Clinical trial NCT00963820: Study Evaluating the Safety and Tolerability of Weekly Dosing of Oral IXAZOMIB in Adult Patients With Relapsed and Refractory Multiple Myeloma
Official title: An Open-Label, Dose-Escalation, Phase 1 Study Evaluating the Safety and Tolerability of Weekly Dosing of the Oral Form of MLN9708, a Second-Generation Proteasome Inhibitor, in Adult Patients With Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: Relapsed multiple myeloma
Refractory multiple myeloma
Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-08-24
Enrollment: 60
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 primary objective of this study is to determine the safety profile, tolerability, and maximum tolerated dose of ixazomib citrate (MLN9708) when taken orally on a weekly dosing schedule by patients with relapsed and refractory multiple myeloma (RRMM). Secondary objectives include pharmacokinetics and response rates.

Detailed description: The drug being tested in this study is called ixazomib citrate (MLN9708). Ixazomib citrate is being tested for people who have multiple myeloma who have relapsed after treatment or become unresponsive to treatment.

This study will determine the maximum tolerated dose (MTD) of ixazomib citrate using a dose escalation scheme. Once MTD is established, participants will be enrolled at MTD into one of the 4 expansion cohorts to characterize the safety, tolerability and efficacy of MLN9708. Blood samples for safety labs, hematology, serum chemistry and pharmacokinetic evaluations will be obtained at the timepoints specified. Disease response assessment is to be performed on the first day of every other cycle beginning with Cycle 3.

The study will enroll approximately 60 patients. All participants will receive treatment with ixazomib citrate. This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 60 days, and participants will make 12-16 visits to the clinic for study procedures.

Eligibility criteria: Inclusion Criteria:

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

* Adult patients with multiple myeloma who have relapsed following at least 2 lines of therapy.
* Patients must have measurable disease.
* Appropriate functional status, including the recovery from the effects of prior antineoplastic therapy, and acceptable organ function as described in the protocol.
* Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
* Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse.
* Willing and able to give written informed consent.
* Suitable venous access for study-required blood sampling.

Exclusion Criteria:

* Peripheral neuropathy that is greater or equal to Grade 2.
* Major surgery or, serious infections, or infections that required systemic antibiotic therapy within 14 days before the first dose of study drug.
* Life-threatening illness unrelated to cancer.
* Diarrhea that is greater than Grade 1 as outlined in the protocol
* Systemic antineoplastic or radiation therapy within 14 days or cytotoxic agents, or treatment with any investigational products within 21 days before the first dose of study treatment.
* Treatment with any investigational proteasome inhibitor.
* Systemic treatment with prohibited medications that are outlined in the protocol within 14 days of study treatment.
* Ongoing therapy with corticosteroids greater than 10mg of prednisone or its equivalent per day.
* Central nervous system involvement.
* Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction 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 (GI) disease or GI procedure that could interfere with the oral absorption of tolerance of IXAZOMIB including difficulty swallowing.

Primary outcomes:
measure: Number of Participants Reporting One or More Treatment-Emergent Adverse Events and Serious Adverse Events
timeFrame: From the first dose through 30 days after last dose of ixazomib citrate or until the start of subsequent antineoplastic therapy (Up to 354 days)
measure: Neurotoxicity Grading
timeFrame: Cycle 1 Day 1 and End of Study (Up to 354 days)
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for MLN2238
timeFrame: Days 1 and 15 of Cycle 1
measure: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for MLN2238
timeFrame: Days 1 and 15 of Cycle 1
measure: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for MLN2238
timeFrame: Days 1 and 15 of Cycle 1
measure: Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238
timeFrame: Day 15 of Cycle 1
measure: Terminal Elimination Rate Constant (λz) for MLN2238
timeFrame: Day 15 of Cycle 1
measure: Terminal Phase Elimination Half-life (T1/2) for MLN2238
timeFrame: Day 15 of Cycle 1
measure: Emax: Maximum Inhibition
timeFrame: Days 1 and 15 of Cycle 1
measure: TEmax: Time of Occurrence of Emax
timeFrame: Days 1 and 15 of Cycle 1
measure: Overall Response to Treatment With Ixazomib Citrate Based on Investigator's Evaluation Over Time
timeFrame: Up to 354 days
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic- Scottsdale
state: Arizona
city: West Hollywood
country: United States
facility: James R. Berenson, MD, Inc
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Weill-Cornell Medical College
state: New York
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
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, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55. doi: 10.1182/blood-2014-01-548941. Epub 2014 Jun 5.