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Ibrutinib + Venetoclax in Untreated WM

Primary Purpose

Waldenstrom Macroglobulinemia, MYD88 Gene Mutation

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
IBRUTINIB
Venetoclax
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Waldenstrom Macroglobulinemia focused on measuring Waldenstrom Macroglobulinemia, ibrutinib, venetoclax

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy & aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1.
  • Clinicopathological diagnosis of Waldenström macroglobulinemia [28].
  • Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.
  • Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia [29].
  • Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation.
  • Age ≥ 18 years
  • ECOG performance status ≤2 (see Appendix A)
  • Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum IgM level of >2 times the upper limit of normal of each institution is required
  • At the time of screening, participants must have acceptable organ and marrow function as defined below:

    • Absolute neutrophil count ≥500/uL (no growth factor permitted)
    • Platelets ≥50,000/uL (no platelet transfusions permitted)
    • Hemoglobin ≥ 7 g/dL (transfusions permitted)
    • Total bilirubin < 1.5 x institutional ULN
    • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
    • Estimated GFR ≥30 mL/min
  • Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
  • Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of ibrutinib or venetoclax during sexual contact with a FCBP
  • Ability to understand and the willingness to sign a written informed consent document.
  • Exclusion Criteria
  • Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
  • Participants who have one or more prior systemic therapies for WM.
  • Participants who are receiving any other investigational agents.
  • Participants with known CNS lymphoma.
  • Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note: Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate.
  • Concurrent administration of medications or foods that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug.
  • Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C (Appendix B).
  • Concurrent administration of warfarin.
  • Concurrent systemic immunosuppressant therapy within 21 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 the study drug.
  • Known bleeding disorders (e.g., congenital von Willebrand's disease or hemophilia)
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Major surgery within 4 weeks of first dose of study drug.
  • Malabsorption syndrome or other condition that precludes enteral route of administration.
  • Female participants who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days of last dose of study drug.
  • Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug
  • Participants with known history of alcohol or drug abuse.
  • Participants with inability to swallow pills.
  • On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
  • 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.
  • Participants with a history of non-compliance to medical regimens.
  • Participants who are unwilling or unable to comply with the protocol.

Sites / Locations

  • Massachusetts General Hospital
  • Dana Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Ibrutinib and Venetoclax (3 dose ramp up)

Ibrutinib and Venetoclax (2 dose ramp up)

Arm Description

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. First 12 participants Ibrutinib will be administered at a predetermined dose, once daily for 28 days TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Ibrutinib will be administered at a predetermined dose, once daily for 28 days TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up schedule during cycle 2.

Outcomes

Primary Outcome Measures

Rate of Very Good Partial Response (VGPR)
Proportion of patients with VGPR to therapy. (VGPR is >90% reduction in serum IgM from baseline)

Secondary Outcome Measures

Rate of Complete Response (CR) 6 Cycles
Proportion of patients with a complete response after 6 cycles of therapy
Rate of Complete Response (CR) 12 Cycles
Proportion of patients with a complete response after 12 cycles of therapy
Rate of Complete Response (CR) 24 Cycles
Proportion of patients with a complete response after 24 cycles of therapy
Overall Response 24 Cycles
Proportion of patients with minor response (MR) , partial response (PR), very good partial response (VGPR), or complete response (CR) to therapy.
Rate of VGPR at 30 months
Proportion of patients with a VGPR at 30 months from beginning therapy.
Median time to response
Time from treatment initiation until first response
Median time to major response
Time from treatment initiation until partial response or better (>50% reduction in serum IgM)
median time to VGPR
Time from treatment initiation until very good partial response (>90% reduction in serum IgM)
Progression Free Survival (PFS)
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Progression Free Survival (PFS)
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Progression Free Survival (PFS)
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Progression Free Survival (PFS)
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Overall survival
Time from initiation of therapy until death
Time to next treatment
Time from initiation of IVEN protocol therapy until initiation of new line of therapy.
Impact of IVEN in the participants' quality of life
Quality of life questionnaire European Organisation for Research and Treatment of Cancer. Scores range from 0-100 with high scores indicating a better outcome.
Number of participants with Treatment Related Adverse Events as Assessed (CTCAE) version 5.0
CTCAE version 5.0
Impact ofCXCR4 mutations on overall response
Comparison of response rates between participants with CXCR4 mutations and without CXCR4 mutations

