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Trial record 1 of 182 for:    Venetoclax
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Rituximab, Idelalisib, and Venetoclax in Relapsed/Refractory CLL (RIVe-CLL)

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ClinicalTrials.gov Identifier: NCT03639324
Recruitment Status : Not yet recruiting
First Posted : August 21, 2018
Last Update Posted : June 28, 2019
Sponsor:
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
This phase 1, multicenter, dose-escalation study is designed to find the Recommended Phase 2 Dose (RP2D) of venetoclax in combination with idelalisib and rituximab in patients with relapsed or refractory CLL and to assess the clinical activity of the combination.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia CLL Relapsed CLL Refractory Chronic Lymphocytic Leukemia Relapsed Chronic Lymphocytic Leukemia Drug: Rituximab, Idelalisib, and Venetoclax Phase 1

Detailed Description:
Participants will receive idelalisib by mouth twice daily and rituximab intravenously in a lead-in phase for 8-13 weeks. Those participants who meet criteria to begin venetoclax will receive venetoclax by mouth once daily using a stepwise dose escalation schedule, along with idelalisib twice daily by mouth. They will continue on idelalisib and venetoclax for up to 12 months or until 6 months after negativity of MRD is achieved in peripheral blood and confirmed in bone marrow in participants with a clinical complete response (CR) or clinical incomplete CR (CRi).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Patients will start on dose level 1 of venetoclax in combination with rituximab and idelalisib, then escalate or de-escalate (if lower dose is available) based upon the estimated probabilities of toxicity from an extension of the continual reassessment method for 2 agents.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Trial of Rituximab, Idelalisib, and Venetoclax in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RIVe-CLL)
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : March 30, 2022
Estimated Study Completion Date : September 30, 2025


Arm Intervention/treatment
Experimental: Rituximab, Idelalisib, & Venetoclax
Idelalisib 50, 100, or 150 mg PO BID; venetoclax 100 or 200 mg daily; rituximab per standard of care during the lead-in phase and then 500 mg/m2 IV every 4 weeks x 6 doses during the treatment phase
Drug: Rituximab, Idelalisib, and Venetoclax
Patients will start on dose level 1, then escalate or de-escalate (if lower dose is available) based upon the estimated probabilities of toxicity from an extension of the continual reassessment method for 2 agents.
Other Name: Rituxan, Venclexta




Primary Outcome Measures :
  1. Recommended Phase 2 Dose (RP2D) of idelalisib and venetoclax in combination with rituximab [ Time Frame: 7 Years ]
    Recommended phase 2 dose of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL following a lead-in period with idelalisib and rituximab.


Secondary Outcome Measures :
  1. Safety Evaluation: Determine adverse events (AEs) reported using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [ Time Frame: 7 Years ]
    Observed adverse events of treatment with idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL following a lead-in period with idelalisib and rituximab utlizing CTCAE Version 4.0

  2. Determination of cumulative complete response (CR) rate. [ Time Frame: 7 Years ]
    Determine the cumulative CR rate to the triple-drug combination at 7 and 13 months using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria.

  3. Summarize objective response rate. [ Time Frame: 7 Years ]
    Determine the cumulative overall disease response to the triple-drug combination at 7 and 13 months using the 2008 IWCLL criteria.

  4. Minimal residual disease (MRD) rate [ Time Frame: 7 Years ]
    To determine Minimal Residual Disease (MRD) negativity status in peripheral blood and/or bone marrow after achieving an objective response using 4-color flow cytometry in peripheral blood and/or bone marrow for responding patients.

  5. Survival Rate [ Time Frame: 7 Years ]
    Determine the proportion of patients who are alive at 24 months following initiation of venetoclax.

  6. Pharmacokinetics of the combination of idelalisib and venetoclax. [ Time Frame: 7 Years ]
    Determine the idelalisib and venetoclax plasma concentrations measured at designated time points throughout the study: pre-Tx; C1D1; C1D15; C1D22; C1D29; C3D1; C7D22; C13D222; at DLT (if feasible); at relapse (if feasible)]



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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:

Age ≥ 18 years of age. Relapsed or refractory B-cell CLL, according to IWCLL criteria, that requires treatment in the opinion of the investigator

Must have had at least one standard treatment with one of the following regimens:

fludarabine-containing regimens, alkylator-containing (eg, chlorambucil, bendamustine) regimens, ibrutinib-based regimens, or rituximab-containing regimens. Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

Adequate bone marrow function as follows:

  • Absolute neutrophil count (ANC) ≥ 1,000/mm3 without support of granulocyte colony stimulating factors for at least 7 days
  • Platelets ≥ 50,000/mm3 (entry platelet count must be independent of transfusion within 14 days prior to initiation of study treatment)
  • Hemoglobin ≥ 9.0 g/dL

Adequate coagulation, renal, and hepatic function as follows:

  • aPTT and PT ≤ 1.2 × upper limit of normal (ULN) for the laboratory
  • Calculated creatinine clearance ≥ 50 mL/min as calculated by the standard Cockcroft- Gault equation using age, actual weight, creatinine, and gender
  • AST and ALT ≤ 1.5 × ULN for the laboratory
  • Bilirubin ≤ 1.5 × ULN for the laboratory.

