Efficacy of Daratumumab in Patients With Relapsed/Refractory Myeloma With Renal Impairment
Study Details
Study Description
Brief Summary
This study will evaluate the effects of Daratumumab with dexamethasone in subjects with relapsed or refractory multiple myeloma and renal impairment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
This is a multicenter, single arm, open-label phase 2 study. Approximately 38 subjects will be enrolled to receive daratumumab + dexamethasone. Treatment cycles have duration of 28 days. Subjects will receive treatment until disease progression, death, unacceptable toxicity or for a maximum of 30 months. Drug administration and follow-up visits will occur more frequently for early cycles (weekly for the first 8 weeks, every two weeks for weeks 9-24 and then every 4 weeks). Disease evaluations will occur monthly and will involve mainly measurements of myeloma proteins. Other assessments may include bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin, and β2- microglobulin and albumin.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Daratumumab + Dexamethasone Daratumumab at a dose of 16 mg/kg administered as an IV infusion at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Dexamethasone 40 mg (20 mg for patients>75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle |
Drug: Daratumumab
Daratumumab will be given at a dose of 16 mg/kg administered as an IV infusion at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Subjects will receive pre-infusion medications before infusions to mitigate potential IRRs
Drug: Dexamethasone
Dexamethasone will be administered at 40 mg (20 mg for patients >75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle
|
Outcome Measures
Primary Outcome Measures
- The evaluation of progression free survival (PFS) in subjects with relapsed or refractory multiple myeloma and renal impairment treated with daratumumab and dexamethasone [Assessed monthly until disease progression (PD) or death whichever occurs first (approximately up to 30 months)]
Progression free survival is defined as the time, in months, from recruitment to the date of the first documented PD or death due to any cause, whichever comes first. PD will be assessed by the investigator based on the analysis of serum and urine protein electrophoresis (sPEP and uPEP), serum free light chain protein (sFLC), Corrected serum calcium assessment, imaging and bone marrow assessments as per modified IMWG guidelines.
Secondary Outcome Measures
- Overall response rate (ORR) [From first dose of Daratumumab until end of treatment, PD or death (approximately up to 30 months]
Overall response rate is defined as the proportion of subjects who achieve a best response of PR or better using modified IMWG criteria as their best overall response.
- Renal response rate (RRR) [From first dose of Daratumumab until end of treatment, PD or death (approximately up to 30 months )]
Renal response rate is defined as the proportion of enrolled subjects who achieve a best response of renal partial response (PRRenal) or better using the IMWG criteria
- Duration of response in patients with RI [Assessed monthly from first dose of Daratumumab until PD or death from any cause (approximately up to 30 months)]
Duration of response will be restricted to the subjects that achieve a best objective response of PR or better. It is measured from the time, in months, that the criteria for objective response are first met until the date of a progression event (according to the primary definition of PFS)
- Time to next therapy [From first dose until the date to next anti-neoplastic therapy or death from any cause, whichever comes first (approximately up to 30 months)]
Time to next therapy will be defined as the time, in months, from Cycle 1 Day 1 to the date to next anti-neoplastic therapy or death from any cause, whichever comes first
- Overall survival [Time from first dose of study treatment to death (approximately up to 30 months)]
Overall survival is defined as the time, in months, from the first dose of therapy to the date of death from any cause
- The incidence of Adverse Events and Treatment Emergent Adverse Events in patients with refractory and relapsed multiple myeloma and renal impairment treated with Daratumumab with dexamethasone. [Continuously throughout the study, starting from informed consent until 30 days after last study treatment (approximately up to 30 months)]
The incidence of Adverse Events will be assessed according to the common Terminology Criteria for Adverse Events
Eligibility Criteria
Criteria
Inclusion Criteria:
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Males and females at least 18 years of age.
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Voluntary written informed consent before performance of any study-related procedure.
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Subject must have documented relapsed or refractory multiple myeloma as defined by the criteria below:
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Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma.
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Measurable disease as defined by any of the following:
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Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL (except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level ≥ 200 mg/24 hours; or
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Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free-light-chain ratio.
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Prior treatment with at least two lines of treatment that included both bortezomib- and lenalidomide-based regimens.
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Documented evidence of progressive disease (PD) as defined by the IMWG 2014 on or after the last regimen if the patient responded to previous regimens.
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Renal impairment defined as eGFR < 30 ml/min/1.72 m2 (calculated with the CKD-EPI formula) or in need for dialysis
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Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
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Willingness and ability to participate in study procedures.
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Reproductive Status
Exclusion Criteria:
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Previous therapy with Daratumumab or other anti-CD38 therapy.
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Anti-myeloma treatment within 2 weeks prior to Cycle 1, Day 1.
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Cumulative dose of corticosteroids greater than or equal to the equivalent of 140mg prednisone for ≥4 days or a dose of corticosteroids greater than or equal to the equivalent of 40 mg/day of dexamethasone for ≥4 days within the 2-week period prior to Cycle 1, Day 1.
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Previous allogenic stem cell transplant; or Autologous Stem Cell Transplantation (ASCT) within 12 weeks before Cycle 1, Day 1.
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Clinical signs of meningeal involvement of multiple myeloma.
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Chronic obstructive pulmonary disease (COPD), persistent asthma, or a history of asthma within 5 years.
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Clinically significant cardiac disease, including:
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Myocardial infarction within 1 year, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
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Cardiac arrhythmia (CTCAE Grade 2 or higher) or clinically significant ECG abnormalities.
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ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF)
470 msec.
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Known active hepatitis B, or C.
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Known HIV infection.
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Prior or concurrent malignancy, except for the following:
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Adequately treated basal cell or squamous cell skin cancer.
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Any cancer (other than in-situ) from which the subject has been disease-free for 3 years prior to study entry.
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Any of the following laboratory test results during Screening:
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Absolute neutrophil count ≤1.0 × 109/L;
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Hemoglobin level ≤7.5 g/dL (≤4.65 mmol/L);
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Platelet count <75 × 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and <50x109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells;
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Alanine aminotransferase level ≥2.5 times the upper limit of normal (ULN);
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Pregnant or nursing women
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | General Hospital of Athens "Alexandra" | Athens | Attica | Greece | 11528 |
Sponsors and Collaborators
- Hellenic Society of Hematology
- Janssen Pharmaceuticals
Investigators
- Principal Investigator: Efstathios Kastritis, Assoc Prof, Department of Clinical therapeutics, National and Kapodistrian University of Athens, School of medicine, Athens, Greece
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EAE-2017/MM02