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

• Sponsor: Steven E. Coutre
• Information provided by (Responsible Party): Steven E. Coutre, Stanford University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma	Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Venetoclax	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	20 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open Label Phase 2 Trial of Venetoclax With Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
Actual Study Start Date :	September 26, 2017
Estimated Primary Completion Date :	December 2020
Estimated Study Completion Date :	September 2021

Arms and Interventions

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; Given PO; Other Names: BTK Inhibitor PCI-32765; CRA-032765; Imbruvica; PCI-32765; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Venetoclax; Given PO; Other Names: ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclexta

Outcome Measures

Primary Outcome Measures :

1. Complete Response Rate [ Time Frame: one year ]
   The proportion of subjects with a complete response (per investigator assessment) will be calculated for all subjects based on IWCLL criteria. A 95% confidence interval based on binomial distribution will be constructed for the calculated CR rate.

Secondary Outcome Measures :

1. Duration of response [ Time Frame: From the date of first response per investigator assessment to the earliest recurrence or progressive disease per investigator assessment, assessed up to 3 years ]
   Will be analyzed by Kaplan-Meier methodology using data for all enrolled subjects. Median duration of response will be calculated and the corresponding 95% confidence interval will be presented.
2. Minimal residual disease (MRD) negativity rate in bone marrow [ Time Frame: Up to 3 years ]
   MRD negativity will be defined as less than one CLL cell per 10,000 leukocytes (or below 10-4) on bone marrow based flow cytometry. Rate of MRD negativity will be defined as the proportion of subjects who achieve MRD negativity status. Ninety-five percent (95%) confidence intervals based on the binomial distribution will be provided.
3. Overall response rate (ORR) [ Time Frame: Up to 3 years ]
   The proportion of subjects with an overall response (per investigator assessment) will be calculated for all subjects based on IWCLL NCI collaborative WG criteria. A 95% confidence interval based on binomial distribution will be constructed for the calculated ORR.
4. Overall survival [ Time Frame: From the date of first dose to the date of death for all dosed subjects, assessed up to 3 years ]
   Will be analyzed by Kaplan-Meier methodology using data from all dosed subjects. Median time survival will be calculated and 95% confidence interval for the median time survival will be presented.
5. Progression-free survival (PFS) [ Time Frame: From the date of first dose to the date of earliest disease progression (per the investigator assessment) or death, assessed up to 3 years ]
   Will be analyzed by Kaplan-Meier methodology using data for all dosed subjects. Median PFS time will be calculated and 95% confidence interval for median PFS time will be presented.
6. Time-to-progression (TTP) [ Time Frame: From the date of first dose (date of enrollment if not dosed) to the date of earliest disease progression (per the investigator assessment), assessed up to 3 years ]
   Will be analyzed by Kaplan-Meier methodology using data for all enrolled subjects. Median time TTP will be calculated and 95% confidence interval for median time TTP will be presented.

Other Outcome Measures:

1. Time to next anti-CLL treatment (TTNT) [ Time Frame: From the date of the first dose of ibrutinib to the date of first dose of new non-protocol anti-leukemia therapy or death from any cause, assessed up to 3 years ]
   Will be analyzed by Kaplan-Meier methodology using data for all dosed subjects. Median TTNT time will be calculated.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)

Contacts and Locations

Contacts

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Contact: Pamela Clay	650-725-9167	pclay@stanford.edu

Locations

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United States, California
City of Hope	Recruiting
Duarte, California, United States, 91010
Contact: Osbaldo Rodrigues 626-218-9108 osrodriguez@coh.org
Stanford University, School of Medicine	Recruiting
Palo Alto, California, United States, 94304
Contact: Pamela Clay 650-725-9167 pclay@stanford.edu
Principal Investigator: Steven E. Coutre

Sponsors and Collaborators

Steven E. Coutre

Investigators

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Principal Investigator:	Steven Coutre	Stanford University

More Information

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Responsible Party:	Steven E. Coutre, Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier:	NCT03045328 History of Changes
Other Study ID Numbers:	HEM0048; NCI-2017-00124 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); IRB-36705 ( Other Identifier: Stanford IRB )
First Posted:	February 7, 2017
Last Update Posted:	February 1, 2019
Last Verified:	January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

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Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders	Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Venetoclax; Antineoplastic Agents