Panobinostat/Bortezomib/Dexamethasone in Relapsed or Relapsed-and-refractory Multiple Myeloma
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT02654990
- Lead Sponsor
- pharmaand GmbH
- Brief Summary
Note: The study data was transferred to zr pharma\& following the divestment of panobinostat to pharma\&. Prior to study completion under the sponsorship of Secura Bio, the study was initiated and conducted in part under the sponsorship of Novartis.
The purpose of this study is to investigate the safety and efficacy of 3 different regimens of panobinostat (20 milligrams \[mg\] thrice a week \[TIW\], 20 mg twice a week \[BIW\], and 10 mg TIW) in combination with subcutaneous bortezomib and dexamethasone and to provide exposure, safety and efficacy data to identify the optimal regimen of panobinostat in a randomized, 3-arm parallel design. This study will also assess the impact of administering subcutaneous bortezomib (in combination with panobinostat and dexamethasone) twice weekly for 4 cycles, and then weekly starting from Cycle 5 until disease progression in participants ≤ 75 years of age. Participants \> 75 years of age will receive subcutaneous bortezomib weekly for the entire treatment period (in combination with panobinostat and dexamethasone) until disease progression.
Participants will be treated until disease progression or until they discontinue earlier due to unacceptable toxicity or for other reasons.
Participants who discontinued study treatment for reasons other than disease progression will be followed for efficacy every 6 weeks.
All participants will be followed for survival until the last participant entering long-term follow-up has completed a 3-year survival follow-up or discontinued earlier.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 248
- multiple myeloma per International Myeloma Working Group 2014 definition
- requiring treatment for relapsed or relapsed/refractory disease
- measurable disease based on central protein assessment
- received 1 to 4 prior lines of therapy
- prior immunomodulatory agent(s) exposure
- acceptable lab values prior to randomization
- primary refractory myeloma
- refractory to bortezomib
- concomitant anti-cancer therapy (other than bortezomib/dexamethasone and bisphosphonates)
- prior treatment with pan-deacetylase inhibitors
- clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months prior to randomization)
- unresolved diarrhea ≥ Common Terminology Criteria for adverse events grade 2 or presence of medical condition associated with chronic diarrhea (such as irritable bowel syndrome and inflammatory bowel disease)
Other protocol-defined inclusion/exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B - 20 mg Panobinostat BIW Panobinostat Capsules 20 mg panobinostat BIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm A - 20 mg Panobinostat TIW Dexamethasone tablets 20 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm B - 20 mg Panobinostat BIW Dexamethasone tablets 20 mg panobinostat BIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm A - 20 mg Panobinostat TIW Bortezomib Injection 20 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm C - 10 mg Panobinostat TIW Dexamethasone tablets 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm A - 20 mg Panobinostat TIW Panobinostat Capsules 20 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm B - 20 mg Panobinostat BIW Bortezomib Injection 20 mg panobinostat BIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm C - 10 mg Panobinostat TIW Panobinostat Capsules 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone Arm C - 10 mg Panobinostat TIW Bortezomib Injection 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) Up to 168 days ORR is defined as the percentage of participants with a confirmed partial response (PR) or better (immunophenotypic complete response \[iCR\] or stringent complete response \[sCR\] or complete response \[CR\] or very good partial response \[VGPR\]) as their best overall response after completion of up to 8 cycles of assigned study regimen. Each cycle was 21 days long. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until progressive disease (PD), death, start of new therapy, withdrawal of consent, or end of study, whatever came first. ORR was assessed blindly per independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria.
- Secondary Outcome Measures
Name Time Method ORR Throughout the Study Up to 5.2 years ORR is defined as the percentage of participants with a confirmed PR or better (iCR or sCR or CR or VGPR) as their best overall response throughout the entire study. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until PD, death, start of new therapy, withdrawal of consent or end of study, whatever came first. ORR was assessed blindly per IRC according to IMWG criteria.
iCR Rate Up to 5.2 years iCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; absence of clonal plasma cells in bone marrow analyzed by immunohistochemistry or 2- to 4-color flow cytometry; absence of phenotypically aberrant plasma cells (clonal) in bone marrow (BM) with a minimum of 1 million total BM cells analyzed by multiparametric flow cytometry (\>4 colors). Results reported as percentage of participants achieving iCR.
sCR Rate Up to 5.2 years sCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal FLC ratio; absence of clonal plasma cells in bone marrow analyzed by immunohistochemistry or 2- to 4-color flow cytometry. Results reported as percentage of participants achieving sCR.
Progression-free Survival (PFS) Up to 5.2 years PFS, assessed based on IMWG criteria per blind IRC assessment, is defined as the time from date of randomization to date of first documented disease progression or death (regardless of cause of death).
Overall Survival (OS) Up to 5.2 years OS is defined as the time from date of randomization to the date of death due to any cause.
