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Phase II Trial of Venetoclax and Rituximab as Initial Therapy in Older Patients With Mantle Cell Lymphoma

Primary Purpose

Mantle Cell Lymphoma

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Venetoclax Oral Tablet [Venclexta]
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mantle Cell Lymphoma

Eligibility Criteria

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

Inclusion Criteria:

  • Subjects must have a histologically confirmed diagnosis of mantle cell lymphoma as defined by the World Health Organization (WHO) classification scheme.
  • Age ≥ 60
  • Subjects must be previously untreated for mantle cell lymphoma and deemed to require treatment by the treating physician
  • ECOG performance status of 0-3
  • Subject must have adequate bone marrow* without growth factor support as follows:

    • Absolute Neutrophil Count (ANC) ≥ 1000/μL
    • Platelets ≥ 75,000/mm3 (entry platelet count must be independent of transfusion within 14 days of Screening)
    • Hemoglobin ≥ 9.0 g/dL * These criteria may be waived by study investigators if there is evidence of bone marrow involvement by MCL that is believed to be the cause of the cytopenias.
  • Subject must have adequate renal, and hepatic function, per laboratory reference range at screening as follows:

    • Subject must have adequate renal, and hepatic function, per laboratory reference range at screening as follows:
    • Calculated creatinine clearance ≥ 40 mL/min; determined via the Cockcroft-Gault formula.
    • AST and ALT ≤ 3.0 × ULN; Bilirubin ≤ 1.5 × ULN*. Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN

      • These criteria may be waived by study investigators if abnormal values believed to be due to lymphoma.
  • Female subjects must be surgically sterile, postmenopausal (for at least 1 year), or have negative results for a pregnancy test performed as follows:

    • At Screening on a serum sample obtained within 14 days prior to the first study drug administration, and
    • Prior to dosing on a urine sample obtained on Cycle 1 Day 1 if it has been > 7 days since obtaining the serum pregnancy test results.
    • All female subjects not surgically sterile or postmenopausal (for at least 1 year) and non-vasectomized male subjects must practice at least 1 of the following methods of birth control:

      1. Total abstinence from sexual intercourse (minimum 1 complete menstrual cycle);
      2. A vasectomized partner(s);
      3. Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at least 3 months prior to study drug administration;
      4. Double-barrier method (condoms and diaphragm with spermicidal [sponge, jellies or creams]).
  • Ability to understand and willingness to sign IRB-approved informed consent

Exclusion Criteria:

  • Subject has blastoid-variant mantle cell lymphoma
  • Subject requires immediate cytoreduction as determined by study investigators
  • Subject has documented CNS involvement of mantle cell lymphoma
  • Subject has Ann Arbor stage I or contiguous stage II mantle cell lymphoma
  • Subject has an uncontrolled infection
  • Subject has HIV infection
  • All subjects will be screened for Hepatitis B (HBsAg, anti-HBs, anti-HBc IgM and total) and Hepatitis C (antibody or RNA). Subjects who are positive for Hepatitis B by HBsAg or DNA as well as subjects positive for Hepatitis C will be excluded. Subjects with anti-HBc positivity and DNA negative may be included but will be required to undergo monthly HBV DNA testing and liver function liver function testing (AST, ALT, alkaline phosphatase, total bilirubin). Patients with HCV antibody positivity and HCV pcr negativity are eligible to be included.
  • Subject requires the use of warfarin
  • Subject has received immunization with live virus vaccine within 28 days prior to the first dose of study drug
  • A female subject is pregnant or breast-feeding

Sites / Locations

  • Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

venetoclax and rituximab in patients over 60 yrs old with previously untreated mantle cell lymphoma

Arm Description

Venetoclax dose escalation for Cycles 1-4. If Complete response (CR) at Cycle 4, continue with cycles 5-12 at fixed venetoclax 400mg dose. If partial response (PR) at Cycle 4, continue with cycles 5-8 at fixed venetoclax 800mg dose. If CR at Cycle 8 after PR, continue with cycles 9-12 at fixed venetoclax 800mg dose. If continued PR at Cycle 8, reduce venetoclax to 400mg and add bendamustine 90 mg/m2.

Outcomes

Primary Outcome Measures

Overall response rate (ORR) after four cycles of venetoclax and rituximab.
The ORR will be the sum of complete (CR) and partial responses (PR)as determined by PET/CT and Lugano criteria. Simon's optimal two-stage design will be used to test the null hypothesis that the true ORR is 50% or less (not considered clinically acceptable).

