Clinical trial NCT01217957: A Study of Ixazomib Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma
Official title: An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Second-Generation Proteasome Inhibitor, Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-10-08
Enrollment: 65
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 Phase 1 of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral ixazomib administered in combination with lenalidomide and low-dose dexamethasone in participants with newly diagnosed multiple myeloma (NDMM). The purpose of Phase 2 of this study was to determine the overall response rate (ORR) and further evaluate the tolerability and toxicity of the combination of oral ixazomib, lenalidomide, and low-dose dexamethasone in patients with NDMM.

Detailed description: The drug being tested in this study is called ixazomib. Ixazomib was being tested to treat people who had newly diagnosed multiple myeloma who had not previously received systemic treatment. This study was conducted in two Phases. Phase 1 looked at side effects and lab results in people who took ixazomib to determine the MTD and RP2D. Phase 2 looked at overall response rates and side effects in people who took ixazomib.

The study enrolled 15 patients in Phase 1 and 50 patients in Phase 2. Participants in Phase 1 were assigned to cohorts and received ixazomib 1.68, 2.23, 2.97, or 3.95 mg/m\^2 in addition to dexamethasone 40 mg and lenalidomide 25 mg. Participants in Phase 2 received ixazomib 4.0 mg fixed dose in addition to dexamethasone 40 mg and lenalidomide 25 mg. In both Phases study treatment was administered in 28-day Cycles as follows: ixazomib Days 1, 8 and 15, dexamethasone Days 1, 8, 15 and 22, and lenalidomide 25 mg Days 1 through 21.

This multi-center trial was conducted in the United States. The overall time to participate in this study was 12, 28-day cycles with the option to continue into a maintenance portion in the absence of disease progression or unacceptable toxicity. Participants made multiple visits to the clinic and a final visit 30 days after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

Each patient must meet all of the following eligibility criteria to be enrolled in the study:

* Male or female patients 18 years or older
* Previously untreated multiple myeloma diagnosed according to standard criteria requiring systemic treatment
* Patients must have measurable disease
* Nonsecretory multiple myeloma based upon standard M-component criteria (i.e., measurable serum/urine M-component) is not allowed unless the baseline serum free light chain level (Freelite™) is evaluated Patients must meet clinical laboratory criteria as specified in study protocol
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
* Female and male patients 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

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

* 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
* Serious infection requiring systemic antibiotic therapy within 14 days before the first dose of study drug
* Diarrhea greater than Grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events
* Central nervous system involvement.
* Evidence of current uncontrolled cardiovascular conditions within the past 6 months
* 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 gastrointestinal condition that could interfere with swallowing or the oral absorption or tolerance of ixazomib
* No other prior malignancy within 2 years except nonmelanoma skin cancer or carcinoma in situ of any type if they have undergone complete resection

Primary outcomes:
measure: Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability
timeFrame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)
measure: Phase 2: Objective Response Rate (ORR) Following Treatment With the Combination Of Oral Ixazomib, Lenalidomide And Low-Dose Dexamethasone
timeFrame: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)
measure: Phase 1: Recommended Phase 2 Dose of Ixazomib Given in Combination With Lenalidomide and Low-Dose Dexamethasone
timeFrame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)
measure: Phase 1: Maximum Tolerated Dose (MTD) of Ixazomib Administered Weekly in Combination With Lenalidomide and Low-Dose Dexamethasone
timeFrame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)
measure: Phase 2: Percentage of Participants With Grade 3 or Higher AEs, SAEs and Treatment Discontinuation
timeFrame: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)
Secondary outcomes:
measure: Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib
timeFrame: Cycle 1, Days 1 and 15
measure: Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib
timeFrame: Cycle 1, Days 1 and 15
measure: Phase 1: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib
timeFrame: Cycle 1, Days 1 and 15
measure: Phase 1: Rac: Accumulation Ratio of Ixazomib
timeFrame: Cycle 1, Day 15
measure: Phase 1: Emax: Maximum Observed Inhibition of Whole Blood 20S Proteasome
timeFrame: Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose
measure: Phase 1: TEmax: Time to the Maximum Observed Inhibition of Whole Blood 20S Proteasome
timeFrame: Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose
measure: Phase 2: Time to Progression (TTP)
timeFrame: From the first dose of study treatment to the date of first documented progressive disease (Up to 787 days)
measure: Phase 2: Overall Survival (OS)
timeFrame: From the first dose of study treatment to the date of death (up to 787 days)
measure: Phase 2: Overall Response Rate (ORR)
timeFrame: Up to 787 days
measure: Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR)
timeFrame: After Cycles 3, 6 and 9 (Up to 787 days)
measure: Phase 2: Percentage of Participants With Complete Response (CR), Stringent Complete Response (sCR), Very Good Partial Response (VGPR), Near Complete Response (nCR), Partial Response (PR) and Minimal Response (MR)
timeFrame: Cycles 3, 6, 9 and 12 (Up to 787 days)
measure: Phase 2: Time to Best Response
timeFrame: Up to 787 days
measure: Phase 2: Duration of Response (DOR)
timeFrame: Up to 787 days
measure: Phase 2: Progression Free Survival (PFS)
timeFrame: Up to 787 days
measure: Phase 2: 1 Year Survival Rate
timeFrame: 1 year after first dose of study drug
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center Rose
state: Colorado
city: Southington
country: United States
facility: Cancer Center of Central Connecticut
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami Beach
country: United States
facility: Mt Sinai Medical Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: Harry and Jeannette Weinberg Cancer Center at Franklin Square Hospital
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: New York Presbyterian Hospital - Weill-Cornell
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Morgantown
country: United States
facility: W VA University Mary Babb Randolph Cancer Center
state: West Virginia
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin, Inc.
state: Wisconsin
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-1512. doi: 10.1016/S1470-2045(14)71125-8. Epub 2014 Nov 14.