Multiple Myeloma
Conditions
Keywords
PCI-32765, Multiple Myeloma, Relapsed Refractory Multiple Myeloma, Bruton's Tyrosine Kinase, Carfilzomib, Dexamethasone, Ibrutinib
Brief summary
A MULTICENTER PHASE 1/2B STUDY OF THE BRUTON'S TYROSINE KINASE INHIBITOR, IBRUTINIB (PCI-32765), IN COMBINATION WITH CARFILZOMIB (KYPROLIS™) IN SUBJECTS WITH RELAPSED OR RELAPSED AND REFRACTORY MULTIPLE MYELOMA
Detailed description
Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoietic 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. PCI-32765 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 PCI-32765 in combination with carfilzomib (Kyprolis™) with and without dexamethasone in subjects with relapsed or relapsed and refractory multiple myeloma (MM).
Interventions
DRUGIbrutinib
DRUGCarfilzomib
DRUGDexamethasone
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Measurable disease of MM as defined by at least ONE of the following: 1. Serum monoclonal protein (SPEP) ≥1 g/dL 2. Urine M-protein ≥200 mg/24 hrs 3. Serum free light chain (SFLC): involved FLC ≥10 mg/dL (≥100 mg/L) AND abnormal kappa to lambda serum free light chain ratio * Relapsed or relapsed and refractory MM after receiving at least 2 previous therapies, including an immunomodulator and bortezomib and had either no response or documented disease progression (according to IMWG criteria) to the most recent treatment regimen * Adequate hematologic, hepatic, and renal function * ECOG performance status of 0-2 Inclusion Criteria for Phase 2 Sub-study Cohort: * Must meet all inclusion criteria defined in main study and in addition the following criteria must be met: * Subject must have received a regimen containing carfilzomib in combination with dexamethasone as their most recent line of therapy and have: 1. Achieved less than a partial response (\<PR) following at least 4 cycles and are without evidence of progression disease (PD). OR 2. Disease progression following an initial confirmed response of MR or better to the combination (according to IMWG response criteria).
Exclusion criteria
* Subject must not have primary refractory disease * Plasma cell leukemia, primary amyloidosis or POEMS syndrome * Unable to swallow capsules or disease significantly affecting gastrointestinal function * Requires anti-coagulation with warfarin or a vitamin K antagonist * Requires treatment with strong CYP3A inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | up to 4 years | -To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to 4 years | The time interval between the date of initial documentation of a response (PR or better) and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects who had not progressed/died. The censoring date was the last adequate tumor assessment date. |
| Overall Survival | Up to 4 years | Time from date of first dose of study treatment to the date of death from any cause |
| Progression Free Survival (PFS) | Up to 4 years | Time from date of first dose of study treatment to the date of first documented evidence of progressive disease, death or date of censoring for the subjects not progressed/died. The censoring date was the last adequate tumor assessment date. |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 84 participants were enrolled and received at least 1 dose of study treatment (All-treated population); of these participants, a total of 59 received treatment at the recommended Phase 2 dose of study drug (All RP2D population).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (560 mg) Ibrutinib PO 560mg + Carfilzomib IV 20/27 mg/m2
Ibrutinib
Carfilzomib | 3 |
| Cohort 2a (560 mg) Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2
Ibrutinib
Carfilzomib | 5 |
| Cohort 2b (560 mg) Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg
Ibrutinib
Carfilzomib
Dexamethasone | 17 |
| All RP2D (840 mg) Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg
Ibrutinib
Carfilzomib
Dexamethasone | 59 |
| Total | 84 |
Baseline characteristics
| Characteristic | Cohort 1 (560 mg) | Cohort 2a (560 mg) | Cohort 2b (560 mg) | All RP2D (840 mg) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 5 Participants | 26 Participants | 38 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 12 Participants | 33 Participants | 46 Participants |
| Age, Continuous | 69.0 years STANDARD_DEVIATION 1.53 | 72.0 years STANDARD_DEVIATION 9.21 | 60.0 years STANDARD_DEVIATION 10.29 | 63.0 years STANDARD_DEVIATION 9.86 | 63.5 years STANDARD_DEVIATION 9.88 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 7 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 5 Participants | 15 Participants | 51 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 3 participants | 5 participants | 17 participants | 59 participants | 84 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 11 Participants | 28 Participants | 41 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants | 31 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 4 / 5 | 9 / 17 | 22 / 59 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 17 / 17 | 58 / 59 |
| serious Total, serious adverse events | 2 / 3 | 5 / 5 | 17 / 17 | 59 / 59 |
Outcome results
Primary
Overall Response Rate (ORR)
-To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone.
Time frame: up to 4 years
Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All-treated population (per protocol).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (560 mg) | Overall Response Rate (ORR) | 2 Participants |
| Cohort 2a (560 mg) | Overall Response Rate (ORR) | 2 Participants |
| Cohort 2b (560 mg) | Overall Response Rate (ORR) | 12 Participants |
| All RP2D (840 mg) | Overall Response Rate (ORR) | 42 Participants |
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 progressive disease, death, or date of censoring for the subjects who had not progressed/died. The censoring date was the last adequate tumor assessment date.
Time frame: Up to 4 years
Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All-treated population (per protocol).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (560 mg) | Duration of Response (DOR) | 7.1 Months |
| Cohort 2a (560 mg) | Duration of Response (DOR) | 15.3 Months |
| Cohort 2b (560 mg) | Duration of Response (DOR) | 9.2 Months |
| All RP2D (840 mg) | Duration of Response (DOR) | 7.2 Months |
Secondary
Overall Survival
Time from date of first dose of study treatment to the date of death from any cause
Time frame: Up to 4 years
Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All RP2D population (per protocol).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (560 mg) | Overall Survival | 35.9 Months |
Secondary
Progression Free Survival (PFS)
Time from date of first dose of study treatment to the date of first documented evidence of progressive disease, death or date of censoring for the subjects not progressed/died. The censoring date was the last adequate tumor assessment date.
Time frame: Up to 4 years
Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All RP2D population (per protocol).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (560 mg) | Progression Free Survival (PFS) | 7.4 Months |