| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Young untreated patients with multiple myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| 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 |
Primary objective:
To evaluate the stringent Complete Response (sCR) rate of the combination of MLN9708, Lenalidomide and Dexamethasone in newly diagnosed multiple myeloma (MM) patients after extended consolidation therapy
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives
•To evaluate the overall response rate after induction therapy
•To evaluate the safety of induction therapy
•To evaluate the quality of stem cell harvest after induction therapy
•To evaluate the overall response rate after high-dose therapy (prior to consolidation)
•To evaluate the overall response rate after consolidation therapy
•To evaluate the feasibility of maintenance with MLN9708
•To evaluate duration of response, progression-free and overall survival |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
INCLUSION CRITERIA
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1.Male or female patients ≥ 18 years and ≤ 65 years at the time of signing informed consent form
2.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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
3.Patients diagnosed with multiple myeloma based on the new International Myeloma Working Group Diagnostic Criteria for plasma cells disorders (Leukemia 2009)
4.Subjects must have symptomatic myeloma with CRAB criteria
5.Subjects must have measurable disease requiring systemic therapy defined by serum M-component ≥ 5g/l, urine M-component ≥ 200 mg/24h or serum FLC ≥ 100 mg/l.
6.Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in a 2-week period before initiation therapy). Two weeks must have elapsed since the date of the last radiotherapy treatment. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy.
7.Subjects must be eligible for high dose therapy.
8.Life expectancy ≥ 3 months
9.Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
10.Patients must meet the following clinical laboratory criteria (enrollment is defined as receiving the first dose.):
Adequate hepatic function, with serum ALT and AST ≤ 3 times the upper limit of normal and serum direct bilirubin ≤ 1.5 times the upper limit of normal within 14 days prior to enrollment
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to enrollment.
Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to enrollment (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines with a wash-out period of 7 days)
Platelet count ≥ 75 × 109/L (≥ 30 × 109/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to enrollment. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
Calculated creatinine clearance ≥ 30 mL/minute (MDRD formula should be used for calculating creatinine clearance values: http://mdrd.com/)
11.Female of childbearing potential (FCBP) :
must have two negative pregnancy tests : one serum pregnancy test within 10 to 14 days prior to therapy and one urine pregnancy test within 24 hours before starting study drug.
must agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 3 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
12.Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to not father a child and agree to use a latex condom during therapy and for 3 months after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential.
13.Affiliation with French social security system
|
|
| E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1.Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test within 24 hours before first dose of study drug
2.Evidence of mucosal or internal bleeding and/or platelet refractory.
3.Prior myeloma systemic therapy
4.Major surgery within 14 days before first dose of study drug.
5.Radiotherapy within 14 days before first dose of study drug. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.
6.Treatment by corticosteroids if exceed the equivalent of 160 mg of dexamethasone within 14 days before first dose of study drug
7.Subjects not eligible for high dose therapy
8.Growth factors within 7 days prior to enrollment
9.Transfusion within 3 days prior to enrollment
10.Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to first dose of study drug
11.Infection requiring systemic antibiotic therapy or other serious infection within 14 days before first dose of study drug.
12.Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within 6 months.
13.Systemic treatment, within 14 days before first dose of study drug, 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.
14.Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis.
15.Co-morbid systemic illnesses or other severe concurrent disease that, 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.
16.Psychiatric illness/social situation that would limit compliance with study requirements.
17.Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
18.Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
19.Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral absorption or tolerance of treatment.
20.Diagnosed or treated for another malignancy within 2 years before study enrollment 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.
21.Patient has significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to enrollment
22. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
23.Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent.
24.Participation in clinical trials with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.
25.Failure to have fully recovered (ie, Grade 1 toxicity) from the reversible effects of prior chemotherapy.
26.Central nervous system involvement. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is sCR rate of the combination of MLN9708, lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients at the completion of consolidation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| five years and a eight months |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints include:
- Overall response rate (CR + VGPR + PR) after induction therapy
- Safety of induction therapy
- Quality of stem cell harvest after induction therapy
- Overall response rate after high-dose therapy (prior to consolidation)
- Overall response rate after consolidation therapy
- Feasibility of maintenance with MLN9708
- Duration of response, measured as the time from the date of first documentation of response to the date of first documented progression, progression-free and overall survival
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints include:
- Overall response rate (CR + VGPR + PR) after induction therapy => after induction therapy : after 63 days
- Safety of induction therapy
=> after induction therapy : after 63 days
- Quality of stem cell harvest after induction therapy
=> after 84 days
- Overall response rate after high-dose therapy (prior to consolidation)
=> after 84 days
- Overall response rate after consolidation therapy
=> after 270 days
- Feasibility of maintenance with MLN9708
=> after 270 days
- Duration of response, measured as the time from the date of first documentation of response to the date of first documented progression, progression-free and overall survival
=> five years and a half |
|
| 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 | 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) | 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.8.3 |
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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
| |
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
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