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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Ixazomib citrate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.24 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 0.48 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 0.80 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 1.20 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 1.68 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 2.23 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 2.97 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: 3.95 mg/m^2<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: Relapsed and Refractory (RR)<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: VELCADE-Relapsed (VR)<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: PI naïve<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Experimental: Carfilzomib<br>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<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Terminal Elimination Rate Constant (λz) for MLN2238 | Terminal elimination rate constant (λz) 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 | 
| 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 | 
| 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 | 
| TEmax: Time of Occurrence of Emax |  | Days 1 and 15 of Cycle 1 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed multiple myeloma, Refractory multiple myeloma, Drug therapy