A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies

Study Overview
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Brief Summary
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This is an open-label, multicenter, phase 1, dose escalation study of IXAZOMIB. The primary purpose of this study is to determine the safety profile, establish the maximum tolerated dose, and inform the phase 2 dose of IXAZOMIB administered intravenously in participants with nonhematologic malignancies.

Official Title
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An Open-Label, Dose Escalation, Phase 1 Study of IXAZOMIB (MLN9708), a Second-Generation Proteasome Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

Conditions
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Advanced Non-hematologic Malignancies

Intervention / Treatment
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* Drug: IXAZOMIB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each participant must meet all of the following inclusion criteria to be enrolled in the study: Male or female participants 18 years or older. Eastern Cooperative Oncology Group performance status 0-2. A diagnosis of a nonhematologic malignancy for which standard treatment is no longer effective. In the expanded cohort, enrollment will be limited to participants with a diagnosis of NSCLC, H&N cancer (squamous cell cancer), STS, or PC. Suitable venous access for pharmacokinetic (PK) and pharmacodynamic evaluations. 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 2 effective methods of contraception or abstain from heterosexual intercourse. Voluntary written consent must be obtained. Adequate clinical laboratory values during the screening period. In the escalation portion of the study, radiographically or clinically evaluable tumor was required, but measurable disease as defined by response evaluation criteria in solid tumors (RECIST) criteria was not required. In the MTD disease expansion cohorts and the TPEC, clinically measurable disease as defined by RECIST criteria was required for evaluation of NSCLC, H&N cancer, and STS. Prostate specific antigen (PSA) alone was acceptable for evaluation of PC. For participants in the TPEC, tumor tissue that, in the opinion of the investigator, could have been safely biopsied using a core needle. 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 treatment. 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 greater than (>) Grade 1 based on the National Cancer Institute Common Terminology .Criteria for Adverse Events (NCI CTCAE) categorization. Systemic antineoplastic therapy / or radiotherapy within 21 days before the first dose of study treatment. Systemic treatment with prohibited medications. Participant has symptomatic brain metastasis. Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months. QTc >470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C positive. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. Treatment with any investigational products within 28 days before the first dose of study treatment. For participants in the TPEC and participants in the MTD disease expansion cohorts who gave informed consent to undergo tumor biopsy, ongoing anticoagulant therapy (example, aspirin, clopidogrel [Plavix ®], warfarin, or heparin) that cannot be held to permit tumor biopsy . Known allergy to boron or excipients.

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: Part 1: Ixazomib 0.125 milligram per square meter (mg/m^2)<br>Ixazomib (MLN9708) 0.125 mg/m^2, injection, intravenously (IV), once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 1: Ixazomib 0.25 mg/m^2<br>Ixazomib (MLN9708) 0.25 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 1: Ixazomib 0.5 mg/m^2<br>Ixazomib (MLN9708) 0.5 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 1: Ixazomib 1 mg/m^2<br>Ixazomib (MLN9708) 1 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 1: Ixazomib 1.33 mg/m^2<br>Ixazomib (MLN9708) 1.33 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 1: Ixazomib 1.76 mg/m^2<br>Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 1: Ixazomib 2.34 mg/m^2<br>Ixazomib (MLN9708) 2.34 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. Once the MTD will be established, participants with NSCLC, Head and Neck Cancer (H&N), Soft Tissue Sarcoma (STC) or Prostate Cancer (PC) will be included in MTD disease expanded cohort. An additional tumor pharmacodynamics expansion cohort (TPEC) will enroll participants with any type of solid tumor that can be biopsied for tissue analysis before and after treatment with ixazomib. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 2:Ixazomib 1.76 mg/m^2-NSCLC<br>Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with NSCLC during Part 2 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 2: Ixazomib 1.76 mg/m^2-H&N<br>Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with H&N during Part 2 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 2: Ixazomib 1.76 mg/m^2-STC<br>Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with STC during Part 2 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 2: Ixazomib 1.76 mg/m^2-PC<br>Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with PC during Part 2 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|
| Experimental: Part 2: Ixazomib 1.76 mg/m^2-TPEC<br>Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with various types of solid tumors suitable for biopsy in tumor pharmacodynamic expansion cohort (TPEC) during Part 2 of the study. | Drug: IXAZOMIB<br>* All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Dose Limiting Toxicity (DLT) | Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. DLT is any of following related to ixazomib:Grade (GR) 4 neutropenia (absolute neutrophil count<500 cells/cubic meter[cells/mm^3])for>7 days; GR 3 neutropenia with coincident fever and/or infection; GR 4 thrombocytopenia (platelets <25,000 cells/mm3)for>7 days; GR 3 thrombocytopenia with clinically significant bleeding; Platelet count<10,000 cells/mm3; GR 3 peripheral neuropathy;>=GR 3 nausea/emesis in absence of optimal antiemetic therapy; >=GR 3 diarrhoea in absence of optimal supportive therapy;GR 3 QTc prolongation noted on average of 3 electrocardiograms (ECGs);>=GR 3 nonhematological toxicity except GR 3 arthralgia/myalgia or GR 3 fatigue for<1 week; Delay in initiation of subsequent therapy cycle by>7 days due to treatment-related toxicity Other>=GR 2 nonhematological toxicity that opinion of investigator, requires discontinuation of therapy with Ixazomib. | Part 1: Cycle 1 Day 1 up to Cycle 1 Day 21 | 
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs) |  | Part 1: Cycle 1 Day 1 up to Cycle 10 Day 41; Part 2: Cycle 1 Day 1 up to Cycle 12 Day 41 | 
| Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities |  | Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41) | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital sign measurements included diastolic and systolic blood pressure, heart rate, weight and oral temperature. | Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post-dose for Ixazomib | AUC (0-72) is a measure of the area under the plasma concentration-time curve from time 0 to 72 hours post-dose for ixazomib. | Part 1: Cycle 1 Days 1 and 11: pre-dose and at multiple time points (up to 72 hours) post-dose | 
| Part 1: C0: Initial Plasma Concentration After Bolus Intravenous Administration | C0 is the plasma drug concentration at time zero following bolus intravenous injection. | Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose | 
| Part 1: Rac: Accumulation Ratio for Ixazomib | Rac was estimated as the ratio of AUC (0-72) on Day 11 and AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time 0 to 72 hours post-dose. | Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| Part 1: Terminal Phase Elimination Half-life (T1/2) for Ixazomib | T1/2 is the time required for half of the drug to be eliminated from the plasma. | Part 1: Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose | 
| Part 1: E Max: Maximum Observed Effect for Ixazomib | E max is the maximum inhibition of 20S proteasome activity in whole blood. | Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose | 
| Part 1: TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib | TEmax is the time to reach the Emax, equal to time (hours) to Emax. | Part 1: Cycle 1 Days 1 and 11 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose | 
| Number of Participants With Best Overall Response | Best overall response for a participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above normal limits. Progressive disease: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions. | Day 18 up to Day 21 of each cycle (Part 1: up to Cycle 10; Part 2: up to Cycle 12) | 
| Part 2: Ixazomib Concentration in Postdose Clinical Tumor Samples in Ixazomib 1.76 mg/m^2-TPEC | The average data of Days 1 and 4 of Cycle 1 was reported. | Cycle 1 Days 1 and 4: Predose and (from 4-20 hours) post-dose | 
| 20S Proteasome Activity of Ixazomib in the Tumor Tissue |  | Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose | 
| Expression of Biomarker (ATF-3) in Tumor Tissue |  | Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy