Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma

NCT01383928 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C16008U1111-1168-1172
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 20

Brief Summary

The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) in phase 1 and to determine the combined response rate of clinical response CR and very good partial response (VGPR) in phase 2 of oral (PO) ixazomib administered twice-weekly in combination with lenalidomide and low-dose dexamethasone in a 21-day cycle in participants with newly diagnosed multiple myeloma (NDDM).

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (10)

• Phase 1: Maximum Tolerated Dose (MTD)

  MTD was highest dose of ixazomib given with combination drugs, at which \<=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cell per cubic millimeter \[cells/mm\^3\]) for \>7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for \>7 days; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count \<10,000/mm\^3; Grade 2 peripheral neuropathy with pain or \>=Grade 3 peripheral neuropathy; \>=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; any \>=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or \<1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by \>14 days; \<=80% lenalidomide doses administered due to other \>=Grade 2 combination study drug-related nonhematologic toxicities requiring therapy discontinuation.

  Cycle 1 (21 days)

• Phase 1: Recommended Phase 2 Dose (RP2D)

  The RP2D of ixazomib was determined after the evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to analyses of efficacy results, toxicity characterization, all grades peripheral neuropathy, and treatment discontinuation. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).

  Cycle 1 (21 days)

• Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

  Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

• Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

  Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

  Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

• Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity

  TEAE related to neurotoxicity grading based on common terminology criteria for adverse events (CTACE) version 4.03 are reported. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening consequences; urgent intervention indicated; Grade 5= death. Only TEAEs related to neurotoxicity with values are reported.

  Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

• Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs

  Vital signs included body temperature, blood pressure and heart rate.

  Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

• Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR)

  CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as 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 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (\>=)1 g/dL; Urine M-protein \>=200 mg/24 hours; Serum FLC assay level \>=10 mg/dL, provided serum FLC ratio was abnormal.

  Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

• Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. As per Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.

  Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

• Phase 2: Percentage of Participants Experiencing Serious Adverse Events

  A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

  Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

• Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

  Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Secondary Outcomes (19)

• Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib

  Cycle 1, Days 1 and 11

• Phase 1: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib

  Cycle 1, Days 1 and 11

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

  Cycle 1, Days 1 and 11

• Phase 1: Rac: Accumulation Ratio of Ixazomib

  Cycle 1, Days 1 and 11

• Phase 1: Percentage of Participants With Best Overall Response

  Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)

Study Arms (2)

Phase 1: Ixazomib 3 mg or 3.7 mg

EXPERIMENTAL

Ixazomib (MLN9708), orally, twice-weekly in combination with lenalidomide orally and dexamethasone orally as prescribed, in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Phase 2: Ixazomib 3 mg

EXPERIMENTAL

Ixazomib (MLN9708), orally, twice-weekly in combination with lenalidomide orally and dexamethasone orally as prescribed, in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Ixazomib DRUG

Ixazomib capsules

Phase 1: Ixazomib 3 mg or 3.7 mg; Phase 2: Ixazomib 3 mg

Lenalidomide DRUG

Lenalidomide capsules

Phase 1: Ixazomib 3 mg or 3.7 mg; Phase 2: Ixazomib 3 mg

Dexamethasone DRUG

Dexamethasone Tablets

Phase 1: Ixazomib 3 mg or 3.7 mg; Phase 2: Ixazomib 3 mg

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 patients 18 years or older
• Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria
• Measurable disease as specified in study protocol
• Hematologic, liver, and renal function as specified in the study protocol.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program
• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse AND must adhere to the guidelines of the lenalidomide pregnancy prevention program
• Must be able to take concurrent aspirin 325 mg daily
• Voluntary written consent

You may not qualify if:

• Peripheral neuropathy that is greater or equal to Grade 2
• Female patients who are lactating or pregnant
• Major surgery or radiotherapy within 14 days before the first dose of study drug
• Uncontrolled infection requiring systematic antibiotics within 14 days before the first dose of study drug
• Diarrhea (\> Grade 1)
• Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient)
• Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment
• Central nervous system involvement
• Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
• Evidence of current uncontrolled cardiovascular conditions
• Prior or concurrent deep vein thrombosis or pulmonary embolism
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
• Known allergy to any of the study medications
• Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption, or tolerance of IXAZOMIB

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (20)

UCSF Medical Center

Berkeley, California, 94704, United States

Location

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Associates of Oncology/Hematology PC

Rockville, Maryland, 20850, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Michigan State University

Lansing, Michigan, 48910, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Mount Sinai Hospital

New York, New York, 31406, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Mercy St Anne Hospital

Toledo, Ohio, 43623, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

SCRI Tennessee Oncology Nashville

Nashville, Tennessee, 37203, United States

Location

Baylor Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Virginia Cancer Care Specialist

Fairfax, Virginia, 22031, United States

Location

Virginia Cancer Specialists PC

Fairfax, Virginia, 22031, United States

Location

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: 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
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2011
• First Posted: June 28, 2011
• Study Start: October 31, 2011
• Primary Completion: October 13, 2014
• Study Completion: November 27, 2017
• Last Updated: March 21, 2019
• Results First Posted: December 18, 2015

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will share

Locations

US (20)