In the currently proposed phase I/II study, the investigators aim to treat patients with relapsed and/or relapsed refractory multiple myeloma (MM) who have progressed on carfilzomib-based therapy with an FDA approved c-MET inhibitor, cabozantinib. Our hypothesis is that the additional rescue blockade with cabozantinib added to the carfilzomib will (1) be safe and tolerable and (2) will show activity by demonstrating objective response to combination carfilzomib/cabozantinib therapy.
To be eligible for this study, patients must have been previously diagnosed with histologically or cytologically confirmed symptomatic MM, must have measurable disease and have had at least two, but not more than four prior lines of therapy for their disease, with lines of therapy being separated by the presence of documented disease progression. Additionally, patients eligible will be those who have failed carfilzomib either as a single agent as the last form of therapy, or carfilzomib in combination with dexamethasone, or carfilzomib in combination with revlimid and dexamethasone.
In Phase I of this study the investigators will determine the maximum tolerated dose (MTD) among three doses. Dose limiting toxicities (DLTs) will be based solely on adverse events that occur during cycle 1. The initial dose of cabozantinib for all patients treated on this study will be 20 mg P.O. daily, which is designated dose level -1. Response assessment will be performed at start and after cycle 2 using the serum and/or urine protein electrophoresis with immunofixation and serum free light chains to assess disease burden. Disease response quality will also be assessed after completion of three cycles of therapy, and then every cycle after that. Bone marrow aspiration and biopsy will be performed after the baseline sampling only to confirm the achievement of a complete remission (CR). All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication. Adverse event and serious adverse events will be followed until baseline or less than or equal to grade 1 levels. Every subject who fulfills all aspects of patient eligibility who receives a partial or complete course of chemotherapy will be evaluable for dose limiting toxicity (DLT).
The following criteria is a partial list of reasons why patients may or may not be eligible to participate in this clinical trial. Further evaluation with a medical professional will be required to determine full eligibility.
The following criteria is provided for health care professionals.
Patients with relapsed disease will be considered to be those who have had progression, as defined above, off of any therapy, and who completed their therapy more than 60 days prior to the finding of progression. Patients with relapsed and refractory disease will be considered to be those who have had progression, as defined above, while still on their last line of therapy, or who progressed within 60 days of finishing their most recent therapy.
Patients must have completed their most recent drug therapy directed at MM in the following time frames:
Any patient with urinary protein (otherwise unrelated to urinary myeloma associated M-protein) with excretion > 3.5 g/day will be considered to have developed nephrotic-range proteinuria, and will be taken off study.
Patients must have evidence of adequate cardiac function, as defined by the following:
Patients who have received radiation therapy (RT) must have completed this at least 4 weeks prior to starting therapy with cabozantinib, with the following exceptions:
Patients who have undergone any recent major surgery within 4 weeks prior to starting therapy with cabozantinib, with the following exceptions:
The subject has experienced any of the following:
GI disorders particularly those associated with a high risk of perforation or fistula formation including:
QTcF > 500 msec within 1 month before the first dose of study treatment:
- Three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.
The following is a listing of trial locations that are open and accepting patients.
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