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: 10 December 2019
• Main ID: EUCTR2011-005496-17-ES
• Date of registration: 29/05/2012
• 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: 01/08/2012
• Target sample size: 703
• Recruitment status: Authorised-recruitment may be ongoing or finished
• 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: no; 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, 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:
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

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.


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

Health Condition(s) or Problem(s) studied

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

Relapsed and/or Refractory Multiple Myeloma
MedDRA version: 14.1 Level: PT Classification code 10028228 Term: Multiple myeloma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: MLN9708
Pharmaceutical Form: Capsule
INN or Proposed INN: MLN9708
CAS Number: 1239908-20-3
Concentration unit: mg/g milligram(s)/gram
Concentration type: equal
Concentration number: 2.3-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: MLN9708
Pharmaceutical Form: Capsule
INN or Proposed INN: MLN9708
CAS Number: 1239908-20-3
Concentration unit: mg/g milligram(s)/gram
Concentration type: equal
Concentration number: 3.0-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: MLN9708
Pharmaceutical Form: Capsule
INN or Proposed INN: MLN9708
CAS Number: 1239908-20-3
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)

Secondary Objective: -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)

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

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

Main Objective: 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)

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)

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)

Secondary ID(s)

2011-005496-17-DE

C16010

Source(s) of Monetary Support

Millennium Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date:
Contact: