Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma
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|ClinicalTrials.gov Identifier: NCT03201250|
Recruitment Status : Recruiting
First Posted : June 28, 2017
Last Update Posted : February 27, 2018
|Condition or disease||Intervention/treatment||Phase|
|Multiple Myeloma Refractory Multiple Myeloma Relapsed/Refractory Multiple Myeloma||Drug: Cabozantinib||Phase 1 Phase 2|
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).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||32 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||February 21, 2018|
|Estimated Primary Completion Date :||October 2020|
|Estimated Study Completion Date :||October 2021|
Combination of cabozantinib, carfilzomib and dexamethasone
Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle.
Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle.
Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23)
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)
- First primary objective: determine the maximum tolerated dose (MTD) of daily cabozantinib given continuously. [ Time Frame: through Phase I completion, an average of 1 year ]The investigators will study three dose levels using the 3+3 algorithm. Overall, depending on the dose escalation portion, the minimum number of study patients enrolled should both phases (I and II) be successful is 26 (23+3), and the maximum 32 (29+3); additional 3 patients represent adjustment to meet the goal of total evaluable patients at the end of the study, accounting for the treatment discontinuation rate of 7-10% in the METEOR study.
- Second primary objective: determine the overall response rate (ORR) [ Time Frame: through study completion, an average of 1 year ]Response will be determined by the IMWG response criteria guidelines. All subjects in phase I that receive the MTD will be included in phase II study analysis. The investigators will use a Simon two-stage design to compare response rates of 0.25 versus 0.05 with alpha=0.05 and power of 0.8083. Nine patients will be enrolled in the first stage. The hypothesis will be rejected and enrollment will cease if no response is seen in the first 9 patients enrolled on the Phase II portion of the study. Otherwise, another 14 patients will be accrued for a total of evaluable 17 patients.
- Identify biological correlates of clinical outcomes and toxicity [ Time Frame: Through study completion, an average of two years ]Measure GEP values as well as MUC20 level of expression in patients at baseline and after cycle 2 of therapy, and activation status of the c-MET/ERK-1/2/ELK1/POMP pathway in primary MM cells at baseline and after each cycles of therapy on protocol.
- Response durability [ Time Frame: Through study completion, an average of 2 years ]This will be measured by estimation of progression free survival (PFS), median Duration of response (DOR), and median time to next treatment. All will be reported in months.
- Impact of therapy on patient reported outcomes [ Time Frame: Through study completion, an average of 2 years ]The impact of cabozantinib and carfilzomib combination for RR MM on patient reported outcomes will be measured using the European Organization for Research on the Treatment of Cancer Quality of Life Questionnaire Core 30, and the myeloma-specific module QLQ-MY20.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03201250
|Contact: Peggy Project Manager, BAemail@example.com|
|Contact: Denise Quality Assurance, MA||402-559-8504|
|United States, Nebraska|
|University of Nebraska Medical Center||Recruiting|
|Omaha, Nebraska, United States, 68198|
|Contact: Penny Nurse Coordinator, RN 402-559-4135 firstname.lastname@example.org|
|Principal Investigator:||Muhamed Baljevic, MD||UNMC|