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

• Sponsor: Pharmacyclics Switzerland GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02902965
• Collaborator: Janssen Research & Development, LLC (Industry)
• Enrollment: 74
• Locations: 33
• Arm: 1
• Actual Duration (Months): 25.2
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

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.

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

• Study Type: Interventional
• 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: Sep 20, 2016
• Actual Primary Completion Date: Oct 26, 2018
• Actual Study Completion Date: Oct 26, 2018

Arms and Interventions

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 Names: 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 Names: 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

Primary Outcome Measures

1. 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

1. 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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Fakultní nemocnice Brno	Brno		Czechia
2	Fakultní nemocnice Hradec Králové	Nový Hradec Králové		Czechia
3	Fakultní nemocnice Ostrava	Ostrava-Poruba		Czechia
4	Všeobecná fakultní nemocnice v Praha	Praha 2		Czechia
5	Helios-Kliniken Berlin-Buch	Berlin		Germany
6	Vivantes Klinikum Spandau	Berlin		Germany
7	Universitätsklinikum Jena	Jena		Germany
8	Klinikum der Universität München Campus Grosshadern	München		Germany
9	251 General Air Force Hospital	Athens		Greece
10	General Hospital of Athens "Alexandra"	Athens		Greece
11	General Hospital of Athens "Evangelismos"	Athens		Greece
12	General Hospital of Athens "LAIKO"	Athens		Greece
13	University General Hospital of Patra	Patras		Greece
14	General Hospital of Thessaloniki "G. Papanikolau"	Thessaloniki		Greece
15	IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Foggia	Italy
16	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi	Bologna		Italy
17	Istituto Scientifico Romagnolo Per lo Studio e la Cura dei Tumori	Meldola (FC)		Italy
18	Ospedale Santa Maria delle Croci	Ravenna		Italy
19	Ospedale degli Infermi	Rimini		Italy
20	Azienda Ospedaliera S. Maria di Terni	Terni		Italy
21	Hospital Universitario Rey Juan Carlos	Mostoles	Madrid	Spain
22	Complejo Hospitalario Universitario A Coruña	A Coruna		Spain
23	ICO Badalona-Hospital Germans Trias i Pujol	Badalona		Spain
24	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain
25	Hospital Universitario Madrid Sanchinarro	Madrid		Spain
26	Clinica Universidad de Navarra	Pamplona		Spain
27	Hospital Universitario de Salamanca	Salamanca		Spain
28	Hospital Universitario Virgen del Rocio	Sevilla		Spain
29	Hospital Universitario Dr. Peset	Valencia		Spain
30	Ankara University Medical Faculty	Ankara		Turkey
31	Dokuz Eylul University Medicine Faculty	Izmir		Turkey
32	Erciyes University Medical Faculty	Kayseri		Turkey
33	Ondokuz Mayis Univ. Med. Fac.	Samsun		Turkey

Sponsors and Collaborators

• Pharmacyclics Switzerland GmbH
• Janssen Research & Development, LLC

Investigators

• Study Director: Bernhard Hauns, MD, Pharmacyclics Switzerland GmbH

Study Documents (Full-Text)

• Study Protocol - May 12, 2017
• Statistical Analysis Plan - Jun 20, 2018

More Information

Publications

None provided.

• Responsible Party: Pharmacyclics Switzerland GmbH
• ClinicalTrials.gov Identifier: NCT02902965
• Other Study ID Numbers: PCYC-1139-CA
• First Posted: Sep 16, 2016
• Last Update Posted: Mar 16, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Pharmacyclics Switzerland GmbH: Bruton's Tyrosine Kinase; Bortezomib; Dexamethasone; Ibrutinib
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Period Title: Overall Study
STARTED	74
COMPLETED	64
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone(D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8 and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter.
Overall Participants	74
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	29 39.2%
>=65 years	45 60.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.9 (10.14)
Sex: Female, Male (Count of Participants)
Female	39 52.7%
Male	35 47.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.7%
Not Hispanic or Latino	68 91.9%
Unknown or Not Reported	4 5.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	71 95.9%
More than one race	0 0%
Unknown or Not Reported	3 4.1%
Region of Enrollment (participants) [Number]
Greece	11 14.9%
Turkey	13 17.6%
Czechia	23 31.1%
Italy	10 13.5%
Germany	1 1.4%
Spain	16 21.6%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

All participant received: see description on Arm/Group description. Following implementation of 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 and 29 on each 42-day cycle (Cycles 9-12) and unchanged thereafter.

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Measure Participants	74
Median (95% Confidence Interval) [Months]	8.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib+ Bortezomib+ Dexamethasone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	median PFS
	Estimated Value	8.5
	Confidence Interval	(2-Sided) 95%; 6.2 to 10.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Kaplan-Meier estimates for median PFS and its associated 95% confidence intervals using log-log transformed Greenwood variance estimate were calculated.

2. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Measure Participants	74
Number (95% Confidence Interval) [percentage of participants]	56.8 76.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib+ Bortezomib+ Dexamethasone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ORR in %
	Estimated Value	56.8
	Confidence Interval	(2-Sided) 95%; 44.7 to 68.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Overall response = confirmed sCR + CR + VGPR + PR with corresponding 95% Exact binomial Cl

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Measure Participants	74
Number (95% Confidence Interval) [percentage of participants]	6.6 8.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib+ Bortezomib+ Dexamethasone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	PFS rate
	Estimated Value	6.6
	Confidence Interval	(2-Sided) 95%; 1.6 to 16.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Kaplan-Meier method used for PFS rate and its associated 95% confidence intervals using log-log transformed Greenwood variance estimate were calculated.

4. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Measure Participants	74
Median (95% Confidence Interval) [Months]	9.5

5. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Measure Participants	74
Number (95% Confidence Interval) [percentage of participants]	53.6 72.4%

6. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8, and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter
Measure Participants	74
Median (95% Confidence Interval) [Months]	10.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib+ Bortezomib+ Dexamethasone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	median TTP
	Estimated Value	10.6
	Confidence Interval	(2-Sided) 95%; 7.8 to 12
	Parameter Dispersion	Type: Value:
	Estimation Comments	KM estimates for median TTP with associated 95% CI

7. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8 and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter.
Measure Participants	74
Count of Participants [Participants]	74 100%

