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Study of Ibrutinib in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed/Relapsed and Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT02902965
Recruitment Status : Completed
First Posted : September 16, 2016
Results First Posted : January 2, 2020
Last Update Posted : March 16, 2020
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Pharmacyclics Switzerland GmbH

Study Description
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Brief Summary:
This is a Phase 2 open-label study to evaluate the efficacy and safety of ibrutinib in combination with bortezomib and dexamethasone for patients with relapsed or relapsed and refractory multiple myeloma.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Ibrutinib Drug: Bortezomib Drug: Dexamethasone Phase 2

Detailed Description:
Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoeitic 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. Ibrutinib 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 ibrutinib in combination with bortezomib and dexamethasone in subjects with relapsed/relapsed and refractory multiple myeloma.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 74 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Study of Ibrutinib in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma
Actual Study Start Date : September 20, 2016
Actual Primary Completion Date : October 26, 2018
Actual Study Completion Date : October 26, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Ibrutinib+ Bortezomib+ Dexamethasone Drug: Ibrutinib
Ibrutinib 840 mg orally, once daily continuously starting day 1 of cycle 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation
Other Name: Imbruvica

Drug: Bortezomib
Cycles 1-8: (21-day cycle): Bortezomib 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each Cycle Cycles 9-12: (42-day cycle): Bortezomib 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each Cycle
Other Name: Velcade

Drug: Dexamethasone

Cycles 1-8: (21-day cycle): Dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle Cycles 9-12: (42-day cycle): Dexamethasone 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each cycle Cycles 13+ (28-day cycle): Dexamethasone 40 mg orally once weekly

Dose adjustment of dexamethasone to 10 mg on days specified during cycles 1-12 and 20 mg weekly during cycles 13+ is recommended for subjects >75 years of age.

Following implementation of Protocol Amendment 4, dexamethasone administration was reduced to Days 1, 4, 8 and 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, 29 on each 42-day cycle (Cycles 9-12) and unchanged thereafter.


Outcome Measures
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Primary Outcome Measures :
  1. Median Progression-Free Survival (PFS) [ Time Frame: The median time on study was 19.6 months (range: 0.16+, 24.64). Participants were evaluated for Progression-Free Survival (PFS) during their entire time on the study. ]
    The primary efficacy endpoint of this study is mPFS. Progression free survival is defined as the time from the date of first dose of study treatment to confirmed disease progression or death from any cause, whichever occurs first.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: The median time on study was 19.6 months (range: 0.16+, 24.64). Participants were evaluated for Overall Response (OR) during the entire time on the study. ]
    Overall Response Rate is the percentage of participants who achieve a PR or better over the course of the study but prior to initiation of subsequent anti-cancer therapy

  2. Progression Free Survival (PFS) at Landmark Points - 20 Months [ Time Frame: The median time on study was 19.6 months (range: 0.16+, 24.64), with the 20 month Progression-Free Survival (PFS) rate presented based on Kaplan-Meier estimates. ]
    PFS at landmark points are the percentage of participants without progression (i.e., KM estimates) at the landmark time endpoints.

  3. Duration of Response (DOR) [ Time Frame: The median time on study was 19.6 months (range: 0.16+, 24.64). ]
    The time interval between the date of initial documentation of a response (PR or better) and the date of first documented evidence of PD, death, or date of censoring for the participants not progressed/died. The censoring date is the last adequate tumor assessment date.

  4. Overall Survival (OS) at 24 Months [ Time Frame: The median time on study was 19.6 months (0.16+, 24.64), with the 24 month Overall Survival (OS) rate presented based on Kaplan-Meier estimates. ]
    As the median overall survival has not been reached, the data for the landmark analysis at 24 months are provided.

  5. Time to Progression (TTP) [ Time Frame: The median time on study was 19.6 months (range: 0.16+, 24.64). ]
    Time from date of first dose of study treatment to the date of first documented evidence of PD or date of censoring for the participants not progressed. The censoring date is the last adequate tumor assessment date.

  6. Safety and Tolerability of Ibrutinib in Combination With Bortezomib and Dexamethasone as Measured by the Number of Participants With Adverse Events. [ Time Frame: From first dose of Ibrutinib to within 30 days of last dose for each participant or until study closure. This is the median treatment duration for Ibrutinib of 5.7 months (range: 0.1 - 23.7 months) +30 days (Adverse Events collection period). ]
    Safety and tolerability of ibrutinib in combination with bortezomib and dexamethasone as measured by the frequency and type of adverse events graded using the NCI CTCAE v 4.03. Frequency and Type of Adverse Events are reported in the Adverse Events module


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects with multiple myeloma (MM) who have received 1-3 prior lines of therapy and have demonstrated disease progression since the completion of the most recent treatment regimen. (Subjects may have received prior bortezomib exposure if it does not meet the exclusion criteria for prior proteasome inhibitor use)

  • Measurable disease defined by at least one of the following:

    • Serum monoclonal protein (SPEP) ≥1 g/dL (for subjects with immunoglobulin A (IgA), immunoglobulin D (IgD), immunoglobulin E (IgE) or immunoglobulin M (IgM) multiple myeloma SPEP ≥0.5 g/dL)
    • Urine monoclonal protein (UPEP) ≥200 mg by 24 hour urine electrophoresis
  • Adequate hematologic, hepatic and renal function
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

Exclusion Criteria:

  • Subject must not have primary refractory disease
  • Refractory or non-responsive to prior proteasome inhibitor (PI) therapy (bortezomib or carfilzomib)
  • Peripheral neuropathy Grade ≥2 or Grade 1 with pain at Screening
  • Plasma cell leukemia, primary amyloidosis, or POEMS syndrome
  • Unable to swallow capsules or disease significantly affecting gastrointestinal function
  • Requires treatment with strong CYP3A inhibitors
  • Women who are pregnant or breast feeding
Contacts and Locations
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Information from the National Library of Medicine

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): NCT02902965


Locations
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Sponsors and Collaborators
Pharmacyclics Switzerland GmbH
Janssen Research & Development, LLC
Investigators
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Study Director: Bernhard Hauns, MD Pharmacyclics Switzerland GmbH
  Study Documents (Full-Text)

Documents provided by Pharmacyclics Switzerland GmbH:
Study Protocol  [PDF] May 12, 2017
Statistical Analysis Plan  [PDF] June 20, 2018

More Information
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Responsible Party: Pharmacyclics Switzerland GmbH
ClinicalTrials.gov Identifier: NCT02902965    
Other Study ID Numbers: PCYC-1139-CA
First Posted: September 16, 2016    Key Record Dates
Results First Posted: January 2, 2020
Last Update Posted: March 16, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Pharmacyclics Switzerland GmbH:
Bruton's Tyrosine Kinase
Bortezomib
Dexamethasone
Ibrutinib
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
 Dexamethasone
Bortezomib
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents