E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with relapsed multiple myeloma (MM). |
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E.1.1.1 | Medical condition in easily understood language |
Multiple myeloma (MM) is an incurable cancer arising from an over-production of mature white blood cells (B cells). |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
For the Phase 1 Portion:
To identify the maximum tolerated dose of elotuzumab given in combination with lenalidomide and dexamethasone in subjects with relapsed multiple myeloma.
For the Phase 2 Portion:
To evaluate the efficacy of elotuzumab given in combination with lenalidomide and dexamethasone in subjects with multiple myeloma after 1 to 3 prior therapies. |
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E.2.2 | Secondary objectives of the trial |
For the Phase 1 portion:
To evaluate the efficacy of elotuzumab given in combination with lenalidomide and dexamethasone
For both Phase 1 and Phase 2:
1. To evaluate the safety of elotuzumab when given in combination with lenalidomide and dexamethasone.
2. To evaluate the pharmacokinetics of elotuzumab when given in combination with lenalidomide and dexamethasone.
3. To evaluate the immunogenicity of elotuzumab when given in combination with lenalidomide and dexamethasone.
4. To explore pharmacodynamic markers of elotuzumab when given in combination with lenalidomide and dexamethasone.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 years or older with confirmed diagnosis of Multiple Myeloma (MM) and documentation of one to three prior therapies.
2. Confirmed evidence of disease progression from immediately prior MM therapy(see Appendix A - for the definition of disease progression) or refractory to the immediately prior treatment.
3. Measurable disease M-protein component in serum (at least 0.5 g/dL) and/or urine (if present ≥0.2 g excreted in a 24-hour collection sample). Subjects with light chain only disease are excluded.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
5. Creatinine clearance ≥50 mL/min measured by Cockcroft-Gault.
6. Hematological parameters defined by:
•Absolute neutrophil count >1000 cells/mm3 without growth factors for 7 days.
•Platelets ≥75,000 cells/mm3 (75 × 109/L),
•Hemoglobin ≥8 g/dL without red blood cell transfusion within 72 hours of screening.
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3 × upper limit of normal.
8. Total bilirubin <2 × upper limit of normal (ULN), direct bilirubin <2.0 mg/dL.
9. Negative urine pregnancy test in women of childbearing potential at screening and prior to prescribing lenalidomide. Females of childbearing potential (FCBP) must either commit to continued abstinence from heterosexual intercourse or begin acceptable methods of birth control for 28 days prior to prescribing lenalidomide. Men must agree to use a latex condom during sexual contact with FCBP even if they have had a successful vasectomy, and must agree not to donate semen during study drug therapy and for a period of time after therapy. See protocol Appendix L for United States of America (USA) requirements and Appendix M for all non-USA requirements, including the definition of FCBP.
10. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject’s privacy regulations).
11. Able to take aspirin daily as prophylactic anticoagulation therapy (subjects intolerant to aspirin may use warfarin or low molecular weight heparin).
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E.4 | Principal exclusion criteria |
1. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years.
2. Active or prior plasma cell leukemia (defined as either 20% of peripheral WBC comprised of plasma / CD138+ cells or an absolute of 2*10^9/L)
3. Uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary disease, and symptomatic heart failure.
4. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia.
5. Treatment with any investigational drug within 2 weeks or 3 half lives (whichever is longer) of the first dose of elotuzumab.
6. Use of therapeutic corticosteroids, thalidomide, bortezomib, or cytotoxic chemotherapy within 2 weeks of the first dose of elotuzumab except for steroids with to no systemic absorption (ie, topical or inhaled steroids).
7. Prior lenalidomide therapy.
8. Prior peripheral stem cell transplant within 12 weeks of the first dose of elotuzumab.
9. Treatment with nitrosoureas, such as BiCNU (carmustine), nitrogen mustard agents, or melphalan, within 6 weeks of first dose of elotuzumab.
10. Neuropathy ≥Grade 3 or painful neuropathy ≥Grade 2 (National Cancer Institute Common Terminology Criteria of Adverse Events [NCI CTCAE] v3.0).
11. Known active infections requiring IV antibiotic, antiviral, or antifungal therapy.
12. Hypersensitivity to recombinant proteins or excipients in elotuzumab, lenalidomide, or dexamethasone.
13. Female subjects who are pregnant or breastfeeding.
14. Subjects with serum calcium (corrected albumin) ≥ 12 mg/dL |
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E.5 End points |
E.5.1 | Primary end point(s) |
The maximum tolerated dose as determined by the incidence of dose-limiting toxicity in the first treatment cycle of each dosing cohort.
Objective response to treatment, according to the International Myeloma Working Group Uniform Response Criteria (IMWG, Appendix A). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response to treatment will be assessed at least one time each treatment cycle, termination visit, 30 Day and 60 Day Follow-up Visits. |
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E.5.2 | Secondary end point(s) |
For the Phase 1 portion:
1) Objective response according to the International Myeloma Working Group Uniform Response Criteria (IMWG, Appendix A).
For both Phase 1 and Phase 2:
1) Frequency, severity, and relationship of adverse events and serious adverse events to the combination of elotuzumab with lenalidomide and dexamethasone
2) Incidence and severity of infusion-related adverse events at all doses of elotuzumab and with different premedication regimens.
3) Pharmacokinetic profile, including maximum serum drug concentration, area under the concentration-time curve from time zero to infinity, systemic clearance, volume of distribution, and elimination half-life.
4) Duration of response, time to progression, and progression-free survival.
5) Incidence of elotuzumab-specific antidrug antibodies.
6) Plasma cell myeloma cytogenetic subtype using standard karyotyping and/or fluorescence in situ hybridization.
7) Changes in pharmacodynamic variables as they relate to dose, response, and toxicity of elotuzumab in combination with lenalidomide and dexamethasone, including the following:
· Percentage of bone marrow cells expressing cell surface glycoprotein, CS1.
· Saturation of CS1 antigen on bone marrow plasma/multiple
myeloma cells, bone marrow lymphocytes and peripheral blood lymphocyte subsets.
· Serum and tissue biomarker levels, including soluble CS1, and prognostic factors such as beta-2 microglobulin (β2M).
· Peripheral blood lymphocyte percentages and cell counts by flow cytometry, phenotyping, and quantitation of NK-cell subtypes by flow cytometry, and assessment of NK-cell functional activity. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints are evaluated at the time patient signs ICF through 60 Day Follow-up or Monthly Follow-up (if applicable). |
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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 | No |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity of elotuzumab when given in combination with lenalidomide and dexamethasone |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
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 | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Canada |
France |
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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60 days after the last dose of elotuzumab for the last subject treated. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |