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

NCT01564537 | Completed Phase 3 Results DMC FDA Drug

• 9 other identifiers: C160102011-005496-17CTR20130908U1111-1164-7646NL40132.018.1212/LO/0949JapicCTI-1323451015042370C16010CTIL
• Study Type: interventional
• Target: 722
• Locations: 2 countries
• Sites: 24

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).

Conditions

Relapsed Multiple Myeloma; Refractory Multiple Myeloma

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)

  Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurs first. Response including PD was assessed by independent review committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. PD requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl); Urine M-component (absolute increase ≥ 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 10 mg/dl); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease. Status evaluated every 4 weeks until disease progression (PD) was confirmed.

  From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months)

Secondary Outcomes (14)

• Overall Survival (OS)

  From date of randomization until death (up to approximately 97 months)

• Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)]

  From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

• Overall Response Rate (ORR) as Assessed by the IRC

  Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months(approximate median follow-up 15 months)

• Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC

  Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

• Duration of Response (DOR)

  Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 38 months

Study Arms (2)

Ixazomib + Lenalidomide + Dexamethasone

EXPERIMENTAL

Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) up to approximately 42.9 months.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Placebo + Lenalidomide + Dexamethasone

PLACEBO COMPARATOR

Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to approximately 41 months.

Drug: Lenalidomide; Drug: Dexamethasone; Drug: Placebo

Interventions

Ixazomib DRUG

Ixazomib capsules

Also known as: MLN9708, NINLARO®

Ixazomib + Lenalidomide + Dexamethasone

Lenalidomide DRUG

Lenalidomide capsules

Ixazomib + Lenalidomide + Dexamethasone; Placebo + Lenalidomide + Dexamethasone

Dexamethasone DRUG

Dexamethasone tablets

Ixazomib + Lenalidomide + Dexamethasone; Placebo + Lenalidomide + Dexamethasone

Placebo DRUG

Ixazomib placebo-matching capsules

Placebo + Lenalidomide + Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants 18 years of age or older.
• 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.
• 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.
• 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.
• 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.

You may not qualify if:

• Was refractory to lenalidomide or proteasome inhibitor-based therapy at any line.
• Participants who were refractory to thalidomide-based therapy were eligible.
• Female participants who were breast feeding or pregnant.
• 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.
• Major surgery within 14 days before randomization.
• Radiotherapy within 14 days before randomization.
• Central nervous system involvement.
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before randomization.
• 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.
• 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.
• 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.
• Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus positive.
• 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).
• Psychiatric illness/social situation that would limit compliance with study requirements.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

Sponsors & Collaborators

• Takeda: lead

Study Sites (24)

University of Arkansas Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

Pacific Cancer Medical Center Inc

Anaheim, California, 92801, United States

Location

West Contra Costa Healthcare District

Berkeley, California, 94704, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Cancer & Blood Disease Center

Lecanto, Florida, 34461, United States

Location

Northwest Georgia Oncology Center

Marietta, Georgia, 30060, United States

Location

John H. Stroger, Jr. Hospital of Cook County

Chicago, Illinois, 60612, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 2215, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 7601, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Blood and Cancer Clinic

Fayetteville, North Carolina, 28303, United States

Location

Scranton Hematology Oncology

Scranton, Pennsylvania, 18510, United States

Location

MUSC Hollings Cancer Center

Charleston, South Carolina, 29425, United States

Location

Fred Hutchinson Cancer Research

Seattle, Washington, 98109, United States

Location

West Virginia University Hospitals and Clinic

Morgantown, West Virginia, 26506-9300, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N 4N2, Canada

Location

Cross Cancer Institute

Edmonton, Alberta, T6G 1Z2, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, V5Z 1M9, Canada

Location

Saint John Regional Hospital

Saint John, New Brunswick, E2L 4L2, Canada

Location

CHUM Notre-Dame Hospital

Montreal, Quebec, H2L 4M1, Canada

Location

MUHC Glen Site Cedars Cancer Centre

Montreal, Quebec, H4A 3J1, Canada

Location

Related Publications (8)

• 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.

  PMID: 34111952 DERIVED

• 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.

  PMID: 32145111 DERIVED

• 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.

  PMID: 29054911 DERIVED

• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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Related Links

• Related Info

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ixazomib; Lenalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Study Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2012
• First Posted: March 28, 2012
• Study Start: August 1, 2012
• Primary Completion: October 1, 2014
• Study Completion: February 8, 2022
• Last Updated: March 10, 2023
• Results First Posted: January 27, 2016

Record last verified: 2023-02

Locations

US (18); CA (6)