Multiple Myeloma Clinical Trial
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
Verified date | December 2017 |
Source | Takeda |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 60 |
Est. completion date | January 2014 |
Est. primary completion date | September 2012 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
United States | University of Chicago | Chicago | Illinois |
United States | Weill-Cornell Medical College | New York | New York |
United States | Mayo Clinic | Rochester | Minnesota |
United States | Mayo Clinic- Scottsdale | Scottsdale | Arizona |
United States | Fred Hutchinson Cancer Research Center | Seattle | Washington |
United States | James R. Berenson, MD, Inc | West Hollywood | California |
Lead Sponsor | Collaborator |
---|---|
Millennium Pharmaceuticals, Inc. |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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) | |
Primary | 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 | Cmax: Maximum Observed Plasma Concentration for MLN2238 | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). | Days 1 and 15 of Cycle 1 | |
Secondary | Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for MLN2238 | Tmax: Time to reach the maximum observed plasma concentration (Cmax), equal to time to Cmax. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). | Days 1 and 15 of Cycle 1 | |
Secondary | AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for MLN2238 | AUC(0-168) is a measure of the area under the plasma concentration-time curve over the dosing interval (tau) (AUC[0-tau]), where tau is the length of the dosing interval - 168 hours in this study). MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). | Days 1 and 15 of Cycle 1 | |
Secondary | Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238 | MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). | Day 15 of Cycle 1 | |
Secondary | Terminal Elimination Rate Constant (?z) for MLN2238 | Terminal elimination rate constant (?z) is the rate at which drugs are eliminated from the body and the values were used for calculation of T1/2. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). | Day 15 of Cycle 1 | |
Secondary | Terminal Phase Elimination Half-life (T1/2) for MLN2238 | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). | Day 15 of Cycle 1 | |
Secondary | Emax: Maximum Inhibition | A Whole Blood 20S Proteasome Inhibition Parameter. There were no subjects in the Pharmacodynamic (PD) Analysis Set for the 2.23 mg/m^2 cohort, so PD tables do not include that arm. | Days 1 and 15 of Cycle 1 | |
Secondary | TEmax: Time of Occurrence of Emax | Days 1 and 15 of Cycle 1 | ||
Secondary | Overall Response to Treatment With Ixazomib Citrate Based on Investigator's Evaluation Over Time | Responses were based on International Myeloma Working Group Uniform Criteria. Complete Response (CR)=Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Partial Response (PR)= reduction in M-Protein =50% in serum and =90% in 24-hour urine. If M-protein unmeasurable, =50% decrease in difference of involved and uninvolved Free Light Chain (FLC). If M-protein and FLC unmeasurable, =50% reduction in plasma cells is required, if baseline bone marrow plasma cell =30%. And =50% reduction in the size of soft tissue plasmacytomas. Minimal Response (MR)= 25-49% reduction in serum paraprotein for 6 weeks. 50-89% reduction in 24 hour urinary light chain excretion for 6 weeks. For Non-secretory myeloma patients, 25-49 % reduction in plasma cells in bone marrow and trephine biopsy for a 6 weeks. 25-49% reduction in the size of soft tissue plasmacytomas. No increase in the size or number of lytic bone lesions. |
Up to 354 days |
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