Full Information

First Posted
February 14, 2020
Last Updated
July 24, 2023
Sponsor
Dana-Farber Cancer Institute
Collaborators
AbbVie, Pharmacyclics LLC.
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1. Study Identification

Unique Protocol Identification Number
NCT04273139
Brief Title
Ibrutinib + Venetoclax in Untreated WM
Official Title
Phase II Study on the Combination of Ibrutinib and Venetoclax in Treatment naïve Patients With Waldenström Macroglobulinemia
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 24, 2020 (Actual)
Primary Completion Date
June 1, 2023 (Actual)
Study Completion Date
June 1, 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
AbbVie, Pharmacyclics LLC.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study evaluates the safety and efficacy of Ibrutinib combined with Venetoclax (IVEN) in the treatment of adults diagnosed with Waldenstrom's macroglobulinemia (WM) cancer with a specific MYD88 gene mutation. This research study involves an experimental drug combination of targeted therapies. The names of the study drugs involved in this study are: Venetoclax ibrutinib
Detailed Description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied. The names of the study drugs involved in this study are: Venetoclax ibrutinib The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants will be on the research study for up to 2 years on combined venetoclax and ibrutinib and 4 years of follow-up . It is expected that about 50 people will take part in this research study. The U.S. Food and Drug Administration (FDA) has not approved venetoclax for your specific disease but it has been approved for other uses. -- Venetoclax is a targeted therapy that blocks BCL-2, a protein that is important for the survival of WM cells. Laboratory studies and early clinical data have shown that the investigational new agent, venetoclax, may kill cancer cells and may cause tumors to shrink. The U.S. Food and Drug Administration (FDA) has approved ibrutinib as a treatment option for this disease. --Ibrutinib is a targeted therapy that blocks BTK. It has been FDA approved in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft vs. host disease (cGVHD), and Waldenstrom's macroglobulinemia (WM). It is also used in research studies in participants with recurrent B-cell lymphoma), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated. The U.S. Food and Drug Administration (FDA) has not approved the combination of ibrutinib and venetoclax as a treatment for any disease. The U.S. Food and Drug Administration (FDA) has not approved the MYD88 test. This test is investigational.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Waldenstrom Macroglobulinemia, MYD88 Gene Mutation
Keywords
Waldenstrom Macroglobulinemia, ibrutinib, venetoclax

