relapsed/refractory multiple myeloma MedDRA version: 16.1 Level: HLT Classification code 10028229 Term: Multiple myelomas System Organ Class: 100000004851
Conditions
Interventions
Trade Name: Darzalex
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DARATUMUMAB
CAS Number: 945721-28-8
Current Sponsor code: JNJ-54767414
Other descriptive name: HuMa
Sponsors
VU University Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age >=18 years 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: - 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 or refractory disease. Relapse is defined as progression of disease after an initial response 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 35
Exclusion criteria
Exclusion criteria: 1. Prior therapy with daratumumab or other anti-CD38 therapies 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. Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody 7. Subject has previously received an allogeneic stem cell transplantation (at any time) 8. Inadequate marrow reserve as defined by a platelet count <75 x 109/L (<50 x 109/L if =50% of bone marrow mononucleated cells are plasma cells) or an absolute neutrophil count <1.0 x 109/L 9. a) Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal. b) Subject has known moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study). 10. Subject has clinically significant cardiac disease 11. Significant hepatic dysfunction (total bilirubin ? 1.5 times normal value (except subjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL) or transaminases ? 3 times normal value), unless related to myeloma 12. Creatinine clearance <30 ml/min. 13. Known hypersensitivity to components of the investigational products or severe allergic or anaphylactic reactions to humanized products. 14. Subject has any concurrent severe and/or uncontrolled medical condition 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. 15. Subject is known to be seropositive for HIV or known to have AIDS, or any positive test for hepatitis B or hepatitis C indicating acute or chronic infection. 16. History of active malignancy during the past 3 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast and incidental histologic finding of prostate cancer or prostate cancer that is curative, 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 3 years. 17. Subjects with active interstitial pneumonitis 18. Subjects with active, known or suspected autoimmune disease or inflammatory disorder. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 19. Subjects with a condition (other than MM) requiring
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: PART A: To determine which regimen of nivolumab with daratumumab (either with or without low dose cyclophosphamide) merits further evaluation in MM patients with previous exposure to proteasome inhibitor and with lenalidomide-resistant disease, based on safety and efficacy data. PART B: To investigate the efficacy of nivolumab combined with daratumumab with or without low dose cyclophosphamide, as determined by the (s)CR+VGPR+PR rate.;Secondary Objective: PART A: Evaluate the safety of nivolumab-daratumumab with or without low dose cyclophosphamide in MM pts with previous exposure to proteasome inhibitor and lenalidomide-refractory disease Evaluate the preliminary efficacy of nivolumab-daratumumab with or without low dose cyclophosphamide in MM pts with previous exposure to proteasome inhibitor and lenalidomide-resistant disease Evaluate the immunomodulatory effects of nivolumab-daratumumab with or without low dose cyclophosphamide in blood and bone marrow by using flow cytometric analysis PART B: Evaluate toxicity, progression free survival, overall survival Evaluate prognostic factors for response and survival Evaluate the effects of daratumumab-nivolumab with or without low dose cyclophosphamide on CD38 expression levels, and immune cells by using flow cytometric analysis and CYTOF Analyze the prognostic value of myeloma gene expression profiles Assess the prognostic value of mutations as determined by sequencing;Primary end point(s): PART A: ? Selection of nivolumab-daratumumab regimen for further evaluation in part B (nivolumab and daratumumab with or without low dose cyclophosphamide) based on efficacy and adverse events. PART B: ? Overall response rate. In this analysis we will consider the best response obtained during treatment ;Timepoint(s) of evaluation of this end point: every cycle | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PART A: ? Toxicity, especially myelosuppression, polyneuropathy, autoimmune diseases, and thrombosis ? Preliminary efficacy (response rate, PFS, and OS) ? Immunomodulatory effects of nivolumab and daratumumab with or low dose cyclophosphamide PART B: ? Overall response rate of treatment with nivolumab and daratumumab with or without low dose cyclophosphamide. 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 including cytogenetic abnormalities by FISH, ß2-microgloublin, LDH, and MRD-negativity, and expression of CD38, CIPs (CD46, CD55, and CD59), PD-L1 and PD1. ? Effects of nivolumab and daratumumab with or without low dose cyclophosphamide on CD38 levels, CIPs (CD46, CD55, and CD59) expression levels, and immune cells (e.g. NK cells, T cells, Tregs, and MDSCs) by using flow cytometric analysis and CYTOF. ;Timepoint(s) of evaluation of this end point: every cycle | — |
Countries
Netherlands
Contacts
Public ContactTrial office dept. of Hematology
VUmc
Outcome results
None listed