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).
Adverse Event Reporting Description	Number of participants who had experienced at least one treatment emergent AE.
Arm/Group Title	Ibrutinib+ Bortezomib+ Dexamethasone
Arm/Group Description	Ibrutinib (I): I 840 mg orally, once daily continuously starting day 1 of Cycle (C) 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation Bortezomib (B): C 1-8: (21-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 4, 8, and 11 of each C C 9-12: (42-day C): B 1.3 mg/m^2 sub-cutaneously on days 1, 8, 22 and 29 of each C Dexamethasone (D): C 1-8: (21-day C): D 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each C C 9-12: (42-day C): D 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each C C 13+ (28-day C): D 40 mg orally once weekly Dose adjustment of D to 10 mg on days specified during C 1-12 and 20 mg weekly during C 13+ is recommended for subjects >75 years of age. Following implementation of Protocol Amendment 4, D administration was reduced to Days 1, 4, 8 and 11 during each 21-day C (C 1-8) and on Days 1, 8, 22 and 29 on each 42-day C (C 9-12) and unchanged thereafter.
All Cause Mortality
	Ibrutinib+ Bortezomib+ Dexamethasone
	Affected / at Risk (%)	# Events
Total	27/74 (36.5%)
Serious Adverse Events
	Ibrutinib+ Bortezomib+ Dexamethasone
	Affected / at Risk (%)	# Events
Total	47/74 (63.5%)
Blood and lymphatic system disorders
Anaemia	1/74 (1.4%)	1
Thrombocytopenia	2/74 (2.7%)	7
Spontaneous haematoma	3/74 (4.1%)	3
Cardiac disorders
Atrial fibrillation	3/74 (4.1%)	3
Atrial flutter	1/74 (1.4%)	1
Sinus bradycardia	1/74 (1.4%)	1
Gastrointestinal disorders
Diarrhoea	1/74 (1.4%)	1
Gastrointestinal inflammation	1/74 (1.4%)	1
Mouth ulceration	1/74 (1.4%)	1
General disorders
Asthenia	1/74 (1.4%)	1
Death	1/74 (1.4%)	1
Pyrexia	1/74 (1.4%)	1
Sudden death	1/74 (1.4%)	1
Hepatobiliary disorders
Cholangitis acute	1/74 (1.4%)	1
Infections and infestations
Atypical pneumonia	1/74 (1.4%)	1
Bacteraemia	1/74 (1.4%)	1
Brain abscess	1/74 (1.4%)	1
Bronchitis	2/74 (2.7%)	2
Bronchitis viral	1/74 (1.4%)	1
Bronchopulmonary aspergillosis	1/74 (1.4%)	1
Erysipelas	1/74 (1.4%)	1
Gastroenteritis	1/74 (1.4%)	1
Gastrointestinal infection	1/74 (1.4%)	1
Haemophilus bacteraemia	1/74 (1.4%)	1
Haemophilus infection	1/74 (1.4%)	1
Herpes simplex	1/74 (1.4%)	1
Infection	1/74 (1.4%)	1
Influenza	1/74 (1.4%)	1
Lung infection	2/74 (2.7%)	2
Pneumococcal sepsis	1/74 (1.4%)	1
Pneumocystis jirovecii pneumonia	1/74 (1.4%)	1
Pneumonia	11/74 (14.9%)	12
Pneumonia bacterial	2/74 (2.7%)	2
Pneumonia escherichia	1/74 (1.4%)	1
Pneumonia haemophilus	2/74 (2.7%)	2
Pneumonia pneumococcal	2/74 (2.7%)	2
Pseudomonal sepsis	1/74 (1.4%)	1
Respiratory tract infection	1/74 (1.4%)	1
Salmonellosis	1/74 (1.4%)	1
Sepsis	3/74 (4.1%)	4
Staphylococcal infection	1/74 (1.4%)	1
Upper respiratory tract infection	2/74 (2.7%)	2
Injury, poisoning and procedural complications
Humerus fracture	1/74 (1.4%)	1
Spinal compression fracture	1/74 (1.4%)	1
Thoracic vertebral fracture	1/74 (1.4%)	1
Investigations
Weight decreased	1/74 (1.4%)	1
Metabolism and nutrition disorders
Decrease appetite	1/74 (1.4%)	1
Hypoglycaemia	1/74 (1.4%)	1
Hyponatraemia	2/74 (2.7%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/74 (1.4%)	1
Nervous system disorders
Cerebral haemorrhage	1/74 (1.4%)	1
Generalised tonic-clonic seizure	1/74 (1.4%)	1
Polyneuropathy	1/74 (1.4%)	1
Syncope	1/74 (1.4%)	1
Psychiatric disorders
