Study of Oral Ixazomib in Adult Participants With Relapsed and/or Refractory (RR) Multiple Myeloma

Relapsed and Refractory Multiple Myeloma Clinical Trial

Official title:

An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Form of Ixazomib (MLN9708), a Second-Generation Proteasome Inhibitor, in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00932698
• Other study ID #: C16003
• Secondary ID: U1111-1177-7936
• Status: Completed
• Phase: Phase 1
• Start date: October 12, 2009
• Est. completion date: May 23, 2017

Study information

• Verified date: June 2019
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will determine the safety profile, tolerability, and maximum tolerated dose (MTD) and disease response of Ixazomib administered orally in participants with relapsed and/or refractory multiple myeloma.

Description:

The drug being tested in this study is ixazomib. Ixazomib is being tested to treat people who have multiple myeloma. This study will look at the safety and efficacy of ixazomib and will enroll approximately 60 participants.

Participants will receive ixazomib by oral capsule twice weekly on Days 1, 4, 8, and 11 of a 21-day cycle. The study will consist of a dose escalation phase to determine the MTD, followed by an expansion phase in which participants will be treated at the MTD.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 8 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: May 23, 2017
• Est. primary completion date: June 20, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

• Multiple myeloma diagnosed according to the standard criteria.

• Participants with multiple myeloma who have relapsed following at least 2 lines of therapy.

• Participants must have measurable disease.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.

• Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse.

• Voluntary written consent.

• Suitable venous access for study-required blood sampling.

Exclusion Criteria:

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

• Peripheral neuropathy greater than or equal to (>=) Grade 2.

• Female participants who are lactating or have a positive serum pregnancy test during the screening period.

• Major surgery within 14 days before the first dose of study drug.

• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.

• Life-threatening illness unrelated to cancer.

• Diarrhea > Grade 1, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) categorization.

• Systemic antineoplastic or radiation therapy within 14 days of cytotoxic agents within 21 days before the first dose of study treatment.

• 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 medication.

• Ongoing therapy with corticosteroids greater than 10mg of prednisone or its equivalent per day. Inhaled and topical steroids are permitted.

• 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.

• Corrected QT interval (QTc) > 470 milliseconds on a 12-lead electrocardiogram (ECG) obtained during the screening period.

• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.

• Any 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.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Relapsed and Refractory Multiple Myeloma

Intervention

Drug:
• Ixazomib
Ixazomib capsules

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	M.D. Anderson Cancer Center	Houston	Texas
United States	H. Lee Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Millennium Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death;is life-threatening;requires inpatient hospitalization or prolongation of present hospitalization;results in persistent or significant disability/incapacity;is a congenital anomaly/birth defect;or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.	From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Primary	Number of Participants With Clinically Significant Abnormalities Reported as TEAEs	The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis.	From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Primary	Number of Participants With a TEAE of Peripheral Neuropathy	Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.	From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Primary	Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs	The number of participants with any clinically significant changes in vital signs collected throughout the study that were reported as TEAEs. Measurement of vital signs, included oral temperature, blood pressure, and heart rate.	From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Primary	Maximum Tolerated Dose (MTD) of Ixazomib	MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT was 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 (platelets < 25,000/mm^3) 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; Grade 3 QTc prolongation (QTc >500 millisecond [msec]);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 >2 weeks; other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation.	Cycle 1 (21 days)
Primary	Recommended Phase 2 Dose (RP2D) of Ixazomib	The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic data observed in Cycle 1 and beyond.	Cycle 1 through Cycle 39 (Up to 28.3 months)
Secondary	Cmax: Maximum Observed Plasma Concentration for Ixazomib		Cycle 1, Days 1 and 11: Predose and at multiple time points (up to 264 hours) postdose
Secondary	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib		Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Secondary	AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib		Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Secondary	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: Predose and at multiple time points (Up to 72 hours) postdose
Secondary	?z: Terminal Disposition Phase Rate Constant for Ixazomib		Cycle 1, Day 11: predose and at multiple time points (Up to 264 hours) postdose
Secondary	T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib		Cycle 1, Day 11: predose and at multiple time points (up to 264 hours) postdose
Secondary	CL/F: Blood Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Ixazomib	CL/F is apparent clearance of the drug from the plasma.	Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Secondary	Emax: Maximum Observed Effect for Ixazomib	Emax was determined to characterize the whole blood 20S proteasome inhibition parameters.	Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Secondary	TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib	TEmax was determined to characterize the whole blood 20S proteasome inhibition parameters.	Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Secondary	Overall Response Rate (ORR)	ORR is defined as percentage of participants with complete response (CR) or partial response (PR) or minimal response (MR) as assessed by the investigator using International Myeloma Working Group Uniform Response criteria. CR=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. PR==50% reduction of serum M-protein and reduction in 24-h urinary M-protein by =90% or to <200 mg /24 h. MR=25-49% reduction in the serum monoclonal paraprotein maintained for a minimum of 6 weeks; 50-89% reduction in 24-h urinary light chain excretion, which still exceeds 200 mg/24 h, maintained for a minimum of 6 weeks; for participants with non-secretory myeloma only, 25-49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks; 25-49% reduction in the size of soft tissue plasmacytomas; no increase in the size or number of lytic bone lesions.	Cycle 1 through Cycle 115 (Up to 80.1 months)