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

Multiple Myeloma Clinical Trial

Official title:

An Open-label Study of Ibrutinib in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02902965
• Other study ID #: PCYC-1139-CA
• Status: Completed
• Phase: Phase 2
• Start date: September 20, 2016
• Est. completion date: October 26, 2018

Study information

• Verified date: March 2020
• Source: Pharmacyclics Switzerland GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: October 26, 2018
• Est. primary completion date: October 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

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
• 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
• 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.

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Pharmacyclics Switzerland GmbH	Janssen Research & Development, LLC

Countries where clinical trial is conducted

Czechia,  Germany,  Greece,  Italy,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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	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	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.
Secondary	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.	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.
Secondary	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.	The median time on study was 19.6 months (range: 0.16+, 24.64).
Secondary	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.	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.
Secondary	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.	The median time on study was 19.6 months (range: 0.16+, 24.64).
Secondary	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	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).