| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma (NDMM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed multiple myeloma in subjects with age ≥ 65 years, and not candidate for transplant |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the overall survival (OS) of maintenance therapy with lenalidomide versus placebo after Melphalan Prednisone Velcade® (MPV) induction therapy in subjects with NDMM who are either ≥ 65 years of age or are not otherwise candidates for stem cell transplantation (SCT). |
|
| E.2.2 | Secondary objectives of the trial |
| -To compare the safety of lenalidomide alone versus placebo given until documented PD |
|
| 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 |
1)To explore the minimal residual disease (MRD) and clonal heterogeneity/clonal succession in subjects who enter the study (subjects with partial response [PR]/very good partial response [VGPR]/complete response [CR]) and subjects achieving or maintaining a CR during study treatment and at progression/discontinuation during or after completion of treatment by analysis of bone marrow aspirate and/or whole blood or serum. Minimal residual disease measurement will be made by a FLOW cytometry based method developed by the Euroflow consortium.
2)To explore molecular and/or immune markers for mechanism of action of lenalidomide by analysis of bone marrow aspirates and whole blood.
3) To explore preexisting myelodysplastic syndromes (MDS) by cytomorphology |
|
| E.3 | Principal inclusion criteria |
Related to initial diagnosis and prior MPV induction therapy
1. Previously untreated and symptomatic multiple myeloma.
2. All 3 criteria (Durie, 2003) including and at least one of the CRAB criteria must be met
(Appendix K).
3. Measurable disease by serum and / or urine protein electrophoresis analyses.
4. All subjects must be treated with a minimum of 6 and a maximum of 9 cycles of MPV induction regimen, and must have achieved at least PR as best overall response and maintained at MPV discontinuation. If a subject achieves CR prior to at least 6 cycles, the subject will be eligible, but a minimum of 6 cycles must be administered otherwise. For the MPV approved regimen, please refer to the Velcade® European Public Assessment Report (EPAR), version 07 Jun 2013. Per investigator decision, the following
modifications to the EPAR dosing regimen can be accepted:
a. Velcade® administration adaptation as long as a minimum of 24 injections and a
maximum of 52 injections is given,
b. Prednisone can be replaced by Dexamethasone,
c. Melphalan can be administered intravenously if dose-intensity is similar to oral
Melphalan.
5. Subjects must not have received any prior anti-myeloma chemotherapy or any investigational agent except 6-9 cycles of induction therapy with MPV.
6.Subjects must have β-2 microglobulin and serum albumin (ISS Stage) (Appendix L) and cytogenetic (17 p deletion, and 4;14 translocation abnormalities [Appendix O]), results from their initial diagnosis available at the time of screening. However, if the cytogenetic test at initial diagnosis was not performed or the results were inconclusive, the test should be performed at any time before study entry. Any conclusive results from initial diagnosis will be used (Appendix O).
Related to the subject
7. Must understand and voluntarily sign the informed consent document prior to the conduct of any study related assessments/procedures,
8. Age ≥ 65 years: if < 65 years of age, the subject must be non eligible for stem cell transplantation,
9. Eastern Cooperative Oncology Group (ECOG) (Appendix G) performance status score
≤ 2,
10. Able to adhere to the study visit schedules and other protocol requirements,
11. Females of Childbearing Potential * (FCBP) must:
a. Have two negative pregnancy tests as verified by the study doctor prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after the end of study therapy. This applies even if the subject practices true abstinence2 from heterosexual contact (Appendices A-E).
b. Either commit to true abstinence † from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study
therapy (Appendices A-E).
12. Male Subjects must:
a. Practice true abstinence † or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions and for at least 28 days following IP discontinuation, even if he has undergone a successful vasectomy (Appendices A-E).
b. Agree to not donate semen during IP therapy and for 28 days after end of study
therapy (Appendices A-E).
13. All subjects must:
a. Have an understanding that the study medication could have a potential teratogenic risk (Appendices A-E).
b. Agree to abstain from donating blood while taking IP therapy and following discontinuation of IP therapy (Appendices A-E).
c. Agree not to share study medication with another person (Appendices A-E).
d. All FCBP and male subjects must be counseled about pregnancy precautions and risks of fetal exposure (Appendices A-E). |
|
| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude the subject from the study enrollment:
1. Previous treatment with anti-myeloma therapy other than the required 6-9 cycles of MPV induction therapy (does not include local radiotherapy, bisphosphonates, or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of randomization]).
2. Subjects who didn’t achieve PR or better after getting at least 6 cycles of MPV (see the Velcade EPAR, Version 07 Jun 2013) and at the end of MPV whatever the overall response are not eligible.
3. Prior therapy with immunomodulating or immunosuppressive agents, or epigenetic or DNA modulating agents. Subjects who received investigational agents are also excluded.
4. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
5. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
6. Pregnant or lactating females.
7. Any of the following laboratory abnormalities:
-Absolute neutrophil count (ANC) < 1,000/L (1.0 x 109/L)
-Untransfused platelet count < 50,000 cells/L (50 x 109/L)
-Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)
-Serum bilirubin levels > 1.5 x ULN
8. Renal insufficiency (creatinine clearance [CrCl] < 30 mL/min by Cockcroft-Gault method,Appendix N) or actual CrCl result, or renal failure requiring hemodialysis or peritoneal dialysis.
9. Prior history of malignancies , other than multiple myeloma, unless the subject has been
free of the disease for ≥ 5 years. Exceptions include the following :
a. Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c. Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e. Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
10. Prior history of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 6months of randomization.
11. Subjects who are unable or unwilling to undergo anti-thrombotic therapy.
12. Peripheral neuropathy of > Grade 2 severity according to the NCI CTCAE Version 4.0.
13. Known Human Immunodeficiency Virus (HIV) positivity or known active infectious hepatitis, type A, B, or C.
14. Primary amyloidosis (immunoglobulin light chain) and myeloma complicated by amyloidosis.
15. Prior allogeneic or autologous stem cell transplantation.
16. Significant active cardiac disease within the previous 6 months including:
-New York Heart Association class II-IV congestive heart failure
-Unstable angina or angina requiring surgical or medical intervention
-Myocardial infarction
17. Any condition that confounds the ability to interpret data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| OS defined as the time from the date of randomization to the date of death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| OS defined as the time from the date of randomization to the date of death due to any cause. |
|
| E.5.2 | Secondary end point(s) |
-Safety (AEs [type, frequency, and severity of AEs, and relationship of AEs to investigational product(IP)], SAEs, laboratory abnormalities, hospitalizations, and SPMs)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| -Safety (AEs [type, frequency, and severity of AEs, and relationship of AEs to investigational product(IP)], SAEs, laboratory abnormalities, hospitalizations, and SPMs) |
|
| 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 | No |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 160 |
| 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
|
| the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan, whichever is the later date. |
|
| 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 | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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