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

Phase 2

Completed

Conditions: Multiple Myeloma

Interventions: Drug: Ibrutinib
Drug: Bortezomib
Drug: Dexamethasone

Registration Number: NCT02902965

Lead Sponsor: Pharmacyclics Switzerland GmbH

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 74

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ibrutinib+ Bortezomib+ Dexamethasone	Ibrutinib	-
Ibrutinib+ Bortezomib+ Dexamethasone	Bortezomib	-
Ibrutinib+ Bortezomib+ Dexamethasone	Dexamethasone	-

Primary Outcome Measures

Name	Time	Method
Median Progression-Free Survival (PFS)	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

Name	Time	Method
Progression Free Survival (PFS) at Landmark Points - 20 Months	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.
Safety and Tolerability of Ibrutinib in Combination With Bortezomib and Dexamethasone as Measured by the Number of Participants With Adverse Events.	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
Duration of Response (DOR)	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.
Overall Response Rate (ORR)	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
Time to Progression (TTP)	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.
Overall Survival (OS) at 24 Months	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.

Trial Locations

Locations (33): Fakultní nemocnice Brno
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Brno, Czechia
Fakultní nemocnice Hradec Králové
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Nový Hradec Králové, Czechia
Fakultní nemocnice Ostrava
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Ostrava-Poruba, Czechia
Všeobecná fakultní nemocnice v Praha
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Praha 2, Czechia
Vivantes Klinikum Spandau
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Berlin, Germany
Universitätsklinikum Jena
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Jena, Germany
General Hospital of Athens "Evangelismos"
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Athens, Greece
General Hospital of Athens "LAIKO"
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Athens, Greece
Ospedale Santa Maria delle Croci
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Ravenna, Italy
Azienda Ospedaliera S. Maria di Terni
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Terni, Italy
Istituto Scientifico Romagnolo Per lo Studio e la Cura dei Tumori
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Meldola (FC), Italy
Ospedale degli Infermi
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Rimini, Italy
Complejo Hospitalario Universitario A Coruña
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A Coruna, Spain
ICO Badalona-Hospital Germans Trias i Pujol
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Badalona, Spain
Hospital Clínic i Provincial de Barcelona
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Barcelona, Spain
Hospital Universitario Madrid Sanchinarro
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Madrid, Spain
Clinica Universidad de Navarra
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Pamplona, Spain
Hospital Universitario de Salamanca
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Salamanca, Spain
Hospital Universitario Virgen del Rocio
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Sevilla, Spain
Hospital Universitario Dr. Peset
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Valencia, Spain
Dokuz Eylul University Medicine Faculty
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Izmir, Turkey
Klinikum der Universität München Campus Grosshadern
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München, Germany
General Hospital of Athens "Alexandra"
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Athens, Greece
Helios-Kliniken Berlin-Buch
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Berlin, Germany
251 General Air Force Hospital
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Athens, Greece
University General Hospital of Patra
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Patras, Greece
Erciyes University Medical Faculty
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Kayseri, Turkey
General Hospital of Thessaloniki "G. Papanikolau"
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Thessaloniki, Greece
IRCCS Ospedale Casa Sollievo della Sofferenza
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San Giovanni Rotondo, Foggia, Italy
Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
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Bologna, Italy
Ankara University Medical Faculty
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Ankara, Turkey
Ondokuz Mayis Univ. Med. Fac.
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Samsun, Turkey
Hospital Universitario Rey Juan Carlos
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Mostoles, Madrid, Spain