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
The first 12 participants will be assigned to Arm 1. All subsequent participants will be assigned to Arm 2.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ibrutinib and Venetoclax (3 dose ramp up)
Arm Type
Experimental
Arm Description
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. First 12 participants Ibrutinib will be administered at a predetermined dose, once daily for 28 days TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2.
Arm Title
Ibrutinib and Venetoclax (2 dose ramp up)
Arm Type
Experimental
Arm Description
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Ibrutinib will be administered at a predetermined dose, once daily for 28 days TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up schedule during cycle 2.
Intervention Type
Drug
Intervention Name(s)
IBRUTINIB
Other Intervention Name(s)
Imbruvica
Intervention Description
Ibrutinib Cycle 1-24 will be administered at a predetermined dose, once daily for 28 days
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclexta
Intervention Description
Venetoclax Cycle 2-24 will be administered daily for 28 days. Predetermined dosage ramp up schedule during cycle 2.
Primary Outcome Measure Information:
Title
Rate of Very Good Partial Response (VGPR)
Description
Proportion of patients with VGPR to therapy. (VGPR is >90% reduction in serum IgM from baseline)
Time Frame
24 Months
Secondary Outcome Measure Information:
Title
Rate of Complete Response (CR) 6 Cycles
Description
Proportion of patients with a complete response after 6 cycles of therapy
Time Frame
6 Cycles (28 day cycle)
Title
Rate of Complete Response (CR) 12 Cycles
Description
Proportion of patients with a complete response after 12 cycles of therapy
Time Frame
12 Cycles (28 day cycle)
Title
Rate of Complete Response (CR) 24 Cycles
Description
Proportion of patients with a complete response after 24 cycles of therapy
Time Frame
24 Cycles (28 day cycle)
Title
Overall Response 24 Cycles
Description
Proportion of patients with minor response (MR) , partial response (PR), very good partial response (VGPR), or complete response (CR) to therapy.
Time Frame
24 Cycles (28 day cycle)
Title
Rate of VGPR at 30 months
Description
Proportion of patients with a VGPR at 30 months from beginning therapy.
Time Frame
30 Months
Title
Median time to response
Description
Time from treatment initiation until first response
Time Frame
12 Months
Title
Median time to major response
Description
Time from treatment initiation until partial response or better (>50% reduction in serum IgM)
Time Frame
12 Months
Title
median time to VGPR
Description
Time from treatment initiation until very good partial response (>90% reduction in serum IgM)
Time Frame
12 Months
Title
Progression Free Survival (PFS)
Description
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Time Frame
24 Months
Title
Progression Free Survival (PFS)
Description
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Time Frame
36 Months
Title
Progression Free Survival (PFS)
Description
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Time Frame
48 Months
Title
Progression Free Survival (PFS)
Description
Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Time Frame
60 Months
Title
Overall survival
Description
Time from initiation of therapy until death
Time Frame
duration of time from start of treatment to time of death or last follow-up up to 72 months
Title
Time to next treatment
Description
Time from initiation of IVEN protocol therapy until initiation of new line of therapy.
Time Frame
24 Months
Title
Impact of IVEN in the participants' quality of life
Description
Quality of life questionnaire European Organisation for Research and Treatment of Cancer. Scores range from 0-100 with high scores indicating a better outcome.
Time Frame
24 Months
Title
Number of participants with Treatment Related Adverse Events as Assessed (CTCAE) version 5.0
Description
CTCAE version 5.0
Time Frame
6 Months
Title
Impact ofCXCR4 mutations on overall response
Description
Comparison of response rates between participants with CXCR4 mutations and without CXCR4 mutations
Time Frame
12 Months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy & aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1. Clinicopathological diagnosis of Waldenström macroglobulinemia [28]. Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory. Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia [29]. Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation. Age ≥ 18 years ECOG performance status ≤2 (see Appendix A) Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum IgM level of >2 times the upper limit of normal of each institution is required At the time of screening, participants must have acceptable organ and marrow function as defined below: Absolute neutrophil count ≥500/uL (no growth factor permitted) Platelets ≥50,000/uL (no platelet transfusions permitted) Hemoglobin ≥ 7 g/dL (transfusions permitted) Total bilirubin < 1.5 x institutional ULN AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN Estimated GFR ≥30 mL/min Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening. Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of ibrutinib or venetoclax during sexual contact with a FCBP Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study: Participants who have one or more prior systemic therapies for WM. Participants who are receiving any other investigational agents. Participants with known CNS lymphoma. Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note: Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate. Concurrent administration of medications or foods that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug. Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C (Appendix B). Concurrent administration of warfarin. Concurrent systemic immunosuppressant therapy within 21 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 the study drug. Known bleeding disorders (e.g., congenital von Willebrand's disease or hemophilia) History of stroke or intracranial hemorrhage within 6 months prior to enrollment. Major surgery within 4 weeks of first dose of study drug. Malabsorption syndrome or other condition that precludes enteral route of administration. Female participants who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days of last dose of study drug. Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug Participants with known history of alcohol or drug abuse. Participants with inability to swallow pills. On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin. 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. Participants with a history of non-compliance to medical regimens. Participants who are unwilling or unable to comply with the protocol.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jorge J Castillo, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02214
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
IPD Sharing Time Frame
Data can be shared no earlier than 1 year following the date of publication
IPD Sharing Access Criteria
Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Learn more about this trial

Ibrutinib + Venetoclax in Untreated WM

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