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Venetoclax With High-dose Ibrutinib for CLL Progressing on Single Agent Ibrutinib

Primary Purpose

Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Venetoclax

Ibrutinib

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring venetoclax, ibrutinib, high-dose ibrutinib, chronic lymphocytic leukemia, progressive disease, Small Lymphocytic Lymphoma, cancer

Eligibility Criteria

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

Inclusion Criteria:

Clinical and phenotypic verification of B cell CLL or SLL and measurable disease.
Prior therapy: Patients must have been receiving single agent ibrutinib therapy at the time of disease progression. Patient may have received other therapy in combination with ibrutinib earlier in their treatment course.
Women of childbearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study.
Adequate hematologic, hepatic and renal function

Exclusion Criteria:

Known CNS lymphoma or leukemia
History of Richter's or prolymphocytic transformation.
Primary ibrutinib resistance
Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP)
History of major surgery within 4 weeks prior to first dose on this study.
History of prior malignancy, with the exception of adequately treated non-melanoma skin cancer, malignancies treated with curative intent and with no evidence of active disease for more than 3 years, or adequately treated cervical carcinoma in situ without current evidence of disease.
Active clinically significant cardiovascular disease or history of myocardial infarction within 6 months of first dose.
Active hepatitis B or C infection.
Known history of infection with human immunodeficiency virus (HIV).
Unable to swallow capsules or disease significantly affecting gastrointestinal function.
History of stroke or intracranial hemorrhage within 6 months of first dose.
Requires anticoagulation with warfarin or other Vitamin K antagonists.
Requires treatment with a strong cytochrome P(CYP)450 3A inhibitor.
Pregnant or breast-feeding women
Current infection requiring parenteral antibiotics.
Active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification.
Patients who require immediate cytoreduction due to high risk of tumor lysis syndrome (ie, absolute lymphocyte count greater than 100k/uL).

Sites / Locations

UC San Diego Moores Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

venetoclax with high-dose ibrutinib

Arm Description

venetoclax with high-dose ibrutinib for the treatment of patients with chronic lymphocytic leukemia with progressive disease on single agent ibrutinib.

Outcomes

Primary Outcome Measures

Maximum tolerated dose or biologically active dose.

Secondary Outcome Measures

Treatment-emergent adverse events

Treatment-emergent adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and relatedness)

Overall response rate

Partial Response, Partial Response with Lymphocytosis, and Complete Response) based on international working group guidelines. Best overall response will be determined

Progression free survival rate at completion of combination therapy

Progression free survival rate at completion of combination therapy, duration of response, as determined by International Working Group in CLL (iwCLL) criteria.

Stable disease rate

Stable disease rate (also based on 2008 iwCLL guidelines), also at the time of primary endpoint response assessment.

Full Information

NCT ID

NCT03422393

First Posted

January 30, 2018

Last Updated

May 8, 2023

Sponsor

Michael Choi

Collaborators

Pharmacyclics LLC.

1. Study Identification

Unique Protocol Identification Number

NCT03422393

Brief Title

Venetoclax With High-dose Ibrutinib for CLL Progressing on Single Agent Ibrutinib

Official Title

A Phase 1 Clinical Trial to Evaluate Venetoclax With High-dose Ibrutinib for the Treatment of Patients With Chronic Lymphocytic Leukemia With Progressive Disease on Single Agent Ibrutinib.

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

May 1, 2018 (Actual)

Primary Completion Date

August 2023 (Anticipated)

Study Completion Date

August 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Michael Choi

Collaborators

Pharmacyclics LLC.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of the study is to investigate whether the combination of venetoclax and ibrutinib (administered up to 840 mg per day) might be useful for the treatment of CLL or SLL that is not responding or no longer responding to treatment with ibrutinib alone. The study will evaluate whether this regimen can reduce the amount of cancerous cells in your body. If you agree, you will receive ibrutinib at a dose of up to 840 mg a day by mouth, as well as venetoclax. Although both of these agents are approved by the FDA for the treatment of CLL or SLL, the combination and the dosing schedule of ibrutinib are considered experimental.

