| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsed/refractory multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| relapsed/refractory multipel myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
|
|
| E.4 | Principal 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 systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
20. Subject is known or suspected of not being able to comply with the study protocol
(eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
21. Pregnant or lactating females
22. Women of childbearing potential not willing to use adequate contraception, defined as hormonal birth control or intrauterine device, during the trial and for 1 year after the last dose of daratumumab or nivolumab or lenalidomide. Men who are sexually active with women of childbearing potential who are not willing to use adequate contraception for the duration of treatment with the study drugs and for 1 year after the last dose of daratumumab or nivolumab or lenalidomide.
23. Peripheral neuropathy of ≥grade 2.
24. History of allergy to study drug components |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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, β2-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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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