Phase I/II Trial of Ibrutinib, Dexamethasone, and Lenalidomide as Initial Therapy for Transplant Ineligible Multiple Myeloma Patients
Overview
- Phase
- Phase 1
- Intervention
- Dexamethasone
- Conditions
- Recurrent Plasma Cell Myeloma
- Sponsor
- Mayo Clinic
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD) defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (Phase I)
- Status
- Terminated
- Last Updated
- 8 months ago
Overview
Brief Summary
This phase I/II trial studies the best dose and side effects of ibrutinib when given together with lenalidomide and dexamethasone and how well they work in treating patients with multiple myeloma that are not eligible for transplant. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib, lenalidomide, and dexamethasone may work better in treating patients with multiple myeloma.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of ibrutinib that can be combined with lenalidomide and dexamethasone in relapsed multiple myeloma (MM) patients. (Phase I) II. To estimate the overall response rate (ORR) including partial response (PR) or better of the combination of ibrutinib, lenalidomide, and dexamethasone in subjects with newly diagnosed MM who are not candidates for high dose chemotherapy and autologous stem cell transplantation (ASCT). (Phase II) SECONDARY OBJECTIVES: I. To evaluate the safety profile of this regimen in relapsed MM patients. (Phase I) II. To evaluate the progression free survival (PFS) of the combination of ibrutinib, lenalidomide, and dexamethasone in MM patients. (Phase II) III. To evaluate the safety profile of this regimen in untreated MM patients. (Phase II) IV. To evaluate the duration of response for patients treated with this 3-drug regimen. (Phase II) V. To evaluate overall survival (OS) for patients treated with this 3-drug regimen. (Phase II) EXPLORATORY OBJECTIVES: I. To explore compliance to treatment. II. To assess effects of treatment on patient-reported quality of life (QoL) measures. CORRELATIVE RESEARCH OBJECTIVES: I. To determine the role of members of the BTK signalosome in achievement or lack thereof of response to ibrutinib. II. To explore biologic effects of ibrutinib on microenvironment in MM and correlate with response to treatment. III. To evaluate pharmacodynamic measures including receptor occupancy for BTK prior to introducing lenalidomide in patients treated with ibrutinib and dexamethasone. IV. To evaluate the impact of ibrutinib on platelet aggregation. OUTLINE: This is a phase I, dose-escalation study of ibrutinib followed by a phase II study. PHASE I: Patients receive ibrutinib orally (PO) on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I. After completion of study treatment, patients are followed up every 3 months, then every 6 months for up to 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>= 18 years
- •Diagnosis
- •Phase I: confirmed diagnosis of relapsed or refractory multiple myeloma
- •Phase II: confirmed diagnosis of active multiple myeloma and must be newly diagnosed
- •NOTE: all tests for establishing disease status must be completed =\< 28 days prior to registration
- •Measurable disease =\< 28 days prior to registration, defined by at least one of the following:
- •Serum monoclonal protein \>= 1.0 g/dL
- •\> 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
- •Serum immunoglobulin free light chain \> 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
- •Monoclonal bone marrow plasmacytosis \> 30% (evaluable disease)
Exclusion Criteria
- •Non-secretory MM or known amyloid light-chain (AL) amyloidosis
- •Clinically significant active infection requiring intravenous antibiotics =\< 14 days prior to registration
- •\>= grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- •Other prior malignancy; EXCEPTIONS:
- •Adequately treated basal cell or squamous cell skin cancer
- •Any in situ cancer
- •Adequately treated stage I or II cancer from which the patient is currently in complete remission, or
- •Any other cancer from which the patient has been disease-free for \>= at least three years prior to registration
- •Concurrent therapy considered to be investigational; NOTE: patients must not be planning to receive any radiation therapy (except localized radiation for palliative care that must be completed prior to starting cycle 1, day 1)
- •Any of the following:
Arms & Interventions
Treatment (ibrutinib, lenalidomide, dexamethasone)
PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
Intervention: Dexamethasone
Treatment (ibrutinib, lenalidomide, dexamethasone)
PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
Intervention: Ibrutinib
Treatment (ibrutinib, lenalidomide, dexamethasone)
PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
Intervention: Laboratory Biomarker Analysis
Treatment (ibrutinib, lenalidomide, dexamethasone)
PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
Intervention: Lenalidomide
Treatment (ibrutinib, lenalidomide, dexamethasone)
PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
Intervention: Pharmacological Study
Treatment (ibrutinib, lenalidomide, dexamethasone)
PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
Intervention: Quality-of-Life Assessment
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD) defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (Phase I)
Time Frame: Up to 28 days
Rate of confirmed response defined as patient who has achieved a stringent (s) complete response (CR), CR, very good partial response (VGPR), or partial response (PR) on two consecutive evaluations at any time during treatment (Phase II)
Time Frame: Up to 3 years
Response will be evaluated using all cycles of treatment. Responses will be summarized by simple descriptive summary statistics delineating depth of response as well as stable and progressive disease in this patient population. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
Secondary Outcomes
- Progression-free survival (Phase II)(From registration to the time of progression or death due to any cause, assessed up to 3 years)
- Overall survival (Phase II)(From registration to death due to any cause, assessed up to 3 years)
- Duration of response (Phase II)(The date at which the patient's objective status is first noted to be a sCR, CR, VGPR, or PR to the earliest date progression is documented, assessed up to 3 years)
- Incidence of adverse events assessed by CTCAE v 4.0 (Phase II)(Up to 30 days after last dose of study treatment)