To determine whether adding MLN9708 to the combination of lenalidomide and dexamethasone improves survival in patients with multiple myeloma whose disease is no longer responding or has not responded, to previous treatment.

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2011-005496-17-SE
• Date of registration: 27/06/2012
• Prospective Registration: Yes
• Primary sponsor: Millennium Pharmaceuticals, Inc.
• Public title: To determine whether adding MLN9708 to the combination of lenalidomide and dexamethasone improves survival in patients with multiple myeloma whose disease is no longer responding or has not responded, to previous treatment.
• Scientific title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma
• Date of first enrolment: 23/08/2012
• Target sample size: 703
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005496-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czech Republic, 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

Contacts

• Name: Millennium, Drug Information Call C
• Affiliation: Millennium Pharmaceuticals, Inc.

• Name: Millennium, Drug Information Call C
• Affiliation: Millennium Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

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 commerc
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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsed and/or Refractory Multiple Myeloma
MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Ixazomib 2.3 mg
Product Code: MLN9708 2.3 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.3-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Ixazomib 3.0 mg
Product Code: MLN9708 3.0 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3.0-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Ixazomib 4.0 mg
Product Code: MLN9708 4.0 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4.0-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

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.

Main Objective: 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.

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

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.

Secondary Objective: -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.

Secondary Outcome(s)

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.

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.

Secondary ID(s)

C16010

2011-005496-17-DE

Source(s) of Monetary Support

Millennium Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date: 11/07/2012
Contact: