Multiple Myeloma
Conditions
Keywords
Bruton's Tyrosine Kinase, Bortezomib, Dexamethasone, Ibrutinib
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.
Interventions
DRUGIbrutinib
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
DRUGBortezomib
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
DRUGDexamethasone
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.
Sponsors
Janssen Research & Development, LLC
Pharmacyclics Switzerland GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
| 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. |
Countries
Czechia, Germany, Greece, Italy, Spain, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone 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. | 74 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 10 |
Baseline characteristics
| Characteristic | Ibrutinib+ Bortezomib+ Dexamethasone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 45 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 65.9 years STANDARD_DEVIATION 10.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 71 Participants |
| Region of Enrollment Czechia | 23 participants |
| Region of Enrollment Germany | 1 participants |
| Region of Enrollment Greece | 11 participants |
| Region of Enrollment Italy | 10 participants |
| Region of Enrollment Spain | 16 participants |
| Region of Enrollment Turkey | 13 participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 27 / 74 |
| other Total, other adverse events | 74 / 74 |
| serious Total, serious adverse events | 47 / 74 |
Outcome results
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.
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.
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Median Progression-Free Survival (PFS) | 8.5 Months |
95% CI: [6.2, 10.8]
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.
Time frame: The median time on study was 19.6 months (range: 0.16+, 24.64).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Duration of Response (DOR) | 9.5 Months |
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Overall Response Rate (ORR) | 56.8 percentage of participants |
95% CI: [44.7, 68.2]
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Overall Survival (OS) at 24 Months | 53.6 percentage of participants |
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Progression Free Survival (PFS) at Landmark Points - 20 Months | 6.6 percentage of participants |
95% CI: [1.6, 16.9]
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
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).
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Safety and Tolerability of Ibrutinib in Combination With Bortezomib and Dexamethasone as Measured by the Number of Participants With Adverse Events. | 74 Participants |
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.
Time frame: The median time on study was 19.6 months (range: 0.16+, 24.64).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib+ Bortezomib+ Dexamethasone | Time to Progression (TTP) | 10.6 Months |
95% CI: [7.8, 12]