Phase I Clinical Trial of Venetoclax (ABT-199) in Combination with Ixazomib and Dexamethasone for Patients with Relapsed Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Dexamethasone
- Conditions
- Recurrent Plasma Cell Myeloma
- Sponsor
- Mayo Clinic
- Enrollment
- 8
- Locations
- 3
- Primary Endpoint
- Maximum tolerated dose (MTD) of venetoclax in combination with ixazomib and dexamethasone (Phase 1)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase I trial studies the side effects and best dose of venetoclax when given together with ixazomib citrate and dexamethasone and to see how well they work in treating patients with multiple myeloma that has come back. Venetoclax and ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with ixazomib citrate and dexamethasone may work better in treating patients with multiple myeloma.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of venetoclax in combination with ixazomib citrate (ixazomib) and dexamethasone in patients with relapsed multiple myeloma (MM). (Phase 1) SECONDARY OBJECTIVES: I. To describe toxicities associated with venetoclax, in combination with ixazomib and dexamethasone in patients with relapsed MM. (Phase 1) TERTIARY OBJECTIVES: I. To explore levels of BCL-2 family member proteins (BCL-2, BCL-x, MCL-1) on bone marrow biopsies using ribonucleic acid sequencing (RNASeq) and immunohistochemistry. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. Patients receive venetoclax orally (PO) daily on days 1-28, ixazomib citrate PO once weekly on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22 for courses 1-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 or 6 months for 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Phase 1: Relapsed MM with at least one prior line of therapy and should have received a proteasome inhibitor and an immunomodulatory drug
- •Phase 2: 1-3 prior lines of therapy and should have received a proteasome inhibitor and an immunomodulatory drug
- •Obtained =\< 14 days prior to registration: Calculated creatinine clearance (using Cockcroft-Gault equation) \>= 30 mL/min
- •Obtained =\< 14 days prior to registration: Absolute neutrophil count (ANC) \>= 1000/uL (without growth factor support)
- •Obtained =\< 14 days prior to registration: Un-transfused platelet count \>= 75000/uL (\>= 50,000/uL if marrow plasma cells \[PC\]% \> 50%)
- •Obtained =\< 14 days prior to registration: Hemoglobin \>= 8.0 g/dL
- •Obtained =\< 14 days prior to registration: Total bilirubin =\< 1.5 x upper limit of normal (ULN)
- •Obtained =\< 14 days prior to registration: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN
- •Obtained =\< 14 days prior to registration: Alkaline phosphatase =\< 750 U/L
- •Expansion cohort only: Plasma cell fluorescence in situ hybridization (FISH) test demonstrating presence of t(11;14)
Exclusion Criteria
- •Diagnosed or treated for another malignancy =\< 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; NOTE: Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
- •Any of the following:
- •Pregnant women
- •Nursing women
- •Men or women of childbearing potential who are unwilling to employ adequate contraception
- •Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease
- •Other concurrent chemotherapy or any ancillary therapy considered investigational
- •NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
- •Peripheral neuropathy \>= grade 2 on clinical examination or grade 1 with pain during the screening period
- •Major surgery =\< 14 days prior to study registration
Arms & Interventions
Treatment (venetoclax, ixazomib citrate, dexamethasone)
Patients receive venetoclax PO daily on days 1-28, ixazomib citrate PO once weekly on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22 for courses 1-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Dexamethasone
Treatment (venetoclax, ixazomib citrate, dexamethasone)
Patients receive venetoclax PO daily on days 1-28, ixazomib citrate PO once weekly on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22 for courses 1-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ixazomib Citrate
Treatment (venetoclax, ixazomib citrate, dexamethasone)
Patients receive venetoclax PO daily on days 1-28, ixazomib citrate PO once weekly on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22 for courses 1-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (venetoclax, ixazomib citrate, dexamethasone)
Patients receive venetoclax PO daily on days 1-28, ixazomib citrate PO once weekly on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22 for courses 1-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD) of venetoclax in combination with ixazomib and dexamethasone (Phase 1)
Time Frame: Up to 28 days
Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). Will be examined in an exploratory and hypothesis-generating fashion.
Overall survival
Time Frame: Time from registration to death due to any cause, assessed up to 3 years
The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Rate of confirmed response in patients with t(11;14) translocation
Time Frame: Up to 3 years
Will be estimated by the number of patients with a confirmed sCR, CR, VGPR, or PR divided by the total number of evaluable patients with t(11;14) translocation. Exact binomial 95% confidence intervals for the true success proportion will be calculated.
Rate of CR defined as the number of patients with an sCR or CR divided by the total number of evaluable patients
Time Frame: Up to 3 years
Exact binomial 95% confidence intervals for the true success proportion will be calculated.
Progression-free survival
Time Frame: Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 3 years
The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Rate of confirmed response defined as a patient who has achieved an stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) on two consecutive evaluations (Phase 2)
Time Frame: Up to 3 years
The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
Secondary Outcomes
- Incidence of adverse events(Up to 3 years)