| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Refractory 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 | 15.0 |
| 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) |
|
| 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 the background therapy of lenalidomide and dexamethasone improves progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (RRMM) |
|
| E.2.2 | Secondary objectives of the trial |
-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 the OS in high-risk patients carrying deletion del(17)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female patients 18 years of age or older.
2.Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis.
NOTE: The initial diagnosis must be symptomatic MM, although the relapsed disease does not need to be symptomatic.
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 with relapsed and/or refractory MM who have received 1 to 3 prior therapies.
NOTE: This patient population includes the following 3 categories of patients:
•Patients who relapsed from their previous treatment(s) but were not refractory to any previous treatment.
•Patients who were refractory to all lines of previous treatment(s) (ie, patients who have never responded to any therapies received).
•Patients who were relapsed from at least 1 previous treatment AND additionally were refractory to at least 1 previous treatment. For the purposes of this study, refractory disease is defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy.
A line of therapy is defined as 1 or more cycles of a planned treatment program. This may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance is considered 1 line of therapy. Autologous and allogenic transplants are permitted.
5.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 X the upper limit of the normal range (ULN).
•Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN.
•Calculated creatinine clearance ≥ 30 mL/min
NOTE: Patients with creatinine clearance of 30 to 50 mL/min will receive lenalidomide at a reduced dose (10 mg), which may subsequently be increased if well tolerated and no response.
6.ECOG performance status of 0, 1, or 2.
7.Patients who received prior allogenic transplant must have no active graft-versus-host disease (GVHD).
8.Female patients who:
•Are postmenopausal for at least 24 months 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 at least 28 days before starting study drug through 30 days after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse, AND
•Must also adhere to the guidelines of the lenalidomide pregnancy prevention program:
Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, 1 highly effective method and 1 additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
•Agree to completely abstain from heterosexual intercourse, OR
•Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment if their partner is of childbearing potential, even if they have had a successful vasectomy, AND
•Must also adhere to the guidelines of the lenalidomide pregnancy prevention program.
9.Must be able to take concurrent aspirin 325 mg daily (or enoxaparin 40 mg subcutaneously daily [or its equivalent] if allergic to aspirin) as prophylactic anticoagulation.
NOTE: For patients with prior history of DVT, low molecular weight heparin (LMWH) is mandatory.
10.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.
11.Patient is willing and able to adhere to the study visit schedule and other protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Patient was refractory to lenalidomide or proteasome inhibitor-based therapy at any line.
NOTE: Refractory disease defined as disease progression on treatment or
progression within 60 days after the last dose of a given therapy. Patients who progress after 60 days from the last dose of a given therapy will be considered relapsed and are eligible for inclusion in the study. Patients who were refractory to thalidomide-based therapy are eligible.
2. Female patients who are lactating or pregnant.
3. Failure to have fully recovered (ie, < Grade 1 toxicity) from the effects of prior chemotherapy regardless of the interval since last treatment.
4. Major surgery within 14 days before randomization.
5. Radiotherapy within 14 days before randomization.
6. Central nervous system involvement.
7. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before randomization.
8. 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.
9. 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.
10. 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.
11. Ongoing or active systemic infection, active hepatitis B virus infect, active hepatitis C infection, or known human immunodeficiency virus (HIV) positive.
12. 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.
13. Psychiatric illness/social situation that would limit compliance with study requirements.
14. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
15. 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.
16. Diagnosed or treated for another malignancy within 2 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. |
|
| 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 international myeloma working group (IMWG) criteria as evaluated by an independent review committee (IRC), or death due to any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 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 international myeloma working group (IMWG) criteria as evaluated by an independent review committee (IRC), or death due to any cause, whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
- OS, measured as the time from the date of randomization to the date of death
- OS in high-risk patients carrying del(17) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS, measured as the time from the date of randomization to the date of death in high risk patients carrying del(17) |
|
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 107 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| 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
|
| Patients will be considered to have completed the study if they are followed until death or until the sponsor terminates the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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