| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with refractory or relapsed and refractory multiple myeloma (rrMM) who have failed at least 2 lines of prior treatment and have been previously exposed to an immunomodulatory drug (IMiDs) as lenalidomide or thalidomide and a proteasome inhibitor as bortezomib or carfilzomib. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with multiple myeloma that has progressed after receaving at least 2 lines of prior treatment. These treatments must have included lenalidomide or thalidomide and a proteasome inhibitor. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| Compare the Progression Free Survival (PFS) as assessed by CAC blinded central review according to the International Myeloma Working Group response criteria, (IMWG criteria) between treatment arms. |
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| E.2.2 | Secondary objectives of the trial |
1.Compare the Overall Survival (OS).
2.Evaluate Overall Response Rate (ORR) and Disease Control Rate (DCR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria or EBMT criteria for minor response only and Duration of Response (DOR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria.
3.Compare the Progression Free Survival (PFS) as assessed by the investigator using IMWG criteria between treatment arms.
4.To evaluate the safety and tolerability in both treatment arms.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
1.Must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy and must have failed their last line of treatment defined as documented disease progression during or within 60 days of completing their last anti-myeloma therapy (refractory to last line of treatment).
2.Prior anti-myeloma treatments must have included an IMiD (lenalidomide or thalidomide) AND proteasome inhibitor (bortezomib or carfilzomib) alone or in combination and subject must have failed therapy with an IMiD OR proteasome inhibitor defined as one of the following:
•Refractory: Documented progressive disease on or within 60 days of completing treatment with an IMiD and/or proteasome inhibitor OR
•Relapsed and refractory: In case of prior response [≥ partial response (PR)] to an IMiD or proteasome inhibitor, subjects must have relapsed within 6 months after stopping treatment with and IMiD and/or proteasome inhibitor containing regimens
3.Confirmed diagnosis of active MM and measurable disease defined as:
•Serum monoclonal protein (M-protein) levels ≥ 0.5 g/dL or
•Urine monoclonal protein (M-protein) levels ≥200 mg/24-hours or
•Subjects without measurable serum and urine M-protein levels, an abnormal serum free light chain ratio (FLC κ/λ) with involved FLC level ≥100 mg/L. (Normal serum FLC κ/λ value: 0.26 - 1.65)
•Presence of CRAB features
4.Provide, archival (≤60 days) or newly obtained bone marrow biopsy or aspirate material for disease assessment and biomarker analysis.
5.Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
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| E.4 | Principal exclusion criteria |
1.Subjects with non-secretory or oligo-secretory myeloma, smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukemia or Waldenström's macroglobulinemia.
2.History of repeated infections, primary amyloidosis, hyperviscosity or POEMS syndrome.
3.Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
4.Has had prior anti-myeloma therapy including but not limited to dexamethasone, IMiDs, proteasome inhibitors, chemotherapy, or radiation therapy within 2 weeks prior to Study Day 1 who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
5.Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease (GVHD).
6.Has received autologous stem cell transplant (auto-SCT) within 12 weeks before the first infusion or are planning for or are eligible for auto-SCT.
7.Has known hypersensitivity to thalidomide, lenalidomide or dexamethasone.
8.Has received previous therapy with pomalidomide.
9.Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.
10.Subjects with peripheral neuropathy ≥ Grade 2.
11.Has evidence of active, non-infectious pneumonitis.
12.Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary end point of the study is Progression-free survival (PFS) – the International Myeloma Working Group response criteria (IMWG 2006) by blinded central review.
PFS is defined as the time from randomization to the first documented disease progression per IMWG 2006 based on blinded central review or death due to any cause, whichever occurs first.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1.PFS Analysis/First OS Analysis: ~ 20 months after trial starts (when all subjects are enrolled, 230 PFS events and ~123 OS events are observed). |
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| E.5.2 | Secondary end point(s) |
1.Compare the Overall Survival (OS).
2.Evaluate Overall Response Rate (ORR) and Disease Control Rate (DCR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria or EBMT criteria for minor response only and Duration of Response (DOR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria
3.Compare the Progression Free Survival (PFS) as assessed by the investigator using IMWG criteria between treatment arms
4.To evaluate the safety and tolerability in both treatment arms.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.An interim safety analysis will take place after 15 subjects in each treatment arm have completed 1 cycle of therapy.
2.Final OS Analysis: ~ 10 mos after main PFS analysis or ~ 185 OS events, whichever comes first. |
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| 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 | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Spain |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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