Study Evaluating the Safety and Tolerability of Weekly Dosing of Oral IXAZOMIB in Adult Patients With Relapsed and Refractory Multiple Myeloma

NCT00963820 | Completed Phase 1 Results

• 2 other identifiers: C16004U1111-1166-8401
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 6

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.

Conditions

Multiple Myeloma

Keywords

Relapsed multiple myeloma; Refractory multiple myeloma; Drug therapy

Outcome Measures

Primary Outcomes (2)

• Number of Participants Reporting One or More Treatment-Emergent Adverse Events and Serious Adverse Events

  An Adverse Event 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 (eg, 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) was any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

  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)

• Neurotoxicity Grading

  Neurotoxicity is graded using participant responses to 11 functional questions on a 5-point scale, where 0=Not at all and 4=Very much, using the Functional Assessment of Cancer Therapy/Gynecology Oncology Group - Neurotoxicity Questionnaire, Version 4.0(14). Neurotoxicity subscale is a sum of 11 reversed item scores where each original score is transformed as (4 - score). The highest possible score is 44, and a higher score indicates more neurotoxicity.

  Cycle 1 Day 1 and End of Study (Up to 354 days)

Secondary Outcomes (9)

• Cmax: Maximum Observed Plasma Concentration for MLN2238

  Days 1 and 15 of Cycle 1

• Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for MLN2238

  Days 1 and 15 of Cycle 1

• AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for MLN2238

  Days 1 and 15 of Cycle 1

• Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238

  Day 15 of Cycle 1

• Terminal Elimination Rate Constant (λz) for MLN2238

  Day 15 of Cycle 1

Study Arms (12)

0.24 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 0.24 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate

Drug: Ixazomib citrate

0.48 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 0.48 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

0.80 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 0.80 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

1.20 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 1.20 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period.

Drug: Ixazomib citrate

1.68 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 1.68 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

2.23 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 2.23 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

2.97 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 2.97 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

3.95 mg/m^2

EXPERIMENTAL

Ixazomib citrate, 3.95 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

Relapsed and Refractory (RR)

EXPERIMENTAL

Ixazomib citrate, 2.97 mg/m\^2 established Maximum Tolerated Dose (MTD), capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the Relapsed and Refractory (RR) expansion cohort. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

VELCADE-Relapsed (VR)

EXPERIMENTAL

Ixazomib citrate, 2.97 mg/m\^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the VELCADE-relapsed (VR) expansion cohort. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

PI naïve

EXPERIMENTAL

Ixazomib citrate, 2.97 mg/m\^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in expansion cohort of participants who were proteasome inhibitor-naïve (PI naïve). All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

Carfilzomib

EXPERIMENTAL

Ixazomib citrate, 2.97 mg/m\^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the expansion cohort of participants who received their last dose of carfilzomib between 21 and 60 days prior to the first dose of ixazomib citrate. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Drug: Ixazomib citrate

Interventions

Ixazomib citrate DRUG

Ixazomib citrate capsules

Also known as: MLN9708

0.24 mg/m^2; 0.48 mg/m^2; 0.80 mg/m^2; 1.20 mg/m^2; 1.68 mg/m^2; 2.23 mg/m^2; 2.97 mg/m^2; 3.95 mg/m^2; Carfilzomib; PI naïve; Relapsed and Refractory (RR); VELCADE-Relapsed (VR)

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (6)

Mayo Clinic- Scottsdale

Scottsdale, Arizona, 85259, United States

Location

James R. Berenson, MD, Inc

West Hollywood, California, 90069, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Weill-Cornell Medical College

New York, New York, 10011, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (2)

• 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.

  PMID: 28803351 DERIVED

• 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.

  PMID: 24904120 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ixazomib

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

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: August 20, 2009
• First Posted: August 24, 2009
• Study Start: October 1, 2009
• Primary Completion: September 1, 2012
• Study Completion: January 1, 2014
• Last Updated: January 10, 2018
• Results First Posted: August 28, 2015

Record last verified: 2017-12

Locations

US (6)