NCT03201250

Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma

A Phase I/II Study of the c-Met Inhibitor Cabozantinib as a Targeted Strategy to Reverse Resistance to the Proteasome Inhibitor Carfilzomib in Refractory Multiple Myeloma

• Status: Terminated
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 11 (actual)
• Sponsor: University of Nebraska · Academic / Other
• Sex: All
• Age: 19 Years
• Healthy volunteers: Not accepted

Summary

In the currently proposed phase I/II study, the investigators aim to treat patients with relapsed and/or relapsed refractory Multiple Myeloma who have progressed on carfilzomib-based therapy with an FDA approved c-MET inhibitor, cabozantinib.

Detailed description

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. In correlative studies, the investigators aim to show that (1) the serum and marrow MUC20 levels which will be judged by genomic and flow cytometric studies will directly correlate with primary plasma cell MUC20/c-Met pathway activation and inversely correlate with protease inhibitor (PI) resistance; and (2) a correlation of the gene and MUC20 expression profiles of patients with clinical outcomes may confirm the biomarker MUC20 as a predictor of disease sensitivity to PI, and allow future personalization of c-Met-targeted therapies, as well as combination approaches based on c-Met inhibitors. 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).

Conditions

• Multiple Myeloma
• Refractory Multiple Myeloma
• Relapsed/Refractory Multiple Myeloma

Interventions

Type	Name	Description
DRUG	Cabozantinib	Cabozantinib: Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 Phase II: One of phase I dosing levels identified as MTD, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)

Timeline

• Start date: 2018-02-21
• Primary completion: 2021-04-12
• Completion: 2021-04-12
• First posted: 2017-06-28
• Last updated: 2023-09-08
• Results posted: 2022-12-23

Locations

2 sites across 1 country: United States

Regulatory

• FDA-regulated drug study