| 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 | 14.1 |
| 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 the combined response rate of complete response (CR) (including stringent CR [sCR]) + very good partial response (VGPR) following treatment of oral MLN9708 when added to a standard regimen of cyclophosphamide, and low-dose dexamethasone (Cd) during the induction phase |
|
| E.2.2 | Secondary objectives of the trial |
* To evaluate the tolerability and toxicity of the combination of oral MLN9708 with Cd in patients with newly diagnosed multiple myeloma (NDMM)
* To characterize the pharmacokinetics (PK) in plasma of oral MLN9708 in combination with Cd in patients with NDMM
* To determine the overall response rate (ORR) (CR + VGPR + partial response [PR]), CR, VGPR, and PR during the induction phase and the ORR (CR + VGPR + PR), CR + VGPR, CR, VGPR, and PR throughout the entire treatment period
* To determine time to response for patients who respond during the induction phase
* To determine duration of response (DOR) for patients who respond during the induction phase
* To determine time to progression (TTP)
* To evaluate progression-free survival (PFS)
* To describe the safety, tolerability, and efficacy of MLN9708 as maintenance therapy in patients who continue treatment beyond 13 cycles of induction therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult male or female patients 18 years of age or older with a confirmed diagnosis of symptomatic MM according to standard criteria (see Section 14.1 and Section 14.5) who have not received prior treatment for MM.
2. Patients for whom cyclophosphamide and dexamethasone treatment is appropriate and who are considered 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) ≥ 1000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to study drug dosing.
* Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤ 3 x ULN.
* Calculated creatinine clearance (CrCL) ≥ 30 mL/min (see Section 14.2).
5. Eastern Cooperative Oncology Group performance status of 0, 1, or 2 (see Section 14.3).
6. Female patients who:
* Are postmenopausal for at least 1 year before the screening visit, or
Are surgically sterile, or
* If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or
* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
* Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
7. 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.
8. Suitable venous access for the study-required blood sampling.
9. Patient is willing and able to adhere to the study visit schedule and other protocol requirements. |
|
| 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 (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is permitted as long as it is below a therapeutic level and administered at least 14 days prior to the first dose of study treatment.)
2. Diagnosis of smoldering MM, Waldenström’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
3. Central nervous system involvement.
4. Diagnosed or treated for another malignancy within 2 years before the first dose 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.
5. Peripheral neuropathy Grade 1 with pain or ≥ Grade 2 of any cause on clinical examination during the Screening period.
6. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
7. Infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection
9. 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 the first dose of study treatment.
10. Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
11. Major surgery within 14 days before the first dose of study drug. (NOTE: Kyphoplasty or vertebroplasty is not considered major surgery.)
12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
13. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
14. 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.
15. Treatment with any investigational products for reasons other than MM within 30 days before the first dose of study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Combined response rate of complete response (CR) (including stringent complete response (sCR)) + very good partial response (VGPR) in patients treated with MLN9708 when added to a standard care regimen of cyclophosphamide and low-dose dexamethasone (Cd) during the induction phase |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| SPEP, UPEP, immunofixation of blood and urine, and serum free light chain at screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. For suspected CRs, one bone-marrow aspirate assessment required. To determine a response of sCR, bone marrow, immunohistochemistry or immunofluorescence for kappa/lambda ratio, and serum free light chain required for all patients suspected to be in CR to meet this requirement of this response category. |
|
| E.5.2 | Secondary end point(s) |
1. All adverse events (AEs), Grade 3 or higher AEs, AEs resulting in discontinuation, AEs resulting in dose reduction, serious adverse events (SAEs), and assessments of clinical laboratory values
2. Pharmacokinetic (PK) parameters including, but not limited to single-dose maximum (peak) concentration (Cmax), Tmax, and area under the plasma concentration versus time curve (AUC)
3. Overall response rate (ORR) (complete response (CR) + very good partial response (VGPR) + partial response (PR)), CR, VGPR, and PR during the induction phase and throughout the entire study
4. Time to response, defined as the time interval from the date of enrollment to the date of first documented response during the induction phase
5. Duration of response (DOR), defined for responders as the time interval from the date of first response to the date of disease progression
6. Time to progression (TTP), defined as the time interval from the date of enrollment to the date of first documented disease progression
7. Progression-free survival (PFS), defined as the time interval from the date of enrollment to the date of first documented disease progression or death
8. AEs, SAEs, AEs resulting in discontinuation, AEs resulting in dose reduction in patients remaining on treatment after 13 cycles, ORR, CR, VGPR, and PR of single-agent MLN9708 as maintenance therapy in patients remaining on treatment after 13 cycles
9. Comparison of change in global health status between baseline and each postbaseline assessment, as measured by the global health scale, functioning, and symptoms of the EORTC QLQ-C30 and MY-20 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Continuous.
2. On D1-3, 5, 8, 15, 16, 17, 19 and 22 of C1, and D1 of C2 (safety lead-in). On D1, 8, 15 and 22 of C1-3 (other patients).
3. SPEP, UPEP, immunofixation of blood and urine, and serum free light chain at screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. For suspected CRs, one bone-marrow aspirate required.
4. See 3.
5. SPEP and UPEP on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. Chemistry laboratory at screening, on D1, 8, 15 and 22 of C1-3, then D1 of each cycle, and at EOT. Skeletal survey at screening and once annually. Additional skeletal surveys possible. See also 3.
6. See 5.
7. See 5.
8. See 1 and 3.
9. At screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up.
|
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Denmark |
| Greece |
| Hungary |
| New Zealand |
| Poland |
| Sweden |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 24-month (2-year) maintenance and/or progression-free survival (PFS) follow-up period of the last living 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 progression/death or unacceptable toxicity. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 |
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