Clinical trial NCT01564537: A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Participants With Relapsed and/or Refractory Multiple Myeloma
Official title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral Ixazomib (MLN9708) Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-03-28
Enrollment: 722
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether the addition of oral ixazomib to the background therapy of lenalidomide and dexamethasone improves progression free survival (PFS) in participants with relapsed and/or refractory multiple myeloma (RRMM).

Detailed description: The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will look at progression free survival (PFS), overall survival (OS) and safety in participants who take ixazomib in addition to lenalidomide and dexamethasone compared to placebo in addition to lenalidomide and dexamethasone.

The study enrolled 722 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Ixazomib 4 mg + lenalidomide + dexamethasone
* Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient + lenalidomide + dexamethasone

All participants will receive treatment in 28 day cycles until disease progression or unacceptable toxicity.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 80 months. Participants will make multiple visits to the clinic, and will be contacted every 4 weeks for PFS and every 12 weeks for OS.

Eligibility criteria: Inclusion Criteria:

1. Male or female participants 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 have been symptomatic multiple myeloma, although the relapsed disease did not need to be symptomatic.
3. Must have had 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 (FLC) assay: involved FLC level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum FLC ratio was abnormal.
4. Participants with relapsed and/or refractory multiple myeloma (RRMM) who had received 1 to 3 prior therapies.

   NOTE: population included the following 3 categories of participants:
   * Participants who relapsed from their previous treatment(s) but were not refractory to any previous treatment.
   * Participants who were refractory to all lines of previous treatment(s) (ie, participants who had never responded to any therapies received).
   * Participants who 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 was defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy.

   A line of therapy was defined as 1 or more cycles of a planned treatment program. This may have consisted 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 was considered 1 line of therapy. Autologous and allogenic transplants were permitted.
5. Must have met the following clinical laboratory criteria:

   * Absolute neutrophil count (ANC) ≥ 1000/mm\^3 and platelet count ≥ 75,000/mm\^3. Platelet transfusions to help participants meet eligibility criteria were 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: Participants with a low creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min, according to lenalidomide prescribing information/local practice) were to receive a reduced lenalidomide dose of 10 mg once daily (QD) on Days 1 through 21 of a 28-day cycle. The lenalidomide dose may have been escalated to 15 mg QD after 2 cycles if the participant was not responding to treatment and was tolerating the treatment. If renal function normalized (ie, creatinine clearance \>60 mL/min or \>50 mL/min, according to lenalidomide prescribing information/local practice) and the participant continued to tolerate this treatment, lenalidomide may then have been escalated to 25 mg QD.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
7. Participants who received prior allogenic transplant must have had no active graft-versus-host disease.
8. Female participants who:

   * Were postmenopausal for at least 24 months before the screening visit, OR
   * Were surgically sterile, OR
   * If they were of childbearing potential must have: had 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; either agreed to practice true abstinence, when this was in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal were not acceptable methods of contraception.) OR begun 2 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 treatment through 90 days after the last dose of study treatment; and agreed to ongoing pregnancy testing AND must have also adhered 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 were not using commercial supplies).

   Male patients, even if surgically sterilized (ie, status postvasectomy), who:
   * Agreed to practice true abstinence, when this was in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal were not acceptable methods of contraception.) OR
   * Agreed to practice effective barrier contraception during the entire study treatment period and 90 days after the last dose of study treatment if their partner was of childbearing potential, even if they had a successful vasectomy, AND
   * Must have also adhered 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 were not using commercial supplies)
9. Must have been 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.

   NOTE: For participants with prior history of deep vein thrombosis (DVT), low-molecular-weight heparin (LMWH) was mandatory.
10. Voluntary written consent must have been given before performance of any study related procedure not part of standard medical care, with the understanding that consent may have been withdrawn by the participant at any time without prejudice to future medical care.
11. Was willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

1. Was refractory to lenalidomide or proteasome inhibitor-based therapy at any line.

   NOTE: Refractory disease was defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy. Participants who progressed after 60 days from the last dose of a given therapy were considered relapsed and were eligible for inclusion in the study.

   Participants who were refractory to thalidomide-based therapy were eligible.
2. Female participants who were breast feeding 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, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) 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 6 months before randomization in the study.
10. Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2 (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 infection, or known human immunodeficiency virus positive.
12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant 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 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 any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type were not excluded if they had undergone complete resection.