Maximum Plasma Concentration (Cmax): Panobinostat Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose) Serial blood samples were collected for panobinostat Cmax analysis. Results are reported in nanograms/milliliter (ng/mL).
CR Rate Up to 5.2 years CR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; in case the only measurable disease at baseline is the serum FLC assessment, a normal FLC ratio of 0.26 to 1.65 is required additionally to qualify for CR. Results reported as percentage of participants achieving CR.
VGPR Rate Up to 5.2 years VGPR, based on IMWG criteria per blinded IRC assessment, is defined as: serum and/or urine M protein detectable by immunofixation but not on protein electrophoresis, or ≥90% reduction from baseline in serum) and urine M protein \<100 milligrams/24 hours); in the case of the presence of any soft tissue plasmacytoma(s) at baseline, a reduction in the sum of the products of the cross-diameters by ≥50% from baseline is required; in case the only measurable disease in a participant at baseline is the serum FLC level (that is, no measurable disease in serum and urine PEP), a decrease of \>90% in the difference between involved and uninvolved FLC levels from baseline is required. Results reported as percentage of participants achieving VGPR.
Exposure Response: Cmax for Panobinostat Up to 5.2 Years The exposure-response relationship was assessed utilizing Cmax (Cycle 1 Day 1) for panobinostat versus the outcomes of ORR, grade 3/4 thrombocytopenia, and grade 3/4 diarrhea. Two statistical models were used: logistic regression models, in which these 3 outcomes were treated in a binary fashion according to their occurrence; Cox regression models, with the relevant outcomes being the time to occurrence of grade 3/4 thrombocytopenia and the time to occurrence of grade 3/4 diarrhea. Results are reported as model-based probability. An increase in the model-based probability indicates an increase in the occurrence of the outcomes (ORR, grade 3/4 thrombocytopenia, 3/4 diarrhea) with increasing values of Cmax (that is, with increasing dose of panobinostat).
Time to Progression (TTP) Up to 5.2 years TTP, based on IMWG criteria per blinded IRC assessment, is defined as the time from the date of randomization to the date of the first documented disease progression or death due to multiple myeloma.
Cmax: Bortezomib Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose) Serial blood samples were collected for bortezomib Cmax analysis. Results are reported in ng/mL.
Time to Reach Cmax (Tmax): Panobinostat Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose) Serial blood samples were collected for panobinostat Tmax analysis. Results are reported in hours.
Tmax: Bortezomib Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose) Serial blood samples were collected for bortezomib Tmax analysis. Results are reported in hours.
Change From Baseline in European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Core 30-item Questionnaire (QLQ-C30) Global Health Status (GHS) Score Cycle 15 Day 1, at approximately 295 days Health-related quality of life (HRQoL) was assessed by the EORTC QLQ-C30, which is frequently employed in clinical oncology trials and is recognized as reliable and valid. The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact), and a global health scale (GHS) and quality-of-life scale. For each domain and item, a linear transformation is applied to standardize the score between 0 and 100. Results are presented specifically for the GHS score. A higher GHS score indicates a higher HRQoL. Each cycle was 21 days long.
Change From Baseline in the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group-Neurotoxicity (GOG-Ntx) Neurotoxicity Subscale Score Cycle 15 Day 1, at approximately 295 days HRQoL was assessed by the FACT/GOG-Ntx, a 38-item questionnaire designed to assess general quality of life and severity and impact of neurotoxicity from systemic chemotherapy. It is frequently employed in clinical oncology trials and is recognized as a reliable and valid measure to assess symptoms associated with neurotoxicity. It focuses on 4 general quality of life domains for physical well-being, functional well-being, social/family well-being, and emotional well-being, and includes the neurotoxicity subscale domain to characterize treatment-related neurotoxicity. Results are presented specifically for the 11-item neurotoxicity subscale, which uses a 5-point rating scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). Each item is scored from 0-4, with the severity of neurotoxicity measured as the sum of the 11 items, ranging from 0 to 44. Lower scores indicate lower neurotoxicity and higher HRQoL. Each cycle was 21 days long.
Time to Response (TTR) Up to 5.2 years TTR, based on IMWG criteria per blinded IRC assessment, is the time between date of randomization to the date of first onset of PR or better response (iCR or sCR or CR or VGPR).
Duration of Response (DOR) Up to 5.2 years DOR, based on IMWG criteria per blinded IRC assessment, is defined as the duration from the first documented onset of PR or better (iCR or sCR or CR or VGPR) to the date of first documented disease progression or death due to multiple myeloma.
Trial Locations
- Locations (3)
Novartis Investigative Site
🇹🇷Izmir, Turkey
VUmc, Hematology, PK2 BR012
🇳🇱Amsterdam, Netherlands
Albert Schweitzer ziekenhuis, Hematology
🇳🇱Dordrecht, Netherlands