Persons with known HIV infection are eligible if they meet the following:

  • CD4+ T-cell count ≥ 250/mm3
  • Undetectable HIV viral load on standard PCR-based test
  • On a stable regimen of highly active anti-retroviral therapy (HAART) that does not include strong CYP3A4 inducers or inhibitors
  • No ongoing requirement for concurrent antibiotics or antifungal agents for the prevention of HIV-associated opportunistic infections For a woman of childbearing potential (WCBP), a negative serum pregnancy test performed within 7 days prior to initiation of study treatment. Note: WCBP is defined as any woman who has not had a hysterectomy or bilateral oophorectomy or is not postmenopausal (ie, she has had menses in the preceding 24 consecutive months). WCBP and male patients must agree to use a medically accepted form of birth control for the duration of study treatment and for at least 1 month following completion of study treatment. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Known histologic transformation from CLL to an aggressive lymphoma (ie, Richter's transformation). Known history of drug-induced pneumonitis. Undergone an allogeneic stem cell transplant, unless the transplant was ≥ 12 months prior to initiation of study treatment and the patient has not had graft-versus-host disease and does not require immunosuppression. Undergone an autologous stem cell transplant within 6 months prior to inititiation of study treatment. Central nervous system involvement. Clinically significant infection including active hepatitis B or hepatitis C requiring active treatment, or active CMV infection. Vaccination with a live vaccine within 28 days prior to initiation of study treatment.

Ongoing requirement for warfarin (due to potential drug-drug interactions that may increase the exposure of warfarin and ensuing complications).

Has received any of the following within 14 days prior to initiation of study treatment:

  • Anti-cancer therapy
  • Investigational therapy Has not recovered to < grade 2 toxicity(s) from prior therapy. Has not recovered to < grade 2 toxicity(s) from idelalisib and rituximab.

Ongoing or planned treatment with any of the following:

  • Steroid therapy for anti-neoplastic intent
  • Strong or moderate CYP3A inhibitor or inducer, and/or a narrow-therapeutic sensitive substrate
  • P-gp inhibitor or narrow-therapeutic sensitive P-gp substrate If any of these agents have been used, patients must be off them for ≥ 1 week before initiation of study treatment. Has consumed grapefruit, grapefruit products, Seville oranges or Star fruit within 3 days prior to initiation of study treatment. History of a prior exposure to a Bcl-2 family protein inhibitor (eg, venetoclax, navitoclax) or PI3K inhibitor (eg, idelalisib, duvelisib, TGR-1202, copanlisib, buparlisib). History of a prior significant toxicity from rituximab or other CD20 monoclonal antibodies.

A cardiovascular disability status of New York Heart Association Class ≥ II. Diagnosis or treatment for another malignancy within 1 year of study registration, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy.

Patient with active liver disease, inflammatory bowel disease, or Crohn's disease.

Malabsorption syndrome or other condition that precludes enteral route of administration.

Exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

  • Uncontrolled infection (viral, bacterial, or fungal)
  • Grade 3 or greater neutropenic fever within 1 week prior to initiation of study treatment
  • Active autoimmune cytopenias (for 2 or more weeks), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura. Pregnancy or breastfeeding. Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk, interfere with the patient's participation in the study or hinder evaluation of study results.

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): NCT03639324


Contacts
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Contact: Victor Y Yazbek, MD, MS 804-628-2073 victor.yazbeck@vcuhealth.org
Contact: Caryn R Weir, RN, M.P.H. 804-628-2310 cweir@vcu.edu

Locations
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United States, Virginia
Virginia Commonwealth University/ Massey Cancer Center Not yet recruiting
Richmond, Virginia, United States, 23298
Contact: Yazbeck Y Victor, MD, MS    804-628-2073    victor.yazbeck@vcuhealth.org   
Contact: Caryn R Weir, RN, M.P.H.    804-628-2310    cweir@vcu.edu   
Sponsors and Collaborators
Virginia Commonwealth University
Investigators
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Principal Investigator: Victor Y Yazbek, MD, MS Massey Cancer Center

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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT03639324     History of Changes
Other Study ID Numbers: MCC-15-12310
NCI-2018-01661 ( Other Identifier: NCI CTRP )
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: June 28, 2019
Last Verified: June 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

Keywords provided by Virginia Commonwealth University:
venetoclax
idelalisib

Additional relevant MeSH terms:
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Venetoclax
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
Rituximab
Idelalisib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action