| 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 | 21.0 |
| 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 ixazomib to the background
therapy of lenalidomide and dexamethasone improves progression-free
survival (PFS) in patients with relapsed and/or refractory multiple
myeloma (RRMM)
The objective has been met. Upon implementation of Amendment 8, the
objective is to continue to collect long-term safety data from patients
who are continuing on ixazomib (MLN9708) and LenDex or LenDex (note
the placebo capsule will be discontinued) because of continuing clinical
benefit. Data collection for all other study objectives will be complete at
the time of the final analysis and no further formal analyses will be
conducted. The original lists of objectives are retained for reference
only. |
|
| E.2.2 | Secondary objectives of the trial |
-To determine whether the addition of oral ixazomib to lenalidomide and dexamethasone improves overall survival (OS)
- To determine whether the addition of oral ixazomib to lenalidomide and dexamethasone improves the OS in high-risk patients carrying deletion del(17)
The objective has been met. Upon implementation of Amendment 8, the
objective is to continue to collect long-term safety data from patients
who are continuing on ixazomib (MLN9708) and LenDex or LenDex (note
the placebo capsule will be discontinued) because of continuing clinical
benefit. Data collection for all other study objectives will be complete at
the time of the final analysis and no further formal analyses will be
conducted. The original lists of objectives are retained for reference
only. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For a detail list of all inclusion criteria please refer to protocol section 5.1
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.
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).
•Patients who were relapsed from at least 1 previous treatment AND additionally were refractory to at least 1 previous treatment.
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 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.
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
Females of childbearing potential (FCBP – see Section 6.9 for definition) must:
1. Have a negative 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
2. 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 study drug through 90 days after the last dose of study
treatment
3. Agree to ongoing pregnancy testing
4. Adhere to the guidelines of the RevAssist program (United States [US] participants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMate program (Japanese participants) or 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 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), iAccess program (Australian participants),MLN9708 Clinical Study Protocol C16010 Amendment 1 Confidential 51RevMate program (Japanese participants) or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the study Manual (all other participants who are not using commercial supplies)
9. Must be able to take concurrent aspirin 81 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.
10.Voluntary written consent must be given before performance of any study related procedure not part of standard 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 (except for alopecia) 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 or C 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 (eg, peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause).
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) condition 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 IMWG criteria as evaluated by an independent review committee (IRC), or death due to any
cause, whichever occurs first
The endpoint has been met. Upon implementation of Amendment 8,
evaluation of the safety profile of MLN9708 and/or LenDex is the only
endpoint being assessed. Analysis of all other study endpoints will be
complete at the final analysis and no further formal statistical analyses
will be performed. However, the complete list of endpoints is retained
for reference. |
|
| 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 firstdocumentation of disease progression based on central laboratory results and IMWG
criteria as evaluated by an independent review committee (IRC), or death due to any
cause, whichever occurs first
The endpoint has been met. Upon implementation of Amendment 8,
evaluation of the safety profile of MLN9708 and/or LenDex is the only
endpoint being assessed. Analysis of all other study endpoints will be
complete at the final analysis and no further formal statistical analyses
will be performed. However, the complete list of endpoints is retained
for reference. |
|
| 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)
The endpoint has been met. Upon implementation of Amendment 8,
evaluation of the safety profile of MLN9708 and/or LenDex is the only
endpoint being assessed. Analysis of all other study endpoints will be
complete at the final analysis and no further formal statistical analyses
will be performed. However, the complete list of endpoints is retained
for reference. |
|
| 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)
The endpoint has been met. Upon implementation of Amendment 8,
evaluation of the safety profile of MLN9708 and/or LenDex is the only
endpoint being assessed. Analysis of all other study endpoints will be
complete at the final analysis and no further formal statistical analyses
will be performed. However, the complete list of endpoints is retained
for reference. |
|
| 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 | 8 |
| 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 |
| Brazil |
| Canada |
| China |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Russian Federation |
| Singapore |
| Taiwan |
| Thailand |
| Turkey |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
Upon implementation of Amendment 8 patients will no longer be
followed during any of the FUP periods, as PFS and OS data are
not being collected. The end of study will be considered if they
complete study treatment. Patients will attend an EOT visit 30 days (+1
week) after receiving their last dose of the study drug regimen unless
next-line therapy is started before 30 days after the last dose of study
drug in which case the EOT visit should occur before the start of the
next-line therapy |
|
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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