Secondary Outcome Measures

Proportion of CR
Proportion of CR as determined by PET/CT and Lugano criteria after four cycles
Proportion of PR
Proportion of PR as determined by PET/CT and Lugano criteria after four cycles
Proportion of stable disease
Proportion of stable disease as determined by PET/CT and Lugano criteria after four cycles
Proportion of disease progression
Proportion of disease progression as determined by PET/CT and Lugano criteria after four cycles
Rate of CR after 8 cycles of venetoclax and rituximab
Rate of CR as determined by PET/CT and Lugano criteria after 8 cycles of venetoclax and rituximab
Rate of PR after 8 cycles of venetoclax and rituximab
Rate of PR as determined by PET/CT and Lugano criteria after 8 cycles of venetoclax and rituximab
Proportion of progression free survival (PFS)
To evaluate the progression free survival (PFS) in the intent to treat (ITT) population
free survival (PFS)
To evaluate the progression free survival (PFS) in the intent to treat (ITT) population
overall survival (OS)
To evaluate the overall survival (OS) in the intent to treat (ITT) population
duration of response (DOR)
To evaluate the duration of response (DOR) for participants achieving a CR or PR

Full Information

First Posted
August 26, 2021
Last Updated
June 30, 2023
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
AbbVie
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1. Study Identification

Unique Protocol Identification Number
NCT05025423
Brief Title
Phase II Trial of Venetoclax and Rituximab as Initial Therapy in Older Patients With Mantle Cell Lymphoma
Official Title
Phase II Trial of Venetoclax and Rituximab as Initial Therapy in Older Patients With Mantle Cell Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 21, 2022 (Actual)
Primary Completion Date
September 15, 2025 (Anticipated)
Study Completion Date
September 15, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
AbbVie

