Clinical Trials /

Venetoclax-Obinutuzumab +/- Ibrut in R/R CLL

NCT04560322

Description:

This research study is studying a combination of drugs as a possible treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The names of the study drugs involved in this study are: - obinutuzumab - venetoclax - ibrutinib

Related Conditions:
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax-Obinutuzumab +/- Ibrut in R/R CLL
  • Official Title: A Phase 2 Study of MRD Adapted Therapy With Venetoclax-Obinutuzumab in Patients With High or Intermediate Risk Relapsed or Refractory CLL, With Addition of Ibrutinib in Patients Who Fail to Achieve MRD Eradication

Clinical Trial IDs

  • ORG STUDY ID: 19-743
  • NCT ID: NCT04560322

Conditions

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
VenetoclaxVenclextaVenetoclax-Obinutuzumab +/- Ibrutinib
ObinutuzumabGazyvaVenetoclax-Obinutuzumab +/- Ibrutinib
IbrutinibImbruvicaVenetoclax-Obinutuzumab +/- Ibrutinib

Purpose

This research study is studying a combination of drugs as a possible treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The names of the study drugs involved in this study are: - obinutuzumab - venetoclax - ibrutinib

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of investigational drugs to learn whether the drugs work in treating a
      specific disease. "Investigational" means that the drugs are being studied.

      The U.S. Food and Drug Administration (FDA) has approved [1] venetoclax- obinutuzumab and [2]
      ibrutinib individually as treatment options for chronic lymphocytic leukemia (CLL) or small
      lymphocytic lymphoma (SLL). However, the combination of all 3 drugs has not yet been approved
      by the FDA.

        -  Venetoclax is a targeted therapy drug that works by blocking a protein called Bcl-2 in
           cancer cells. Bcl-2 helps cancer cells survive and resist the effects of cancer
           treatments. By blocking Bcl-2, venetoclax may kill cancer cells and/or make them more
           open to the effects of other cancer treatments.

        -  Obinutuzumab is a drug that targets a protein called CD20, which is found on the surface
           of B cells, the white blood cells that are affected by CLL. When obinutuzumab attaches
           to CD20, it directly both destroys the B cells and makes them more "visible" to the
           immune system. The immune system then attacks and destroys the cancerous B cells.

        -  Ibrutinib works by blocking Bruton's tyrosine kinase (BTK) signaling. This helps stop
           cancerous B cells from surviving and multiplying, which may slow the spread of cancer.
           It is hoped that the combination of these study drugs might be an effective treatment
           for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

      On this study, participants will receive obinutuzumab and venetoclax. We will monitor for
      minimal residual disease (MRD) using a test called "Adaptive ClonoSEQ" after treatment with
      obinutuzumab and venetoclax. MRD is a molecular test, which can detect whether there is any
      evidence of CLL/SLL in the blood or bone marrow. For participants with detectable MRD despite
      treatment with obinutuzumab and venetoclax, ibrutinib will be added with the goal of
      achieving undetectable MRD. Additionally, for participants who have progressive CLL/SLL
      despite venetoclax and obinutuzumab, ibrutinib will be added.

      The research study procedures include screening for eligibility, study treatment, end of
      treatment visit, follow-up visits and an off-study visit.

        -  Participants will receive study treatment for 2 or 3 years.

        -  Participants will be followed for 2 years after completion of the study.

        -  It is expected that 40 people will take part in this research study

        -  Genentech is supporting this research study by providing venetoclax and obinutuzumab.
    

Trial Arms

NameTypeDescriptionInterventions
Venetoclax-Obinutuzumab +/- IbrutinibExperimentalA treatment cycle is defined as 28 consecutive days. Participants with undetectable MRD (uMRD) at 1 year will complete an additional 1 year of VO then stop therapy. Participants with high detectable MRD at 1 year will complete an additional 1 year of VO plus ibrutinib (I) then stop therapy. Participants with low detectable MRD at 1 year will complete an additional 1 year of VO alone. If this eradicates MRD, they will stop therapy. If there is still residual MRD, they will complete an additional 1 year of IVO then stop therapy. If progression occurs on VO, I will be added and IV will be administered indefinitely. After 2 years, V may be stopped and I continued as monotherapy at investigator discretion. Infused Study Drug: Obinutuzumab on Days 1, 2, 8, and 15 of Cycle 1 and then on Day 1 of Cycles 1-6 Oral Study Drugs: Venetoclax daily starting on Cycle 1 Day 22 Oral Drug: ibrutinib daily for Days 1-28 (if applicable)
  • Venetoclax
  • Obinutuzumab
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of CLL or SLL according to WHO criteria

          -  Participants must require therapy according to iwCLL 2018 guidelines

          -  Participants must have ≥ 2 points (high or intermediate risk disease) according to the
             CLL

        BALL Risk Model:

          -  Beta-2 microglobulin If ≥ 5 mg/L, assign 1 point

          -  Lactate dehydrogenase If >institutional upper limit of normal, assign 1 point

          -  Hemoglobin If <11 g/dL (female) or <12 g/dL (male), assign 1 point

          -  Time from start of last therapy If <24 months, assign 1 point, If 4 points, patient is
             high risk, If 2-3 points, patient is intermediate risk, If 0-1 points, patient is low
             risk

               -  Participants must have received prior systemic therapy for CLL

               -  Age over 18 years

               -  ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

               -  Participants must have adequate organ function as defined below:

          -  total bilirubin ≤2 × institutional upper limit of normal unless considered secondary
             to Gilbert's syndrome, in which case ≤3 x ULN

          -  AST(SGOT)/ALT(SGPT) ≤2 × institutional upper limit of normal

          -  creatinine within normal institutional limits OR

          -  creatinine clearance ≥30 mL/min according to the Cockcroft-Gault Equation for
             participants with creatinine levels above institutional normal.

               -  Participants must have adequate marrow function as defined below (unless clearly
                  due to disease under study per investigator discretion)

          -  absolute neutrophil count ≥1,000/mcL

          -  platelets ≥75,000/mcL OR

          -  > 20,000/mcL if thrombocytopenia is clearly due to disease under study (per
             investigator discretion).

               -  For females of childbearing potential, a negative serum pregnancy test within 7
                  days of study treatment

               -  For female patients of childbearing potential and male patients with partners of
                  childbearing potential, agreement (by patient and/or partner) to use highly
                  effective form(s) of contraception (i.e., one that results in a low failure rate
                  [<1% per year] when used consistently and correctly) and to continue its use for
                  90 days after the last dose of ibrutinib or venetoclax AND for 18 months after
                  the last dose of obinutuzumab (whichever date is later)

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
                  postovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               -  Willingness to not donate sperm or oocytes during the entire study treatment
                  period and after treatment discontinuation

               -  Ability to understand and the willingness to sign a written informed consent
                  document.

        Exclusion Criteria:

          -  Prior therapy with a BTK inhibitor (e.g. ibrutinib) or BCL2 inhibitor (e.g.
             venetoclax), with the following exception:

          -  Patients with undetectable MRD by flow cytometry at 10 (peripheral blood or bone
             marrow) or CR from prior treatment with BCL2 inhibitor (with or without BTK inhibitor)
             are eligible. Note: Patients who received prior BTK inhibitor therapy alone are not
             eligible.

          -  Known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of its
             excipients

          -  Participants who are receiving any other investigational agents unless authorized by
             the overall study principal investigator

          -  Known active histological transformation from CLL to an aggressive lymphoma (i.e.,
             Richter's transformation)

          -  Active malignancy or systemic therapy for another malignancy within 3 years;
             local/regional therapy with curative intent such as surgical resection or localized
             radiation within 3 years of treatment is permitted; active prostate cancer that is
             considered low-risk and appropriate for continued active surveillance strategy is
             permitted.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
             (excluding fungal infections of nail beds) at study enrollment, or any major episode
             of infection requiring treatment with IV antibiotics or hospitalization (relating to
             the completion of the course of antibiotics) within 2 weeks prior to Cycle 1, Day 1

          -  Known bleeding diathesis

          -  Pregnant women are excluded from this study because the study agents have potential
             for teratogenic or abortifacient effects. Because there is an unknown but potential
             risk for adverse events in nursing infants secondary to treatment of the mother with
             the study agents, breastfeeding should be discontinued if the mother is treated with
             study therapy.

