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Venetoclax and Ibrutinib in Treating Participants With High-Risk Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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ClinicalTrials.gov Identifier: NCT03128879
Recruitment Status : Recruiting
First Posted : April 25, 2017
Last Update Posted : August 9, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase II trial studies how well venetoclax and ibrutinib work in treating participants with high-risk chronic lymphocytic leukemia/small lymphocytic lymphoma. Drugs used in chemotherapy, such as venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and ibrutinib may work better in treating participants with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Condition or disease Intervention/treatment Phase
BTK Gene Mutation Chronic Lymphocytic Leukemia PLCG2 Gene Mutation Small Lymphocytic Lymphoma Drug: Ibrutinib Drug: Venetoclax Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the therapeutic efficacy of venetoclax consolidation in patients who have detectable chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) after receiving ibrutinib monotherapy for at least 12 months and who have high risk CLL.

SECONDARY OBJECTIVES:

I. Determine complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate after 6, 12, 18 and 24 cycles of combination therapy and to estimate the time to best response with this combination.

II. 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.

III. Determine the safety of combined ibrutinib and venetoclax. IV. Determine the progression-free and overall survival.

OUTLINE:

Participants receive venetoclax orally (PO) once daily (QD) and ibrutinib PO QD. Courses repeat every 4 weeks for up to 24 courses in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, participants are followed up every 6-12 months.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Venetoclax (ABT-199) Added to Ibrutinib in Patients With High-Risk CLL
Actual Study Start Date : June 16, 2017
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
Experimental: Treatment (venetoclax, ibrutinib)
Participants receive venetoclax PO QD and ibrutinib PO QD. Courses repeat every 4 weeks for up to 24 courses in the absence of disease progression or unaccepted toxicity.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta




Primary Outcome Measures :
  1. Complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate [ Time Frame: At the end of 12 courses (48 weeks) ]
    The complete remission rate will be calculated, with the exact 95% confidence interval.

  2. Incidence of adverse events grade 3 or higher [ Time Frame: At the end of 5 weeks ]
    Frequency tables will be used to summarize categorical variables. Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The proportion of patients with adverse events will be estimated, along with the Bayesian 95% credible interval.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Up to 5 years ]
    The Kaplan-Meier method will be used. time to best response and a Cox regression model will used to assess the association between clinical factors and overall survival.

  2. Progression free survival [ Time Frame: Up to 5 years ]
    The Kaplan-Meier method will be used. time to best response and a Cox regression model will used to assess the association between clinical factors and progression free survival.

  3. Minimal Residual Disease (MRD) Analysis [ Time Frame: Performed pre-treatment and after 6 months,12 months, 18 months, and 24 months ]
    Bone marrow examination (aspiration and biopsy) with minimal residual disease (MRD) analysis by 4-color flow cytometry will be performed to evaluate whether or not and how soon patient will achieve MRD-negative status in bone marrow.



Information from the National Library of Medicine

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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:

  • Patients must have a diagnosis of CLL/SLL 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 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria OR B2M has not normalized after 1 year (y) ibrutinib therapy and/or is elevated at the time of screening

    • Note: some patients treated with ibrutinib may no longer have detectable fluorescence in situ hybridization (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 Clinical Laboratory Improvement Act (CLIA)-accredited laboratory
  • 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 computed tomography (CT); OR Bone marrow with >= 30% lymphocytes 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
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Serum bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert's disease
  • Serum creatinine clearance of >= 50 ml/min (calculated or measured)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN, unless clearly due to disease involvement
  • Platelet count of greater than 20,000/ul, with no platelet transfusion in prior 2 weeks
  • Absolute neutrophil count (ANC) >= 500/ul in the absence of growth factor support unless due to compromised bone marrow production from CLL, indicated by >= 80% CLL in marrow
  • Hemoglobin >= 8mg/dL
  • International normalized ratio (INR) < 1.5
  • Absence of uncontrolled cardiac arrhythmia
  • Echocardiogram demonstrating left ventricular ejection fraction (LVEF) >= 35%
  • New York Heart Association (NYHA) functional class =< 2
  • Ability to provide informed consent and adhere to the required follow-up
  • Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-human chorionic gonadotropin [hCG]) pregnancy test result within 7 days prior to the first dose of study drugs and must agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., 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
  • Patients or their legally authorized representative must provide written informed consent

Exclusion Criteria:

  • Richter transformation
  • 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
  • Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 3 weeks prior to the first dose of the study drug
  • Grade 3 or 4 hemorrhage within the past 3 weeks
  • Uncontrolled active infections (viral, bacterial, and fungal)
  • Females who are pregnant or lactating
  • Known positive serology for human immunodeficiency virus (HIV)
  • Active hepatitis B infection (defined as the presence of detectable hepatitis B virus [HBV] deoxyribonucleic acid [DNA] or hemoglobin E [HBe] antigen). Patients who are hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive are eligible, provided HBV DNA is negative. These patients must have monthly monitoring of HBV DNA for the duration of the study.
  • Active hepatitis C, defined by the detection of hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR)
  • Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy > 20 mg prednisone daily or equivalent, within 7 days of starting venetoclax
  • Received other investigational therapeutic agent for CLL/SLL within 21 days of starting venetoclax
  • Concurrent use of warfarin
  • Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting venetoclax
  • Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting venetoclax
  • Prior treatment with venetoclax or other Bcl-2 inhibitor
  • Malabsorption syndrome or other condition that precludes enteral route of administration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03128879


Contacts
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Contact: Philip A. Thompson 713-792-7430 pathompson2@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Philip A. Thompson    713-792-7430      
Principal Investigator: Philip A. Thompson         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Philip A Thompson M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03128879     History of Changes
Other Study ID Numbers: 2016-0785
NCI-2018-01182 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2016-0785 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: April 25, 2017    Key Record Dates
Last Update Posted: August 9, 2019
Last Verified: August 2019

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