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

Primary Purpose

Multiple Myeloma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Ibrutinib
Bortezomib
Dexamethasone
Sponsored by
Pharmacyclics Switzerland GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Bruton's Tyrosine Kinase, Bortezomib, Dexamethasone, Ibrutinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fakultní nemocnice Brno
  • Fakultní nemocnice Hradec Králové
  • Fakultní nemocnice Ostrava
  • Všeobecná fakultní nemocnice v Praha
  • Helios-Kliniken Berlin-Buch
  • Vivantes Klinikum Spandau
  • Universitätsklinikum Jena
  • Klinikum der Universität München Campus Grosshadern
  • 251 General Air Force Hospital
  • General Hospital of Athens "Alexandra"
  • General Hospital of Athens "Evangelismos"
  • General Hospital of Athens "LAIKO"
  • University General Hospital of Patra
  • General Hospital of Thessaloniki "G. Papanikolau"
  • IRCCS Ospedale Casa Sollievo della Sofferenza
  • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
  • Istituto Scientifico Romagnolo Per lo Studio e la Cura dei Tumori
  • Ospedale Santa Maria delle Croci
  • Ospedale degli Infermi
  • Azienda Ospedaliera S. Maria di Terni
  • Hospital Universitario Rey Juan Carlos
  • Complejo Hospitalario Universitario A Coruña
  • ICO Badalona-Hospital Germans Trias i Pujol
  • Hospital Clínic i Provincial de Barcelona
  • Hospital Universitario Madrid Sanchinarro
  • Clinica Universidad de Navarra
  • Hospital Universitario de Salamanca
  • Hospital Universitario Virgen del Rocio
  • Hospital Universitario Dr. Peset
  • Ankara University Medical Faculty
  • Dokuz Eylul University Medicine Faculty
  • Erciyes University Medical Faculty
  • Ondokuz Mayis Univ. Med. Fac.

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ibrutinib+ Bortezomib+ Dexamethasone

Arm Description

Outcomes

Primary Outcome Measures

Median Progression-Free Survival (PFS)
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

Overall Response Rate (ORR)
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
Progression Free Survival (PFS) at Landmark Points - 20 Months
PFS at landmark points are the percentage of participants without progression (i.e., KM estimates) at the landmark time endpoints.
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 PD, death, or date of censoring for the participants not progressed/died. The censoring date is the last adequate tumor assessment date.
Overall Survival (OS) at 24 Months
As the median overall survival has not been reached, the data for the landmark analysis at 24 months are provided.
Time to Progression (TTP)
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.
Safety and Tolerability of Ibrutinib in Combination With Bortezomib and Dexamethasone as Measured by the Number of Participants With Adverse Events.
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

Full Information

First Posted
August 19, 2016
Last Updated
March 2, 2020
Sponsor
Pharmacyclics Switzerland GmbH
Collaborators
Janssen Research & Development, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02902965
Brief Title
Study of Ibrutinib in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed/Relapsed and Refractory Multiple Myeloma
Official Title
An Open-label Study of Ibrutinib in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
September 20, 2016 (Actual)
Primary Completion Date
October 26, 2018 (Actual)
Study Completion Date
October 26, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pharmacyclics Switzerland GmbH
Collaborators
Janssen Research & Development, LLC

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Bruton's Tyrosine Kinase, Bortezomib, Dexamethasone, Ibrutinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
74 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ibrutinib+ Bortezomib+ Dexamethasone
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Other Intervention Name(s)
Imbruvica
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
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.
Primary Outcome Measure Information:
Title
Median Progression-Free Survival (PFS)
Description
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.
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.
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
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
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.
Title
Progression Free Survival (PFS) at Landmark Points - 20 Months
Description
PFS at landmark points are the percentage of participants without progression (i.e., KM estimates) at the landmark time endpoints.
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.
Title
Duration of Response (DOR)
Description
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.
Time Frame
The median time on study was 19.6 months (range: 0.16+, 24.64).
Title
Overall Survival (OS) at 24 Months
Description
As the median overall survival has not been reached, the data for the landmark analysis at 24 months are provided.
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.
Title
Time to Progression (TTP)
Description
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.
Time Frame
The median time on study was 19.6 months (range: 0.16+, 24.64).
Title
Safety and Tolerability of Ibrutinib in Combination With Bortezomib and Dexamethasone as Measured by the Number of Participants With Adverse Events.
Description
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
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).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bernhard Hauns, MD
Organizational Affiliation
Pharmacyclics Switzerland GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Fakultní nemocnice Brno
City
Brno
Country
Czechia
Facility Name
Fakultní nemocnice Hradec Králové
City
Nový Hradec Králové
Country
Czechia
Facility Name
Fakultní nemocnice Ostrava
City
Ostrava-Poruba
Country
Czechia
Facility Name
Všeobecná fakultní nemocnice v Praha
City
Praha 2
Country
Czechia
Facility Name
Helios-Kliniken Berlin-Buch
City
Berlin
Country
Germany
Facility Name
Vivantes Klinikum Spandau
City
Berlin
Country
Germany
Facility Name
Universitätsklinikum Jena
City
Jena
Country
Germany
Facility Name
Klinikum der Universität München Campus Grosshadern
City
München
Country
Germany
Facility Name
251 General Air Force Hospital
City
Athens
Country
Greece
Facility Name
General Hospital of Athens "Alexandra"
City
Athens
Country
Greece
Facility Name
General Hospital of Athens "Evangelismos"
City
Athens
Country
Greece
Facility Name
General Hospital of Athens "LAIKO"
City
Athens
Country
Greece
Facility Name
University General Hospital of Patra
City
Patras
Country
Greece
Facility Name
General Hospital of Thessaloniki "G. Papanikolau"
City
Thessaloniki
Country
Greece
Facility Name
IRCCS Ospedale Casa Sollievo della Sofferenza
City
San Giovanni Rotondo
State/Province
Foggia
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
City
Bologna
Country
Italy
Facility Name
Istituto Scientifico Romagnolo Per lo Studio e la Cura dei Tumori
City
Meldola (FC)
Country
Italy
Facility Name
Ospedale Santa Maria delle Croci
City
Ravenna
Country
Italy
Facility Name
Ospedale degli Infermi
City
Rimini
Country
Italy
Facility Name
Azienda Ospedaliera S. Maria di Terni
City
Terni
Country
Italy
Facility Name
Hospital Universitario Rey Juan Carlos
City
Mostoles
State/Province
Madrid
Country
Spain
Facility Name
Complejo Hospitalario Universitario A Coruña
City
A Coruna
Country
Spain
Facility Name
ICO Badalona-Hospital Germans Trias i Pujol
City
Badalona
Country
Spain
Facility Name
Hospital Clínic i Provincial de Barcelona
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario Madrid Sanchinarro
City
Madrid
Country
Spain
Facility Name
Clinica Universidad de Navarra
City
Pamplona
Country
Spain
Facility Name
Hospital Universitario de Salamanca
City
Salamanca
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
Country
Spain
Facility Name
Hospital Universitario Dr. Peset
City
Valencia
Country
Spain
Facility Name
Ankara University Medical Faculty
City
Ankara
Country
Turkey
Facility Name
Dokuz Eylul University Medicine Faculty
City
Izmir
Country
Turkey
Facility Name
Erciyes University Medical Faculty
City
Kayseri
Country
Turkey
Facility Name
Ondokuz Mayis Univ. Med. Fac.
City
Samsun
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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