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Stanford, California, United States, 94305
      • Stanford University, School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (ibrutinib, venetoclax); 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; Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1.; Other Names: PCI-32765; Imbruvica; BTK Inhibitor PCI-32765; CRA-032765; Drug: Venetoclax; 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).; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-next-treatment (TTNT)	The time-to-next-treatment (TTNT) is a measure of the period of time from the beginning of treatment until the patient has to receive a different treatment for his/her disease. TTNT was assessed as the time period until the participants next anti-chronic lymphocytic leukemia (CLL) treatment. The outcome will be reported as the median TTNT as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).	Through 117 weeks

Collaborators and Investigators

• Sponsor: Steven E. Coutre

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2017
• Primary Completion (Actual): May 19, 2020
• Study Completion (Actual): August 5, 2021

Study Registration Dates

• First Submitted: February 3, 2017
• First Submitted That Met QC Criteria: February 3, 2017
• First Posted (Estimate): February 7, 2017

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 1, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Lymphoma; Leukemia; Recurrence; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: IRB-36705; NCI-2017-00124 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); HEM0048 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No