Study of BTK Inhibitor, Ibrutinib in Combination With Carfilzomib in Subjects With Relapsed and Refractory Multiple Myeloma

Phase 1

Completed

Brief Summary: A MULTICENTER PHASE 1/2B STUDY OF THE BRUTON'S TYROSINE KINASE INHIBITOR, IBRUTINIB (PCI-32765), IN COMBINATION WITH CARFILZOMIB (KYPROLIS™) IN SUBJECTS WITH RELAPSED OR RELAPSED AND REFRACTORY MULTIPLE MYELOMA

Detailed Description: Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoietic cells other than T cells and is necessary for downstream signal transduction from various hematopoietic receptors including the B cell receptor as well as some Fc, chemokine, and adhesion receptors, and is crucial for both B cell development and osteoclastogenesis. Although down-regulated in normal plasma cells, Btk is highly expressed in the malignant cells from many myeloma patients and some cell lines. PCI-32765 is a potent and specific inhibitor of Btk currently in Phase 2 and 3 clinical trials. The current study is designed and intended to determine the safety and efficacy of PCI-32765 in combination with carfilzomib (Kyprolis™) with and without dexamethasone in subjects with relapsed or relapsed and refractory multiple myeloma (MM).

Recruitment & Eligibility

Inclusion Criteria

Measurable disease of MM as defined by at least ONE of the following:
1. Serum monoclonal protein (SPEP) ≥1 g/dL
2. Urine M-protein ≥200 mg/24 hrs
3. Serum free light chain (SFLC): involved FLC ≥10 mg/dL (≥100 mg/L) AND abnormal kappa to lambda serum free light chain ratio
Relapsed or relapsed and refractory MM after receiving at least 2 previous therapies, including an immunomodulator and bortezomib and had either no response or documented disease progression (according to IMWG criteria) to the most recent treatment regimen
Adequate hematologic, hepatic, and renal function
ECOG performance status of 0-2

Inclusion Criteria for Phase 2 Sub-study Cohort:

Must meet all inclusion criteria defined in main study and in addition the following criteria must be met:
Subject must have received a regimen containing carfilzomib in combination with dexamethasone as their most recent line of therapy and have:
1. Achieved less than a partial response (<PR) following at least 4 cycles and are without evidence of progression disease (PD).
  
  OR
2. Disease progression following an initial confirmed response of MR or better to the combination (according to IMWG response criteria).

Exclusion Criteria

Subject must not have primary refractory disease
Plasma cell leukemia, primary amyloidosis or POEMS syndrome
Unable to swallow capsules or disease significantly affecting gastrointestinal function
Requires anti-coagulation with warfarin or a vitamin K antagonist
Requires treatment with strong CYP3A inhibitors

Exclusion Criteria for Phase 2 Sub-study Cohort:

Must not meet any exclusion criteria defined in main study except for exclusion criteria "Subject must not have primary refractory disease" which is related to prior carfilzomib

Arm && Interventions

Group	Intervention	Description
Phase 2b - Main Study	Carfilzomib	Ibrutinib PO 560mg + Carfilzomib IV 20/36mg/m2 + Dexamethasone PO 20mg
Phase 2b - Sub-study	Ibrutinib	Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg
Phase 2b - Main Study	Ibrutinib	Ibrutinib PO 560mg + Carfilzomib IV 20/36mg/m2 + Dexamethasone PO 20mg
Phase 1 - Dose Finding	Ibrutinib	Ibrutinib PO 560mg + Carfilzomib IV 20/27mg/m2 + Dexamethasone PO 20mg
Phase 1 - Dose Finding	Carfilzomib	Ibrutinib PO 560mg + Carfilzomib IV 20/27mg/m2 + Dexamethasone PO 20mg
Phase 1 - Dose Finding	Dexamethasone	Ibrutinib PO 560mg + Carfilzomib IV 20/27mg/m2 + Dexamethasone PO 20mg
Phase 2b - Main Study	Dexamethasone	Ibrutinib PO 560mg + Carfilzomib IV 20/36mg/m2 + Dexamethasone PO 20mg
Phase 2b - Sub-study	Dexamethasone	Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg
Phase 2b - Sub-study	Carfilzomib	Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	up to 4 years	-To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to 4 years	Time from date of first dose of study treatment to the date of first documented evidence of progressive disease, death or date of censoring for the subjects not progressed/died. The censoring date was the last adequate tumor assessment date.
Duration of Response (DOR)	Up to 4 years	The time interval between the date of initial documentation of a response (PR or better) and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects who had not progressed/died. The censoring date was the last adequate tumor assessment date.
Overall Survival	Up to 4 years	Time from date of first dose of study treatment to the date of death from any cause

Locations (17): Colorado Blood Cancer Institute
🇺🇸
Denver, Colorado, United States
City of Hope
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Duarte, California, United States
University of California Los Angeles
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Los Angeles, California, United States
University of Nebraska Medical Center
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Omaha, Nebraska, United States
New York Presbyterian Hospital - Weill-Cornell
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New York, New York, United States
Mount Sinai Hospital
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New York, New York, United States
Duke University Medical Center
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Durham, North Carolina, United States
Cleveland Clinic
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Cleveland, Ohio, United States
MUSC Hollings Cancer Center
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Charleston, South Carolina, United States
Carolinas Healthcare System
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Charlotte, North Carolina, United States
University of Cincinnati
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Cincinnati, Ohio, United States
University of Texas Southwestern Medical Center
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Dallas, Texas, United States
Virginia Commonwealth University
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Richmond, Virginia, United States
McGill University
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Montreal, Quebec, Canada
Methodist Healthcare System
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San Antonio, Texas, United States
Vanderbilt Ingram Cancer Center
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Nashville, Tennessee, United States
Thomas Jefferson University
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Philadelphia, Pennsylvania, United States