Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone in Transplant-ineligible NDMM Patients (KyDaR)
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|ClinicalTrials.gov Identifier: NCT04065789|
Recruitment Status : Recruiting
First Posted : August 22, 2019
Last Update Posted : August 22, 2019
|Condition or disease||Intervention/treatment||Phase|
|Myeloma Multiple Myeloma, Plasma-Cell Myeloma-Multiple Plasma Cell Myeloma||Drug: Carfilzomib Drug: Daratumumab Drug: Lenalidomide Drug: Dexamethasone||Phase 2|
Patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve at least a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group [IMWG] criteria), will be treated with a quadruple regimen comprised of: Daratumumab 16 mg/Kg weekly during cycles 1-2, q14 days during cycles 3-6, thereafter monthly (1st dose cycle 1 may be split over 2 days); Once-weekly intravenous (IV) administration of Carfilzomib on days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days, alongside concomitant treatment with twice-weekly IV or oral dexamethasone 20mg administered on Days 1-2, 8-9, 15-16, and 22-23 of a 28-day cycle, for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; and oral Lenalidomide 25 mg, administered on days 1-21 of a 28-day cycle. On treatment days that require both Carfilzomib and Daratumumab infusions, Carfilzomib will be administrated prior to Daratumumab administration. All patients will undergo frailty assessment based on IMWG recommendations, and will be classified as fit, intermediate-fit and frail. Frail patients will receive Lenalidomide dose adjustment to 15 mg (throughout the study, from cycle 1 and on), and dexamethasone at 10 mg x 2/week cycles 1-2 followed by 10 mg/week for subsequent cycles. The quadruple regimen will be administered for 18 cycles, followed by long-term follow-up in which patients will receive standard of care treatment with Lenalidomide/dexamethasone (Rd) treatment, unless disease progression, the physician decides otherwise, the patient suffers from unacceptable toxicity, withdraws consent, or dies (whichever occurs first). All patients will be required to receive either thromboprophylaxis or anticoagulation therapy in parallel. Patients will receive prophylaxis to herpes zoster and pneumocystis infection according to institutional guidelines, as well as proton pump inhibitors on dexamethasone treatment days only, according to institutional guidelines.
Patients will be assessed for response, to be determined by multiple myeloma (MM) biomarker profiling, on day 1 of cycle 2 and then every 56 ±4 days thereafter, irrespective of treatment delays or the timing of treatment cycles. Disease status will be followed until confirmed progressive disease (PD).
Long-term follow-up for disease status (only in cases where patients discontinued treatment prior to PD or patients completing all 18 cycles without signs of PD) and for survival (after reaching PD) will continue after treatment discontinuation until the patient has withdrawn consent for further participation, is lost to follow-up, has died, or the sponsor makes a decision to terminate the study. For patients who discontinued treatment before completing 18 cycles , without PD occurred, disease response assessments shall be performed every 56 days (±4 days), according to the original scheduled days of assessment, until disease progression. Patients completing all 18 cycles without signs of PD will be followed-up for disease response every 84±7 days. Follow-up for survival will be performed approximately every 3 months, or as needed, for all surviving patients until study closure. For any patient who is lost to follow-up, the study site will attempt to ascertain survival information via public database search.
The control group in this study (Historical Control) will consist of 144 consecutive patients from a subset of participating centers and will include transplant ineligible NDMM diagnosed between 2011 to 2017 with failure to respond to a bortezomib based induction (as defined in the prospective trial). Control group patients must meet the protocol inclusion and exclusion criteria.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Safety, Tolerability, and Efficacy of Once Weekly Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone, in Transplant-ineligible Multiple Myeloma Patients Non-responsive to a Bortezomib Based Induction|
|Actual Study Start Date :||May 2, 2018|
|Estimated Primary Completion Date :||January 2022|
|Estimated Study Completion Date :||January 2023|
Experimental: Carfilzomib,Daratumumab,revlimid and dexamethasone
Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone
Carfilzomib on Days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days. The quadruple regimen treatment will be administered for 18 cycles.
Other Name: Kyprolis
Daratumumab : 16 mg/Kg weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks thereafter. The quadruple regimen treatment will be administered for 18 cycles.
