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About
This is a Phase Ib/II safety and efficacy trial of single agent ABC294640, an inhibitor of sphingosine kinase 2 and dihydroceramide desaturase, in refractory or relapsed multiple myeloma (MM). Cohorts of patients with refractory or relapsed MM who have previously been treated with proteasome inhibitors and immunomodulatory agents will receive increasing doses of oral ABC294640. The starting dosage for ABC294640 will be 250 mg bis in die (BID) which is known to be safely tolerated as a single agent, and the ABC294640 dose will be escalated to two additional dose cohorts of 500 and 750 mg BID using Bayesian model average continual reassessment method (BMA-CRM) for dose finding. It is expected that 18 patients will be used to determine the maximum tolerated dose (MTD) for ABC294640 in refractory or relapsed MM. Up to 56 additional patients will be treated on the phase II portion of the study at the MTD or maximum dose used in phase I, with interim stopping rules for futility.
Pharmacokinetic (PK) and pharmacodynamic (PD) assessments of ABC294640 will be conducted on Day 1 of Cycle 1. Bone marrow biopsy will be obtained prior to the initiation of ABC294640, at the end of cycle #3 and at the end of cycle #6. In addition to serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) and serum free light chain measurement, correlative studies will be performed to measure sphingosine kinase 2 (SK2) activity, sphingosine metabolites, and additional biomarkers in CD138+ myeloma cells.
Full description
Objectives for Phase 1b:
Primary Objectives • To assess safety and determine the maximum tolerated dose (MTD) of single agent ABC294640 in patients with refractory or relapsed multiple myeloma (MM) who have been previously treated with proteasome inhibitors and immunomodulatory agents.
Secondary Objectives
Objectives for Phase 2:
Primary Objectives
• Assess overall treatment response rate and overall survival in patients with relapsed or refractory MM treated with single-agent ABC294640.
Secondary Objectives
The projected ABC294640 doses for the escalation phase are: 250, 500, and 750 mg BID orally continuously as determined in the single agent trial for ABC294640. The dose will be given under fasting conditions (at least 1 hour before or 2 hours after eating). Each cycle of treatment is 28 days.
Patients will be monitored for safety and pharmacodynamics effects weekly in Cycle 1, biweekly for Cycles 2-4, and monthly for subsequent cycles.
Myeloma treatment response will be assessed as follows:
For the phase II portion of the study, patients will be treated with single agent ABC294640 at the MTD determined from the phase Ib study (or highest dose used, if MTD is not reached) until disease progression or intolerable toxicity occurs.
Enrollment
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Inclusion criteria
Patient must have a diagnosis of symptomatic multiple myeloma, relapsed or refractory after previous treatment with a proteasome inhibitor (bortezomib or carfilzomib) and an immunomodulatory agent (thalidomide, lenalidomide or pomalidomide).
Have measurable disease as defined by at least one of the following:
Voluntary signed and dated institutional review board (IRB) approved informed consent form in accordance with regulatory and institutional guidelines.
Time interval from last systemic chemotherapy (not including low dose dexamethasone) more than 2 weeks prior to initiation of ABC294640. Patients receiving high dose dexamethasone defined as 40mg dexamethasone a day for 4 days will need 2 weeks washout prior to initiation of ABC294640
18 years of age or older.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
Acceptable liver function:
Acceptable hematologic status (with or without transfusion support):
Urinalysis: No clinically significant abnormalities.
PT (partial thromboplastin) and PTT (partial thromboplastin time) ≤ 1.5 X ULN after correction of nutritional deficiencies that may contribute to prolonged PT/PTT.
As determined by the treating investigator, the patient must have well-controlled blood pressure, defined as systolic blood pressure <150mmHg (Millimeter of Mercury)and/or diastolic blood pressure <100 mmHg for the majority of measurements.
A negative pregnancy test (if female of child bearing potential).
For men and women of child-producing potential, willingness to use effective contraceptive methods during the study.
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13 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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