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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Carfilzomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Measurable disease of MM as defined by at least ONE of the following: Serum monoclonal protein (SPEP) ≥1 g/dL Urine M-protein ≥200 mg/24 hrs 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: Achieved less than a partial response (<PR) following at least 4 cycles and are without evidence of progression disease (PD). OR 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Dose Finding<br>Ibrutinib PO 560mg + Carfilzomib IV 20/27mg/m2 + Dexamethasone PO 20mg | Drug: Ibrutinib<br> <br> Drug: Carfilzomib<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase 2b - Main Study<br>Ibrutinib PO 560mg + Carfilzomib IV 20/36mg/m2 + Dexamethasone PO 20mg | Drug: Ibrutinib<br> <br> Drug: Carfilzomib<br> <br> Drug: Dexamethasone<br> <br> |
| Experimental: Phase 2b - Sub-study<br>Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg | Drug: Ibrutinib<br> <br> Drug: Carfilzomib<br> <br> Drug: Dexamethasone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | -To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone. | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | 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. | Up to 4 years | 
| Overall Survival | Time from date of first dose of study treatment to the date of death from any cause | Up to 4 years | 
| Progression Free Survival (PFS) | 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. | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCI-32765, Multiple Myeloma, Relapsed Refractory Multiple Myeloma, Bruton's Tyrosine Kinase, Carfilzomib, Dexamethasone, Ibrutinib