| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.0 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves progression-free survival (PFS) in patients with newly-diagnosed multiple myeloma (NDMM) |
|
| E.2.2 | Secondary objectives of the trial |
* To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves the rate of complete response (CR)
* To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves overall survival (OS)
* To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves pain response rate, as assessed by the Brief Pain Inventory – Short Form (BPI-SF) and analgesic use |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult male or female patients 18 years old and above with a confirmed diagnosis of symptomatic multiple myeloma according to standard criteria who have not received prior treatment for symptomatic multiple myeloma
2. Patients for whom lenalidomide and dexamethasone treatment is appropriate and who are not eligible for HDT-SCT for 1 or more of the following reasons:
* The patient is 65 years of age or older
* The patient is less than 65 years of age but has significant comorbid condition(s) that are, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT-SCT
3. Patients must have measurable disease defined by at least 1 of the following 3 measurements:
* Serum M-protein ≥ 1 g/dL (≥ 10 g/L)
* Urine M-protein ≥ 200 mg/24 hours
* Serum free light chain assay: involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal
4. Patients must meet the following clinical laboratory criteria:
* Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to randomization
* Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN).
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN.
* Calculated creatinine clearance ≥ 30 mL/min
NOTE: Patients with a low creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min, according to local label/practice) will receive a reduced lenalidomide dose of 10 mg once daily on Days 1 through 21 of a 28-day cycle. The lenalidomide dose may be escalated to 15 mg once daily after 2 cycles if the patient is not responding to treatment and is tolerating the treatment. If renal function normalizes (ie, creatinine clearance > 60 mL/min or > 50 mL/min, according to local label/practice) and the patient continues to tolerate this treatment, lenalidomide may then be escalated to 25 mg once daily.
5. ECOG performance status of 0, 1, or 2.
6. Female patients who:
* Are postmenopausal for at least 24 months before the screening visit, OR
* Are surgically sterile, OR
* Females of childbearing potential (FCBP) must:
a. US and European Union (EU): Have TWO medically-supervised negative pregnancy tests (serum or urine with sensitivity of at least 25 mIU/mL), even if continuous abstinence is the chosen method of contraception. One test must be obtained within 10 to 14 days and the other test must be obtained within 24 hours prior to administering the first dose of the study drug regimen at Cycle 1, Day 1. The dates and results of pregnancy tests must be documented
c. Either agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) OR begin TWO reliable methods of birth control: 1 highly effective method and 1 additional effective method AT THE SAME TIME, at least 28 days before starting the study drug regimen through 90 days after the last dose of study treatment
d. Agree to ongoing pregnancy testing
e. Adhere to the guidelines of the The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual (all other participants who are not using commercial supplies)
Male patients, even if surgically sterilized (ie, status postvasectomy), must:
* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) OR
* Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study treatment if their partner is of childbearing potential, even if they have had a successful vasectomy, AND
* Adhere to the guidelines of the RevAssist® program (US participants), RevAid® program (Canadian participants), or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual (all other participants who are not using commercial supplies)
7. Suitable venous access for the study-required blood sampling
8. Must be able to take concurrent aspirin 70 to 325 mg daily (or enoxaparin 40 mg subcutaneously daily [or its equivalent] if allergic to aspirin), per published standard or institutional standard of care, as prophylactic anticoagulation.
NOTE: For patients with prior history of deep vein thrombosis (DVT), low molecular weight heparin (LMWH) is mandatory.
9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen
NOTE: Prior treatment with corticosteroids or localized radiation is permitted as long as it is below a therapeutic level (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over a 2-week period)
2. Radiotherapy within 14 days before randomization
3. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
4. Inability or unwillingness to receive antithrombotic therapy
5. Female patients who are lactating and breastfeeding or have a positive pregnancy test during the screening period
6. Major surgery within 14 days before randomization.
NOTE: Kyphoplasty or vertebroplasty is not considered major surgery
7. Central nervous system involvement
8. Infection requiring IV antibiotic therapy or other serious infection within 14 days before randomization
9. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
11. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before randomization in the study
12. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
13. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause).
14. Psychiatric illness/social situation that would limit compliance with study requirements
15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
16. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment
17. Treatment with any investigational products within 60 days before the first dose of the study drug regimen |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from the date of randomization to the date of first documentation of disease progression based on central laboratory results and IMWG criteria as evaluated by an IRC, or death due to any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| SPEP, UPEP and chemistry laboratory assessments will be performed at screening, day 1 of every cycle, end of treatment, and every 4 weeks during PFS follow-up period. Skeletal survey will be performed at screening and a minimum of every 12 months until disease progression for all patients. More frequent skeletal survey can be done at the discretion of the investigator. |
|
| E.5.2 | Secondary end point(s) |
1. CR rate during the treatment period
2. OS, measured as the time from the date of randomization to the date of death
3. Pain response rate, measured by the proportion of pain responders, as determined by BPI-SF and analgesic use |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Bone marrow aspirate at screening for disease assessment. Repeated when deemed necessary to assess CR or to investigate suspected PD. Radiographic disease assessment for patients with extramedullary disease at screening, day 1 of every other cycle during treatment, and every 8 weeks during the PFS follow-up period until disease progression.
2. Follow-up for survival in the OS follow-up period (patients contacted every 12 weeks until death or termination of the study by the sponsor).
3. Pain assessments at screening, day 1 of every cycle, end of treatment, and every 4 weeks during PFS follow-up period. Patients with new or worsening pain between scheduled visits assessed at unscheduled visits, if necessary, or when next scheduled visit is more than 4 weeks in the future. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | 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 | 38 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Belgium |
| Canada |
| France |
| United States |
|
| 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 trial will end with a 60-month (5-year) follow-up period of the last patient enrolled. The last patient enrolled will start the follow-up period with the “End of Treatment Visit” which will take place 30 days (±1 week) after receiving the last dose of the study drug regimen. The patient will receive the last dose of the study drug regimen due to disease progression, discontinuation for unacceptable toxicity, withdrawal of consent, or death. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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