Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma

NCT01335685 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C160062010-023772-71
• Study Type: interventional
• Target: 61
• Locations: 5 countries
• Sites: 20

Brief Summary

The purpose of this phase 1/2, open-label study was to evaluate the effect of oral formulation of Ixazomib when added to standard melphalan and prednisone (MP) treatment. Both phases of the study included participants who had newly diagnosed multiple myeloma and were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years of age) or coexisting conditions and for whom standard MP treatment was indicated.

Conditions

Multiple Myeloma

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)

  The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).

  Cycle 1, phase 1 (Up to 42 days)

• Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)

  VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) \< 5% plasma cells in bone marrow. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hour.

  Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)

Secondary Outcomes (17)

• Maximum Inhibition Rate (Emax) (Phase 1)

  At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

• Time of Occurrence of Emax (TEmax) (Phase 1)

  At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

• Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)

  Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)

  Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

• AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)

  Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Study Arms (8)

Arm A: Ixazomib 3.0 mg

EXPERIMENTAL

Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles \[34 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm A: Ixazomib 3.7 mg

EXPERIMENTAL

Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles \[21 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm B: Ixazomib 3.0 mg

EXPERIMENTAL

Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles \[25 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm B: Ixazomib 4.0 mg

EXPERIMENTAL

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles \[58 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm B: Ixazomib 5.5 mg

EXPERIMENTAL

Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m\^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles \[24 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm C: Ixazomib 3.0 mg

EXPERIMENTAL

Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m\^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles \[40 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm C: Ixazomib 4.0 mg

EXPERIMENTAL

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles \[24 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Arm D: Ixazomib 4.0 mg

EXPERIMENTAL

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m\^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m\^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles \[38 months\]).

Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone

Interventions

Ixazomib DRUG

Ixazomib capsules

Arm A: Ixazomib 3.0 mg; Arm A: Ixazomib 3.7 mg; Arm B: Ixazomib 3.0 mg; Arm B: Ixazomib 4.0 mg; Arm B: Ixazomib 5.5 mg; Arm C: Ixazomib 3.0 mg; Arm C: Ixazomib 4.0 mg; Arm D: Ixazomib 4.0 mg

Melphalan DRUG

Melphalan tablets

Arm A: Ixazomib 3.0 mg; Arm A: Ixazomib 3.7 mg; Arm B: Ixazomib 3.0 mg; Arm B: Ixazomib 4.0 mg; Arm B: Ixazomib 5.5 mg; Arm C: Ixazomib 3.0 mg; Arm C: Ixazomib 4.0 mg; Arm D: Ixazomib 4.0 mg

Prednisone DRUG

Prednisone tablets

Arm A: Ixazomib 3.0 mg; Arm A: Ixazomib 3.7 mg; Arm B: Ixazomib 3.0 mg; Arm B: Ixazomib 4.0 mg; Arm B: Ixazomib 5.5 mg; Arm C: Ixazomib 3.0 mg; Arm C: Ixazomib 4.0 mg; Arm D: Ixazomib 4.0 mg

Eligibility Criteria

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

You may qualify if:

• Is indicated with standard melphalan prednisone (MP) treatment and is not a candidate for high-dose therapy plus stem cell transplantation (HDT-SCT) for 1 of the following reasons: the participant is 65 years of age or older OR the participant is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT
• Is diagnosed with symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage according to standard criteria
• Has measurable disease as specified in study protocol
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Has adequate hematologic, liver, and renal function

You may not qualify if:

• Has peripheral neuropathy that is greater or equal to Grade 2
• Has major surgery or radiotherapy within 14 days before the first dose of study drug
• Has uncontrolled infection requiring systematic antibiotics
• Has diarrhea (\> Grade 1)
• Has prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the participantt)
• Has central nervous system involvement
• Has cardiac status as described in protocol
• Has known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of IXAZOMIB - Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
• Has Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
• Is 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 with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ
• Has serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (20)

Unknown Facility

Lebanon, New Hampshire, United States

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Morgantown, West Virginia, United States

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Vancouver, British Columbia, Canada

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Toronto, Ontario, Canada

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Québec, Canada

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Brno, Czechia

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Prague, Czechia

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Badalona, Spain

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Barcelona, Spain

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Donostia / San Sebastian, Spain

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Madrid, Spain

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Salamanca, Spain

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Seville, Spain

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Bournemouth, United Kingdom

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Brighton, United Kingdom

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Cambridge, United Kingdom

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London, United Kingdom

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Nottingham, United Kingdom

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Oxford, United Kingdom

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Uxbridge, United Kingdom

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Related Publications (1)

• San-Miguel JF, Echeveste Gutierrez MA, Spicka I, Mateos MV, Song K, Craig MD, Blade J, Hajek R, Chen C, Di Bacco A, Estevam J, Gupta N, Byrne C, Lu V, van de Velde H, Lonial S. A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma. Haematologica. 2018 Sep;103(9):1518-1526. doi: 10.3324/haematol.2017.185991. Epub 2018 Jun 28.

  PMID: 29954932 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ixazomib; Melphalan; Prednisone

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)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

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 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2011
• First Posted: April 14, 2011
• Study Start: June 27, 2011
• Primary Completion: December 29, 2016
• Study Completion: December 29, 2016
• Last Updated: January 23, 2018
• Results First Posted: January 23, 2018

Record last verified: 2017-12

Locations

ES (6); CA (3); GB (7); CZ (2); US (2)