Other Name: Darzalex
Lenalidomide (25 mg), administered on days 1-21 of 28-day cycle.In frail patients, Lenalidomide dose will be reduced according to 15 mg . The quadruple regimen treatment will be administered for 18 cycles.
Other Name: Revlimid
Patients will be treated with IV or oral dexamethasone (20 mg for fit and INT-FIT, 10 mg for frail), administered on Days 1-2, 8-9, 15-16, and 22-23 of each 28-day cycle for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; In frail patients, dexamethasone will be reduced to 10 mg . The quadruple regimen treatment will be administered for 18 cycles.
- Proportion of patients who experience any AE incidence, grade > 2 drug-elicited toxicities, peripheral neuropathy events (Grade 2 or higher). [ Time Frame: from screening through month 20 ]Determined by adverse events, vital signs and clinical laboratory parameters in relation to study intervention.
- PFS [ Time Frame: From treatment initiation to the earlier of disease progression or death due to any cause. Up to 2 years from last patient enrollment ]Progression Free Survival (PFS)
- OS [ Time Frame: From treatment initiation to date of death (whatever the cause). Up to 2 years from last patient enrollment ]Overall Survival (OS)
- Overall response rate (ORR) [ Time Frame: From Screening and up to 2 years from last patient enrollment ]The fraction of patients who experience a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) per IMWG 2016 criteria.
- Duration of response (DOR) [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]Time of first evidence of PR or better to confirmation of PD or death due to any cause
- Time to progression (TTP) [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]From initiation of treatment to documented PD
- Clinical benefit response (CBR) rate [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]Defined as ORR or minimal response (MR)
- Disease control rate (DCR), [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]Defined as ORR or minimal response (MR) or stable disease (SD) lasting at least 8 weeks.
- Changes in Global Health Status and Quality of Life [ Time Frame: From Screening and up to 2 years from last patient enrollment ]The European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Module QLQ-MY20 will be used to evaluate Global Health Status/QoL. Questionnaire Module QLQ-MY20 include 20 questions (items). Score scale is starting from minimum of 1 and up to a maximum of 4. Higher values represent a worse outcome.It is the complementary module of the QLQ-C30 which is specific for Multiple Myeloma patients.
- Changes in Global Health Status and Quality of Life [ Time Frame: From Screening and up to 2 years from last patient enrollment ]
The European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Module QLQ-C30 will be used to evaluate Global Health Status/QoL. Questionnaire Module QLQ-C30 include 30 questions score scale is starting from minimum of 1 and up to a maximum of 7. In most items (1-28) Higher values represent a worse outcome.The exceptions are the items contributing to the global health status / QoL - 2 items (29-30) In which Higher values represent a better outcome .
It incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease.
- Changes in Frailty Status [ Time Frame: From Screening and up to 4 month from last patient enrollment ]
Frailty assessment, for this study will be based only on 4 components : age, the Charlson Comorbidity Scoring System, the Katz Index of Independence in Activities of Daily Living and the Lawton Instrumental Activities of Daily Living Scale.
All above 4 components are summed up and combined into one MM Frailty score - The score system (range 0-5, higher values represent a worse outcome), identifies 3 groups of patients:
fit (score=0) intermediate-fitness (score=1) frail (score≥2)
- exploratory genomic profiling [ Time Frame: From Screening and up to 2 years from last patient enrollment ]mutational transcriptional and post translational changes associated with drug sensitivity and resistance, clonal evolution
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04065789
|Contact: Yael Cohen, MD||+972-3-6947655||Yaelcoh@tlvmc.gov.il|
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|Haemek Medical Center||Recruiting|
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|Soroka Medical Center||Recruiting|
|Be'er Sheva, Israel|
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|Hadassah Ein-Karem Medical Center||Recruiting|
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|Shaare Zedek medical Center||Recruiting|
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|Kfar Saba, Israel|
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|Hematology Department Sourasky Medical Center||Recruiting|
|Tel Aviv, Israel, 6423906|
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|Ziv Medical Center||Recruiting|
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|Principal Investigator:||Yael Cohen, MD||Tel-Aviv Sourasky Medical Center|