Primary outcomes:
measure: Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)
timeFrame: From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomization until death (up to approximately 97 months)
measure: Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)]
timeFrame: From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)
measure: Overall Response Rate (ORR) as Assessed by the IRC
timeFrame: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months(approximate median follow-up 15 months)
measure: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC
timeFrame: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)
measure: Duration of Response (DOR)
timeFrame: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 38 months
measure: Time to Progression (TTP) as Assessed by the IRC
timeFrame: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the date of signing of the informed consent form through 30 days after the last dose of study drug up to approximately 115 months
measure: Number of Participants With Change From Baseline in Pain Response
timeFrame: Baseline and end of treatment (EOT) (up to approximately 38 months)
measure: Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30)
timeFrame: Baseline, EOT and follow-up (up to approximately 97 months)
measure: Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20)
timeFrame: Baseline, EOT and follow-up (up to approximately 97 months)
measure: OS in High-Risk Participants
timeFrame: From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)
measure: PFS in High-Risk Participants
timeFrame: From date of randomization until disease progression or death up to approximately 38 months (approximate median follow-up 15 months)
measure: Plasma Concentration Over Time for Ixazomib
timeFrame: Pre-dose and post-dose at multiple timepoints up to Cycle 10 Day 1 (each cycle length = 28 days)
measure: Overall Response Rate in Participants Defined by Polymorphism
timeFrame: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas Medical Sciences
state: Arkansas
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center Inc
state: California
city: Berkeley
country: United States
facility: West Contra Costa Healthcare District
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Lecanto
country: United States
facility: Cancer & Blood Disease Center
state: Florida
city: Marietta
country: United States
facility: Northwest Georgia Oncology Center
state: Georgia
city: Chicago
country: United States
facility: John H. Stroger, Jr. Hospital of Cook County
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Fayetteville
country: United States
facility: Blood and Cancer Clinic
state: North Carolina
city: Scranton
country: United States
facility: Scranton Hematology Oncology
state: Pennsylvania
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Hospitals and Clinic
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Montreal
country: Canada
facility: CHUM Notre-Dame Hospital
state: Quebec
city: Montreal
country: Canada
facility: MUHC Glen Site Cedars Cancer Centre
state: Quebec
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Richardson PG, Kumar SK, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Gimsing P, Garderet L, Touzeau C, Buadi FK, Laubach JP, Cavo M, Darif M, Labotka R, Berg D, Moreau P. Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2021 Aug 1;39(22):2430-2442. doi: 10.1200/JCO.21.00972. Epub 2021 Jun 11.
citation: Di Bacco A, Bahlis NJ, Munshi NC, Avet-Loiseau H, Masszi T, Viterbo L, Pour L, Ganly P, Cavo M, Langer C, Kumar SK, Rajkumar SV, Keats JJ, Berg D, Lin J, Li B, Badola S, Shen L, Zhang J, Esseltine DL, Luptakova K, van de Velde H, Richardson PG, Moreau P. c-MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide-dexamethasone in myeloma. Eur J Haematol. 2020 Jul;105(1):35-46. doi: 10.1111/ejh.13405. Epub 2020 Apr 15.
citation: Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. doi: 10.1182/blood-2017-06-791228. Epub 2017 Oct 20.
citation: Gupta N, Yang H, Hanley MJ, Zhang S, Liu R, Kumar S, Richardson PG, Skacel T, Venkatakrishnan K. Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses. Target Oncol. 2017 Oct;12(5):643-654. doi: 10.1007/s11523-017-0524-3.
citation: Mateos MV, Masszi T, Grzasko N, Hansson M, Sandhu I, Pour L, Viterbo L, Jackson SR, Stoppa AM, Gimsing P, Hamadani M, Borsaru G, Berg D, Lin J, Di Bacco A, van de Velde H, Richardson PG, Moreau P. Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1. Haematologica. 2017 Oct;102(10):1767-1775. doi: 10.3324/haematol.2017.170118. Epub 2017 Jul 27.
citation: Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. doi: 10.1186/s13045-017-0501-4.
citation: Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-34. doi: 10.1056/NEJMoa1516282.
citation: Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. doi: 10.1182/blood-2016-01-693580. Epub 2016 Mar 21.