| 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) |
|
| 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)
|
|
| 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), 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)
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, 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 |
|
| 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 IMGW 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 | 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 | 7 |
| 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 |
| Czechia |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| 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
|
The study will be considered complete after the third interim analysis (if OS endpoints are met) or after the final analysis for OS has been completed or the study has been terminated by the sponsor. Patients remaining on study after the final analysis will be assessed for either access to commercial drug supply (if available and reimbursable in
their region) or continued treatment in another extension or rollover study, if and when such a study is made available. |
|
| 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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