Delirium	1/74 (1.4%)	1
Renal and urinary disorders
Renal failure	2/74 (2.7%)	2
Renal impairment	1/74 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/74 (1.4%)	1
Dyspnea	1/74 (1.4%)	1
Pneumonitis	1/74 (1.4%)	1
Pulmonary alveolar haemorrhage	1/74 (1.4%)	1
Pulmonary embolism	1/74 (1.4%)	1
Pulmonary toxicity	1/74 (1.4%)	1
Respiratory failure	1/74 (1.4%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/74 (1.4%)	1
Vascular disorders
Circulatory collapse	1/74 (1.4%)	1
Other (Not Including Serious) Adverse Events
	Ibrutinib+ Bortezomib+ Dexamethasone
	Affected / at Risk (%)	# Events
Total	74/74 (100%)
Blood and lymphatic system disorders
Anaemia	28/74 (37.8%)	66
Lymphopenia	11/74 (14.9%)	50
Neutropenia	10/74 (13.5%)	20
Thrombocytopenia	45/74 (60.8%)	293
Cardiac disorders
Atrial fibrillation	6/74 (8.1%)	7
Ear and labyrinth disorders
Vertigo	3/74 (4.1%)	4
Endocrine disorders
Cushingoid	4/74 (5.4%)	5
Eye disorders
Lacrimation increased	4/74 (5.4%)	5
Vision blurred	4/74 (5.4%)	4
Gastrointestinal disorders
Abdominal pain	5/74 (6.8%)	8
Abdominal pain upper	6/74 (8.1%)	7
Constipation	10/74 (13.5%)	17
Diarrhoea	40/74 (54.1%)	119
Dyspepsia	5/74 (6.8%)	5
Mouth haemorrhage	3/74 (4.1%)	3
Nausea	18/74 (24.3%)	24
Stomatitis	4/74 (5.4%)	5
Vomiting	11/74 (14.9%)	13
General disorders
Asthenia	22/74 (29.7%)	60
Fatigue	21/74 (28.4%)	40
Oedema peripheral	21/74 (28.4%)	29
Pain	3/74 (4.1%)	3
Peripheral swelling	5/74 (6.8%)	6
Pyrexia	13/74 (17.6%)	18
Hepatobiliary disorders
Hepatic function abnormal	6/74 (8.1%)	22
Infections and infestations
Bronchitis	9/74 (12.2%)	11
Conjunctivitis	10/74 (13.5%)	11
Herpes zoster	3/74 (4.1%)	4
Infection	3/74 (4.1%)	3
Influenza	3/74 (4.1%)	3
Nasopharyngitis	10/74 (13.5%)	17
Oral candidiasis	4/74 (5.4%)	4
Pharyngitis	3/74 (4.1%)	3
Pneumonia	5/74 (6.8%)	5
Respiratory tract infection	7/74 (9.5%)	11
Tonsillitis	3/74 (4.1%)	3
Upper respiratory tract infection	19/74 (25.7%)	29
Urinary tract infection	8/74 (10.8%)	9
Investigations
Blood creatinine increased	4/74 (5.4%)	6
Weight decreased	4/74 (5.4%)	5
Platelet count decreased	4/74 (5.4%)	16
Metabolism and nutrition disorders
Decreased appetite	10/74 (13.5%)	11
Hyperuricaemia	3/74 (4.1%)	3
Hypomagnesaemia	4/74 (5.4%)	4
Hypokalaemia	13/74 (17.6%)	22
Hypocalcaemia	11/74 (14.9%)	16
Hypophosphataemia	4/74 (5.4%)	8
Hyponatraemia	5/74 (6.8%)	10
Musculoskeletal and connective tissue disorders
Back pain	15/74 (20.3%)	19
Bone pain	4/74 (5.4%)	5
Muscle spasms	5/74 (6.8%)	7
Musculoskeletal pain	3/74 (4.1%)	3
Musculoskeletal chest pain	3/74 (4.1%)	4
Myalgia	5/74 (6.8%)	6
Pain in extremity	6/74 (8.1%)	8
Nervous system disorders
Dizziness	5/74 (6.8%)	6
Headache	6/74 (8.1%)	6
Neuropathy peripheral	4/74 (5.4%)	6
Peripheral sensorimotor neuropathy	5/74 (6.8%)	14
Periperal sensory neuropathy	18/74 (24.3%)	19
Polyneuropathy	5/74 (6.8%)	10
Somnolence	4/74 (5.4%)	6
Syncope	4/74 (5.4%)	4
Psychiatric disorders
Depression	3/74 (4.1%)	3
Insomnia	6/74 (8.1%)	6
Renal and urinary disorders
Renal impairment	3/74 (4.1%)	6
Respiratory, thoracic and mediastinal disorders
Cough	15/74 (20.3%)	20
Dyspnoea	8/74 (10.8%)	11
Epistaxis	7/74 (9.5%)	8
Oropharyngeal pain	5/74 (6.8%)	6
Productive cough	4/74 (5.4%)	4
Skin and subcutaneous tissue disorders
Dermatitis allergic	5/74 (6.8%)	6
Rash maculo-papular	10/74 (13.5%)	15
Vascular disorders
Hypertension	10/74 (13.5%)	14
Hypotension	8/74 (10.8%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.