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

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

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

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Carfilzomib; Drug: Dexamethasone; Drug: Ibrutinib

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).

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, QC H4A 3J1
      • McGill University
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital - Weill-Cornell
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Healthcare System
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC Hollings Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • San Antonio, Texas, United States, 78229
      • Methodist Healthcare System
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2013
• Primary Completion (ACTUAL): March 1, 2019
• Study Completion (ACTUAL): March 1, 2019

Study Registration Dates

• First Submitted: September 27, 2013
• First Submitted That Met QC Criteria: October 10, 2013
• First Posted (ESTIMATE): October 14, 2013

Study Record Updates

• Last Update Posted (ACTUAL): December 21, 2021
• Last Update Submitted That Met QC Criteria: November 24, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Dexamethasone; Ibrutinib; Carfilzomib; PCI-32765; Bruton's Tyrosine Kinase; Relapsed Refractory Multiple Myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: PCYC-1119-CA; Ibrutinib (PCI-32765)