          -  Prior major surgical procedure within 4 weeks of study, or anticipation of need for a
             major surgical procedure during the course of the study

          -  Known CNS hemorrhage or stroke within 6 months of the study

          -  History of progressive multifocal leukoencephalopathy (PML)

          -  History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
             infection

               -  Patients with occult or prior HBV infection (defined as positive total hepatitis
                  B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is
                  undetectable. These patients must be willing to take appropriate anti-viral
                  prophylaxis as indicated and undergo monthly DNA testing.

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV RNA

          -  Congestive heart failure, New York Heart Association classification III/IV

          -  Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis

          -  Receipt of live-virus vaccines within 28 days prior to the initiation of study
             treatment or need for live-virus vaccines at any time during study treatment

          -  Known condition or other clinical situation that would affect oral absorption

          -  Psychiatric illness/social situations that would interfere with study compliance

          -  Receipt of therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and
             CYP2C19, within 7 days prior to the first dose of study drug administration

          -  Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade
             containing Seville oranges), or star fruit within 3 days prior to the first dose of
             study drug administration.

          -  Requires dual antiplatelet therapy or anticoagulation with warfarin
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of participants alive at 1 year
Time Frame:1 year
Safety Issue:
Description:Percent of participants with high and intermediate risk relapsed/refractory CLL who are alive at 1 year. The percent of patients who are alive at one-year (rOS) will be measured by monitoring you in clinic. An rOS of at least 90% will be considered promising whereas the rOS of 75% or less will be considered non-promising.

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:1 year
Safety Issue:
Description:The response will be classified per the 2018 iwCLL guidelines. The overall frequency of overall response will be tabulated and summarized descriptively
Measure:Complete response rate
Time Frame:1 year
Safety Issue:
Description:The response will be classified per the 2018 iwCLL guidelines. The overall frequency of complete response will be tabulated and summarized descriptively
Measure:Frequency of undetectable minimum residual disease (uMRD) after 12 Months
Time Frame:1 year
Safety Issue:
Description:Frequency of undetectable MRD response will be tabulated and summarized descriptively. The frequency of detectable MRD including the frequency of MRD "low positive" and MRD "high positive" will also be tabulated and summarized descriptively
Measure:Undetectable MRD rate with addition of ibrutinib to venetoclax-obinutuzumab among patients who fail to eradicate MRD with venetoclax-obinutuzumab
Time Frame:12 months
Safety Issue:
Description:Among participants who fail to eradicate MRD with venetoclax-obinutuzumab (includes participants with detectable MRD at 12 months as well as those with progression prior to completion of 12 months of venetoclax-obinutuzumab), the frequency of uMRD following addition of ibrutinib to VO will be tabulated and summarized descriptively.
Measure:Progression-free Survival
Time Frame:6 years
Safety Issue:
Description:Progression-free survival (PFS) is defined as the interval between the first treatment day to the first sign of disease progression or death from any cause. Subjects without progression are censored at date of last disease evaluation
Measure:Overall Survival
Time Frame:6 years
Safety Issue:
Description:Overall survival (OS) is defined as the interval between the first treatment day to death from any cause. Subjects without death are censored at date of last visit.
Measure:Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE ver. 5.0.
Time Frame:6 years
Safety Issue:
Description:Participants have their toxicities graded and reported at every visit according to the CTCAE ver. 5.0 grading scale. The nature, frequency, severity, and timing of adverse events will be tabulated and summarized descriptively.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma

Last Updated

September 17, 2020