Phase 2 Study to Evaluate the Oral Combination of Ixazomib (MLN9708) With Cyclophosphamide and Dexamethasone in Patients With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma

NCT02046070 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: C160202013-003113-17U1111-1158-2714
• Study Type: interventional
• Target: 148
• Locations: 5 countries
• Sites: 24

Brief Summary

This is a phase 2, multicenter, open-label study in patients with Newly Diagnosed Multiple Myeloma (NDMM) who have not received prior systemic treatment for multiple myeloma (MM) and who are ineligible for high-dose therapy (HDT)-stem cell transplantation (SCT) due to age (ie, ≥ 65 years) or comorbid disease(s) or with Relapsed and/or Refractory Multiple Myeloma (RRMM).

Conditions

Multiple Myeloma

Keywords

MLN9708; Newly diagnosed; NDMM; IXAZOMIB; RRMM

Outcome Measures

Primary Outcomes (2)

• Combined Response Rate During the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants

  Combined Response Rate is the percentage of participants with Complete Response (CR), including stringent Complete Response (sCR), and Very Good Partial Response (VGPR) according to the International Myeloma Working Group (IMWG) criteria during the Induction Phase (Cycles 1-13, 28-day cycles). CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour.

  Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)

• Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants

  ORR is the percentage of participants with CR, VGPR or PR according to IMWG criteria. CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells (PC) in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved free light chain (FLC) levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas.

  Day 1 of each 28 day cycle (Up to 45 months)

Secondary Outcomes (23)

• Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants

  First dose of study drug through 30 days after last dose of drug (Up to 45 months)

• Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase

  Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)

• Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants

  Day 1 of each 28-day Cycle (Up to 45 months)

• Time to Response (TTR) in NDMM Participants During the Induction Phase

  Up to 1 year

• Duration of Response (DOR) in NDMM Participants

  Up to 45 Months

Study Arms (3)

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)

EXPERIMENTAL

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until progressive disease (PD)/death or unacceptable toxicity \[13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months\] and cyclophosphamide (CYC) 300 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM.

Drug: Cyclophosphamide; Drug: Ixazomib; Drug: Dexamethasone

Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

EXPERIMENTAL

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until PD/death or unacceptable toxicity \[13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months\] and cyclophosphamide (CYC) 400 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM.

Drug: Cyclophosphamide; Drug: Ixazomib; Drug: Dexamethasone

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)

EXPERIMENTAL

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle and cyclophosphamide 300 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle until PD/death or unacceptable toxicity in participants with RRMM.

Drug: Cyclophosphamide; Drug: Ixazomib; Drug: Dexamethasone

Interventions

Cyclophosphamide DRUG

Cyclophosphamide tablets

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM); Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM); Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Ixazomib DRUG

Ixazomib capsules

Also known as: MLN9708

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM); Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM); Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Dexamethasone DRUG

Dexamethasone tablets

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM); Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM); Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Eligibility Criteria

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

You may qualify if:

• Adult male or female participants 18 years of age or older with a confirmed diagnosis of symptomatic multiple myeloma (MM) according to standard criteria.
• Participants for whom cyclophosphamide and dexamethasone treatment is appropriate and who are considered not eligible for high-dose therapy (HDT)-stem cell transplantation (SCT) for 1 or more of the following reasons:
• The participant is 65 years of age or older.
• The participant is less than 65 years of age but has significant comorbid condition(s) that are, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT-SCT.
• Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic MM either currently or at the time of initial diagnosis, according to standard criteria, and relapsed and/or refractory disease after 1 to 3 lines of prior therapy. A participant is considered to have refractory disease if disease progression occurred during the treatment period or within 60 days of receiving the last dose of a given therapy. A line of therapy is defined as 1 or more cycles of a single-agent or combination therapy or a sequence of planned treatments such as induction therapy followed by autologous stem cell transplantation (ASCT) and then maintenance therapy.
• No evidence of graft-versus-host disease for participants who have undergone prior allogeneic stem cell transplantation.
• In addition, all participants (NDMM and RRMM) must meet all of the remaining criteria:
• Participants 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.
• Participants must meet all of 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 are not allowed within 3 days prior to administration of the study drug.
• Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

You may not qualify if:

• Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen (for participants with NDMM only).
• NOTE: Prior treatment with corticosteroids (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is permitted as long as it is below a therapeutic level and administered at least 14 days prior to the first dose of study treatment.
• Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
• Central nervous system involvement.
• Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period.
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
• Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
• Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.
• 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 the first dose of study treatment.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
• Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.)
• Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• 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.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (24)

Unknown Facility

Hazard, Kentucky, United States

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Boston, Massachusetts, United States

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Rochester, Minnesota, United States

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St Louis, Missouri, United States

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New Brunswick, New Jersey, United States

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Rochester, New York, United States

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Camperdown, New South Wales, Australia

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Concord, New South Wales, Australia

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Waratah, New South Wales, Australia

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Adelaide, South Australia, Australia

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Heidelberg, Victoria, Australia

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Melbourne, Victoria, Australia

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Athens, Attica, Greece

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Athens, Greece

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Pátrai, Greece

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Thessaloniki, Greece

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Lublin, Lublin Voivodeship, Poland

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Warsaw, Masovian Voivodeship, Poland

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Chorzów, Poland

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Gdansk, Poland

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Lodz, Poland

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Helsingborg, Skåne County, Sweden

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Stockholm, Södermanland County, Sweden

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Lund, Sweden

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Related Publications (2)

• Dimopoulos MA, Grosicki S, Jedrzejczak WW, Nahi H, Gruber A, Hansson M, Gupta N, Byrne C, Labotka R, Teng Z, Yang H, Grzasko N, Kumar S. All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Eur J Cancer. 2019 Jan;106:89-98. doi: 10.1016/j.ejca.2018.09.011. Epub 2018 Nov 22.

  PMID: 30471652 DERIVED

• Kumar SK, Grzasko N, Delimpasi S, Jedrzejczak WW, Grosicki S, Kyrtsonis MC, Spencer A, Gupta N, Teng Z, Byrne C, Labotka R, Dimopoulos MA. Phase 2 study of all-oral ixazomib, cyclophosphamide and low-dose dexamethasone for relapsed/refractory multiple myeloma. Br J Haematol. 2019 Feb;184(4):536-546. doi: 10.1111/bjh.15679. Epub 2018 Nov 20.

  PMID: 30460684 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Cyclophosphamide; ixazomib; 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)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2013
• First Posted: January 27, 2014
• Study Start: March 5, 2014
• Primary Completion: June 29, 2018
• Study Completion: June 29, 2018
• Last Updated: July 17, 2019
• Results First Posted: July 17, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share

Locations

PL (5); US (6); AU (6); SE (3); GR (4)