Description:
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.
Title
- 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.
Clinical Trial IDs
- ORG STUDY ID:
171613
- NCT ID:
NCT03422393
Conditions
- Chronic Lymphocytic Leukemia
- Small Lymphocytic Lymphoma
Interventions
| Drug | Synonyms | Arms |
|---|
| Venetoclax | Venclexta | venetoclax with high-dose ibrutinib |
| Ibrutinib | Imbruvica | venetoclax with high-dose ibrutinib |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| venetoclax with high-dose ibrutinib | Experimental | venetoclax with high-dose ibrutinib for the treatment of patients with chronic lymphocytic leukemia with progressive disease on single agent ibrutinib. | |
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).
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Maximum tolerated dose or biologically active dose. |
| Time Frame: | 1 year or more |
| Safety Issue: | |
| Description: | Maximum tolerated dose or biologically active dose. |
Secondary Outcome Measures
| Measure: | Treatment-emergent adverse events |
| Time Frame: | 2 years or more |
| Safety Issue: | |
| Description: | Treatment-emergent adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and relatedness) |
| Measure: | Overall response rate |
| Time Frame: | 2 years or more |
| Safety Issue: | |
| Description: | Partial Response, Partial Response with Lymphocytosis, and Complete Response) based on international working group guidelines. Best overall response will be determined |
| Measure: | Progression free survival rate at completion of combination therapy |
| Time Frame: | 2 years or more |
| Safety Issue: | |
| Description: | Progression free survival rate at completion of combination therapy, duration of response, as determined by International Working Group in CLL (iwCLL) criteria. |
| Measure: | Stable disease rate |
| Time Frame: | 2 years or more |
| Safety Issue: | |
| Description: | Stable disease rate (also based on 2008 iwCLL guidelines), also at the time of primary endpoint response assessment. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Michael Choi |
Trial Keywords
- venetoclax
- ibrutinib
- high-dose ibrutinib
- chronic lymphocytic leukemia
- progressive disease
- Small Lymphocytic Lymphoma
- cancer
Last Updated
May 10, 2021