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
The proposed study is an open-label, single arm phase II study of venetoclax in combination with rituximab in patients over the age of 60 with previously untreated mantle cell lymphoma. The primary objective of the trial is to determine whether the combination of venetoclax with rituximab in this patient population yields a clinically acceptable proportion of overall responses (ORR, assessed by PET/CT with Lugano criteria) without chemotherapy.
Detailed Description
For young, fit patients with mantle cell lymphoma, intensive chemotherapy and rituximab followed by ASCT is often used to achieve prolonged disease free survival. However, this therapy is not curative and has not been shown to improve overall survival. For older or frail patients, who are ineligible for stem cell transplantation, improved disease free survival can be achieved with chemotherapy and rituximab without ASCT, but at the cost of significant short and long-term toxicity. Venetoclax monotherapy has shown impressive single-agent activity in relapsed and refractory mantle cell lymphoma with low rates of adverse events. The hypothesis is that initial therapy with venetoclax and rituximab will result in rates of CR and PR that are comparable to historical rates with chemoimmunotherapy. Furthermore, this regimen will have fewer side effects than traditional therapy. Investigators also hypothesize that patients achieving a CR will have long durations of response that will continue after stopping venetoclax. Study investigators will test this hypothesis with an open label, single arm phase II trial with a target accrual of 40 participants. This study will include patients over age 60 who are not candidates for aggressive upfront therapy . Subjects will receive venetoclax and rituximab for up to 12 cycles of 4 weeks each. All patients will stop venetoclax after 12 cycles. Participants who have stable disease or disease progression after 4 cycles will be removed from the trial in order to receive standard of care chemoimmunotherapy. Participants who do not achieve a CR after 8 cycles of venetoclax and rituximab will receive 4 cycles of standard of care bendamustine in addition to continuing rituximab and venetoclax. This is the first phase II study of venetoclax and rituximab alone as initial therapy for mantle cell lymphoma. In the relapsed and refractory setting, venetoclax has shown high activity in MCL, and as such is a promising option for a non-chemotherapy approach to upfront treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mantle Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
Venetoclax dose escalation for Cycles 1-4. If Complete response (CR) at Cycle 4, continue with cycles 5-12 at fixed venetoclax 400mg dose. If partial response (PR) at Cycle 4, continue with cycles 5-8 at fixed venetoclax 800mg dose. If CR at Cycle 8 after PR, continue with cycles 9-12 at fixed venetoclax 800mg dose. If continued PR at Cycle 8, reduce venetoclax to 400mg and add bendamustine 90 mg/m2.
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
venetoclax and rituximab in patients over 60 yrs old with previously untreated mantle cell lymphoma
Arm Type
Experimental
Arm Description
Venetoclax dose escalation for Cycles 1-4. If Complete response (CR) at Cycle 4, continue with cycles 5-12 at fixed venetoclax 400mg dose. If partial response (PR) at Cycle 4, continue with cycles 5-8 at fixed venetoclax 800mg dose. If CR at Cycle 8 after PR, continue with cycles 9-12 at fixed venetoclax 800mg dose. If continued PR at Cycle 8, reduce venetoclax to 400mg and add bendamustine 90 mg/m2.
Intervention Type
Drug
Intervention Name(s)
Venetoclax Oral Tablet [Venclexta]
Other Intervention Name(s)
rituximab infusion [Rituxan], Bendamustine infusion
Intervention Description
Sequential dose levels for Venetoclax dependent on patient response. Fixed doses of 375 mg/m2 rituximab. Fixed dose of Bendamustine 90 mg/m2 added for those with continued PR at Cycle 8
Primary Outcome Measure Information:
Title
Overall response rate (ORR) after four cycles of venetoclax and rituximab.
Description
The ORR will be the sum of complete (CR) and partial responses (PR)as determined by PET/CT and Lugano criteria. Simon's optimal two-stage design will be used to test the null hypothesis that the true ORR is 50% or less (not considered clinically acceptable).
Time Frame
120 days
Secondary Outcome Measure Information:
Title
Proportion of CR
Description
Proportion of CR as determined by PET/CT and Lugano criteria after four cycles
Time Frame
120 days
Title
Proportion of PR
Description
Proportion of PR as determined by PET/CT and Lugano criteria after four cycles
Time Frame
120 days
Title
Proportion of stable disease
Description
Proportion of stable disease as determined by PET/CT and Lugano criteria after four cycles
Time Frame
120 days
Title
Proportion of disease progression
Description
Proportion of disease progression as determined by PET/CT and Lugano criteria after four cycles
Time Frame
120 days
Title
Rate of CR after 8 cycles of venetoclax and rituximab
Description
Rate of CR as determined by PET/CT and Lugano criteria after 8 cycles of venetoclax and rituximab
Time Frame
240 days
Title
Rate of PR after 8 cycles of venetoclax and rituximab
Description
Rate of PR as determined by PET/CT and Lugano criteria after 8 cycles of venetoclax and rituximab
Time Frame
240 days
Title
Proportion of progression free survival (PFS)
Description
To evaluate the progression free survival (PFS) in the intent to treat (ITT) population
Time Frame
240 days
Title
free survival (PFS)
Description
To evaluate the progression free survival (PFS) in the intent to treat (ITT) population
Time Frame
240 days
Title
overall survival (OS)
Description
To evaluate the overall survival (OS) in the intent to treat (ITT) population
Time Frame
240 days
Title
duration of response (DOR)
Description
To evaluate the duration of response (DOR) for participants achieving a CR or PR
Time Frame
240 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects must have a histologically confirmed diagnosis of mantle cell lymphoma as defined by the World Health Organization (WHO) classification scheme. Age ≥ 60 Subjects must be previously untreated for mantle cell lymphoma and deemed to require treatment by the treating physician ECOG performance status of 0-3 Subject must have adequate bone marrow* without growth factor support as follows: Absolute Neutrophil Count (ANC) ≥ 1000/μL Platelets ≥ 75,000/mm3 (entry platelet count must be independent of transfusion within 14 days of Screening) Hemoglobin ≥ 9.0 g/dL * These criteria may be waived by study investigators if there is evidence of bone marrow involvement by MCL that is believed to be the cause of the cytopenias. Subject must have adequate renal, and hepatic function, per laboratory reference range at screening as follows: Subject must have adequate renal, and hepatic function, per laboratory reference range at screening as follows: Calculated creatinine clearance ≥ 40 mL/min; determined via the Cockcroft-Gault formula. AST and ALT ≤ 3.0 × ULN; Bilirubin ≤ 1.5 × ULN*. Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN These criteria may be waived by study investigators if abnormal values believed to be due to lymphoma. Female subjects must be surgically sterile, postmenopausal (for at least 1 year), or have negative results for a pregnancy test performed as follows: At Screening on a serum sample obtained within 14 days prior to the first study drug administration, and Prior to dosing on a urine sample obtained on Cycle 1 Day 1 if it has been > 7 days since obtaining the serum pregnancy test results. All female subjects not surgically sterile or postmenopausal (for at least 1 year) and non-vasectomized male subjects must practice at least 1 of the following methods of birth control: Total abstinence from sexual intercourse (minimum 1 complete menstrual cycle); A vasectomized partner(s); Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at least 3 months prior to study drug administration; Double-barrier method (condoms and diaphragm with spermicidal [sponge, jellies or creams]). Ability to understand and willingness to sign IRB-approved informed consent Exclusion Criteria: Subject has blastoid-variant mantle cell lymphoma Subject requires immediate cytoreduction as determined by study investigators Subject has documented CNS involvement of mantle cell lymphoma Subject has Ann Arbor stage I or contiguous stage II mantle cell lymphoma Subject has an uncontrolled infection Subject has HIV infection All subjects will be screened for Hepatitis B (HBsAg, anti-HBs, anti-HBc IgM and total) and Hepatitis C (antibody or RNA). Subjects who are positive for Hepatitis B by HBsAg or DNA as well as subjects positive for Hepatitis C will be excluded. Subjects with anti-HBc positivity and DNA negative may be included but will be required to undergo monthly HBV DNA testing and liver function liver function testing (AST, ALT, alkaline phosphatase, total bilirubin). Patients with HCV antibody positivity and HCV pcr negativity are eligible to be included. Subject requires the use of warfarin Subject has received immunization with live virus vaccine within 28 days prior to the first dose of study drug A female subject is pregnant or breast-feeding
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Phirun Mindel
Phone
443-287-0388
Email
mailto:pvang1@jhmi.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lode Swinnen, MD
Organizational Affiliation
Johns Hopkins School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lode Swinnen, MD
Phone
410-614-6398
Email
lswinne1@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Phirun Mindel, RN
Phone
4432870388
Email
pvang1@jhmi.edu

12. IPD Sharing Statement

Learn more about this trial

Phase II Trial of Venetoclax and Rituximab as Initial Therapy in Older Patients With Mantle Cell Lymphoma

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