Clinical trial NCT01383928: Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma
Official title: An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Formulation of IXAZOMIB (MLN9708), Administered Twice-weekly in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-06-28
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Detailed description: The drug being tested in this study is called ixazomib. Ixazomib was tested to slow disease progression and improve overall survival in participants who have newly diagnosed multiple myeloma (NDMM). This study looked at the safety, tolerability and response in participants when administered in combination with lenalidomide and low-dose dexamethasone.

The study enrolled 64 patients. Participants were assigned to one of the 3 treatment groups:

* Phase 1 Ixazomib 3 mg
* Phase 1 Ixazomib 3.7 mg
* Phase 2 Ixazomib 3 mg

All participants were administered with Ixazomib capsules, orally, twice-weekly on Days 1, 4, 8, and 11 along with lenalidomide capsules, orally, once daily on Days 1-14 and dexamethasone, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 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 capsules, orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.

This multi-center trial conducted in the United States. The overall time to participate in this study was 2037 days. Participants will make multiple visits to the clinic, and a final visit after 30 days after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria

* 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
* 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

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose (MTD)
timeFrame: Cycle 1 (21 days)
measure: Phase 1: Recommended Phase 2 Dose (RP2D)
timeFrame: Cycle 1 (21 days)
measure: Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)
timeFrame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
measure: Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
measure: Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity
timeFrame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
measure: Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
measure: Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events
timeFrame: Baseline up to 30 days after the last dose of study drug (approximately 1905 days)
measure: Phase 2: Percentage of Participants Experiencing Serious Adverse Events
timeFrame: Baseline up to 30 days after the last dose of study drug (approximately 1905 days)
measure: Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation
timeFrame: Baseline up to 30 days after the last dose of study drug (approximately 1905 days)
Secondary outcomes:
measure: Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib
timeFrame: Cycle 1, Days 1 and 11
measure: Phase 1: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib
timeFrame: Cycle 1, Days 1 and 11
measure: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
timeFrame: Cycle 1, Days 1 and 11
measure: Phase 1: Rac: Accumulation Ratio of Ixazomib
timeFrame: Cycle 1, Days 1 and 11
measure: Phase 1: Percentage of Participants With Best Overall Response
timeFrame: Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)
measure: Phase 2: Percentage of Participants With Overall Response (CR+VGPR+PR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) After Cycles 4, 8, and 16
timeFrame: Cycles 4, 8, and 16
measure: Phase 2: Percentage of Participants With Complete Response (CR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Stringent Complete Response (sCR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Very Good Partial Response (VGPR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Near Complete Response (nCR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Partial Response (PR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Percentage of Participants With Minimal Response (MR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Time to Response
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Phase 2: Duration of Response (DOR)
timeFrame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
measure: Time to Disease Progression (TTP)
timeFrame: Baseline up to a follow-up of 62.1 months
measure: Progression Free Survival (PFS)
timeFrame: Baseline up to a follow-up of 62.1 months
measure: Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Year 1
timeFrame: 1 year after the first dose of study treatment
measure: Overall Survival
timeFrame: Baseline up to a follow-up of 62.1 months
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: UCSF Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Rockville
country: United States
facility: Associates of Oncology/Hematology PC
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Toledo
country: United States
facility: Mercy St Anne Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: SCRI Tennessee Oncology Nashville
state: Tennessee
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Care Specialist
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists PC
state: Virginia
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: