relapsed/refractory multiple myeloma MedDRA version: 16.1 Level: HLT Classification code 10028229 Term: Multiple myelomas System Organ Class: 100000004851
Conditions
Interventions
Trade Name: Name: Darzalex
INN or common name : daratumumab
Product Name: daratumumab
Product Code: HuMax-CD38
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Daratumum
Sponsors
VU University Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age 18 years and older 2. Subject must have documented multiple myeloma as defined by the criteria below: •Monoclonal plasma cells in the bone marrow =10% at some point in their disease history or presence of a biopsy proven plasmacytoma. •Measurable disease as defined by any of the following: o Serum monoclonal paraprotein (M-protein) level =5 g/L (0.5 g/dL); or urine M-protein level =200 mg/24 hours; or serum immunoglobulin free light chain =100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio (See Appendix A) 3. Relapsed from or refractory to 2 or more different prior therapies, including IMiDs (eg, thalidomide, lenalidomide) and proteasome inhibitors, chemotherapy-based regimens, or ASCT and without further established treatment options. --Relapse is defined as progression of disease after an initial response (MR or better) to previous treatment, more than 60 days after cessation of treatment --Refractory disease is defined as =65 years) yes F.1.3.1 Number of subjects for this age range 23
Exclusion criteria
Exclusion criteria: 1. Subject has received daratumumab or other anti-CD38 therapies, within 6 months before start of treatment. 2. Non-secretory myeloma 3. Systemic AL amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom’s macroglobulinemia 4. Subject has known meningeal involvement of multiple myeloma 5. Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment. 6. Subject has previously received an allogeneic stem cell transplantation within 1 year before the date of registration and has not used immunesuppressive drugs within one months before the date of registration. 7. Inadequate marrow reserve as defined by a platelet count 470 msec. 10. Significant hepatic dysfunction (total bilirubin = 3 times normal value or transaminases = 3 times normal value), unless related to myeloma 11. Creatinine clearance <30 ml/min. 12. Known hypersensitivity to components of the investigational product or severe allergic or anaphylactic reactions to humanized products. 13. Subject has any concurrent severe and/or uncontrolled medical condition (e.g.uncontrolled diabetes, infection, hypertension, etc.) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study. 14. Subject is known to be seropositive for human immunodefiency virus (HIV) or have active hepatitis B or hepatitis C. 15. History of active malignancy during the past 5 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 5 years. 16. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluation of the effect of daratumumab in combination with ATRA in patients with relapsed/refractory multiple myeloma. In Phase 1: to determine the maximum tolerated dose (MTD) and recommended phase 2 dose level (RDL) of daratumumab combined with ATRA. For Phase 2: to investigate the efficacy of daratumumab combined with ATRA at the RDL, as determined by the (s)CR+VGPR+PR rate. ;Secondary Objective: - To evaluate toxicity. - To evaluate progression-free survival - To evaluate overall survival - To evaluate prognostic factors for response and survival - To evaluate the effects of daratumumab and daratumumab plus ATRA on CD38 expression levels, complement-inhibitory proteins, and immune cells by using flow cytometric analysis and CYTOF - To analyze the prognostic value of myeloma gene expression profiles - To assess the prognostic value of mutations as determined by sequencing. ;Primary end point(s): Phase 1: Dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RDL) of daratumumab combined with ATRA. Phase 2: Overall response rate of treatment with daratumumab combined with ATRA. In this analysis we will consider the best response obtained during treatment ;Timepoint(s) of evaluation of this end point: for phase 1: up to 1.5 years. For phase 2: up to 5 years. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): For phase 1: Safety and toxicity as defined by type, frequency and severity of adverse events as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4. For Phase 2: Overall response rate of treatment with daratumumab monotherapy. In this analysis we will consider the best response obtained during treatment ? Safety and toxicity as defined by type, frequency and severity of adverse events as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4 ? Progression free survival (PFS; i.e. time from registration to progression or death from any cause, whichever comes first) ? Overall survival measured from registration, measured until death from any cause. Patients still alive or lost to follow up are censored at the date they were last known to be alive ? Prognostic factors for response and survival ? Effects of daratumumab plus ATRA on CD38, CD55, and CD59 expression levels. ? Immunomodulatory effects of daratumumab plus ATRA by evaluation of diverse immune subsets including T cells, NK cells, Tregulatory cells, and MDSCs.;Timepoint(s) of evaluation of this end point: For phase 1: up to 1.5 years. For phase 2: up to 5 years. | — |
Countries
Denmark, Netherlands
Contacts
Public ContactTrial office dept. of Hematology
VUmc
Outcome results
None listed