A phase 2 study of nivolumab combined with daratumumab with or without low-dose cyclophosphamide in relapsed/refractory multiple myeloma

Phase 2

Completed

• Conditions: multiple myeloma; Kahler's disease; 10035227

• Registration Number: NL-OMON47546
• Lead Sponsor: Vrije Universiteit Medisch Centrum

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Last Update Posted: 28 February 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 60

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 <25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment.
4. Subject had at least 2 prior anti-myeloma regimens.
(Note: Induction, bone marrow transplant with or without maintenance therapy is
considered one regimen.)
5. Subject has developed lenalidomide-refractory disease during prior treatment with a lenalidomide-containing regimen.
Refractory disease is defined as <25% reduction in M-protein or progression of disease
during treatment or within 60 days after cessation of treatment.
6. Subject received prior treatment with a proteasome inhibitor-containing regimen for at
least 2 consecutive cycles.
7. WHO performance 0, 1, or 2
8. Life expectancy at least 3 months
9. Written informed consent

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 10^9/L (<50 x 10^9/L if *50% of bone marrow mononucleated cells are plasma cells) or an absolute neutrophil count <1.0 x 10^9/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 cured, 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. Subj

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Part A:<br /><br>Primary objective<br /><br>- To determine which regimen of nivolumab with daratumumab (either with or<br /><br>without low dose cyclophosphamide) merits further evaluation in MM patients<br /><br>with previous exposure to proteasome inhibitor and lenalidomide-resistant<br /><br>disease, based on safety and efficacy data<br /><br><br /><br>Part B<br /><br>Primary objective<br /><br>- To investigate the efficacy of nivolumab combined with daratumumab with or<br /><br>without low dose cyclophosphamide, as determined by the (s)CR+VGPR+PR rate.</p><br>