Detailed Description

This is phase 1 study for patients with CLL or small lymphocytic lymphoma (SLL) experiencing disease progression on single ibrutinib. This study will evaluate the optimal ibrutinib dose (including doses higher than 420 mg) when combined with venetoclax During the screening period, patients will continue on ibrutinib at their previous tolerated dose, unless required to stop (e.g.: by a preceding clinical trial). On cycle 1, day 1, the dose of ibrutinib will be assigned based on the dose cohort. Patients in cohort 1 will receive ibrutinib 420 mg PO daily. Patients in cohort 2 will receive ibrutinib 560 mg PO daily. Cohort 3 will be 840 mg PO daily. On cycle 1, day 1, patients will initiate venetoclax. The dose of venetoclax will ramp-up from 20 mg PO daily to 400 mg PO daily over a 5 week period. The primary safety endpoint is determination of DLTs during the first 35 days (completion of dose ramp up). The primary efficacy endpoint of overall response rate will be assessed on approximately Cycle 7, Day 1. Rationale: The optimal management of patients that progress on ibrutinib, including those with acquired Btk or PLCg2 mutations, is not determined. In other cancers, continued treatment with small molecule inhibitors beyond disease progression provides significant benefit, with additional agents or adjustments to ablate the resistant subclone. Venetoclax is approved for the treatment of patients with CLL, and is well-tolerated and effective in high-risk disease, and so is an appropriate agent for this trial.

6. Conditions and Keywords

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

Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Keywords

venetoclax, ibrutinib, high-dose ibrutinib, chronic lymphocytic leukemia, progressive disease, Small Lymphocytic Lymphoma, cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

venetoclax with high-dose ibrutinib

Arm Type

Experimental

Arm Description

venetoclax with high-dose ibrutinib for the treatment of patients with chronic lymphocytic leukemia with progressive disease on single agent ibrutinib.

Intervention Type

Drug

Intervention Name(s)

Venetoclax

Other Intervention Name(s)

Venclexta

Intervention Description

On cycle 1, day 1, patients will initiate venetoclax. The dose of venetoclax will ramp-up from 20 mg PO daily to 400 mg PO daily over a 5 week period.

Intervention Type

Drug

Intervention Name(s)

Ibrutinib

Other Intervention Name(s)

Imbruvica

Intervention Description

During the screening period, patients will continue on ibrutinib at their previous tolerated dose, unless required to stop (e.g.: by a preceding clinical trial). On cycle 1, day 1, the dose of ibrutinib will be assigned based on the dose cohort. Patients in cohort 1 will receive ibrutinib 420 mg PO daily. Patients in cohort 2 will receive ibrutinib 560 mg PO daily. Cohort 3 will be 840 mg PO daily.

Primary Outcome Measure Information:

Title

Maximum tolerated dose or biologically active dose.

Description

Maximum tolerated dose or biologically active dose.

Time Frame

1 year or more

Secondary Outcome Measure Information:

Title

Treatment-emergent adverse events

Description

Treatment-emergent adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and relatedness)

Time Frame

2 years or more

Title

Overall response rate

Description

Partial Response, Partial Response with Lymphocytosis, and Complete Response) based on international working group guidelines. Best overall response will be determined

Time Frame

2 years or more

Title

Progression free survival rate at completion of combination therapy

Description

Progression free survival rate at completion of combination therapy, duration of response, as determined by International Working Group in CLL (iwCLL) criteria.

Time Frame

2 years or more

Title

Stable disease rate

Description

Stable disease rate (also based on 2008 iwCLL guidelines), also at the time of primary endpoint response assessment.

Time Frame

2 years or more

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Clinical and phenotypic verification of B cell CLL or SLL and measurable disease. Prior therapy: Patients must have been receiving single agent ibrutinib therapy at the time of disease progression. Patient may have received other therapy in combination with ibrutinib earlier in their treatment course. Women of childbearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study. Adequate hematologic, hepatic and renal function Exclusion Criteria: Known CNS lymphoma or leukemia History of Richter's or prolymphocytic transformation. Primary ibrutinib resistance Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP) History of major surgery within 4 weeks prior to first dose on this study. History of prior malignancy, with the exception of adequately treated non-melanoma skin cancer, malignancies treated with curative intent and with no evidence of active disease for more than 3 years, or adequately treated cervical carcinoma in situ without current evidence of disease. Active clinically significant cardiovascular disease or history of myocardial infarction within 6 months of first dose. Active hepatitis B or C infection. Known history of infection with human immunodeficiency virus (HIV). Unable to swallow capsules or disease significantly affecting gastrointestinal function. History of stroke or intracranial hemorrhage within 6 months of first dose. Requires anticoagulation with warfarin or other Vitamin K antagonists. Requires treatment with a strong cytochrome P(CYP)450 3A inhibitor. Pregnant or breast-feeding women Current infection requiring parenteral antibiotics. Active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification. Patients who require immediate cytoreduction due to high risk of tumor lysis syndrome (ie, absolute lymphocyte count greater than 100k/uL).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael Choi, MD

Organizational Affiliation

University of California, San Diego

Official's Role

Principal Investigator

Facility Information:

Facility Name

UC San Diego Moores Cancer Center

City

La Jolla

State/Province

California

ZIP/Postal Code

92093

Country

United States

12. IPD Sharing Statement

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Venetoclax With High-dose Ibrutinib for CLL Progressing on Single Agent Ibrutinib

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