A Dose Escalation Study of MLN7243 (TAK-243) in Adult Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate safety and tolerability (establish maximum tolerated dose [MTD], inform the recommended phase 2 dose [RP2D], and identify the dose-limiting toxicities [DLTs]) of MLN7243.

Detailed Description
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This is a single arm Phase I study with multiple dosing cohorts as noted below: Schedule A: MLN7243 1 mg Schedule A: MLN7243 2 mg Schedule A: MLN7243 4 mg Schedule A: MLN7243 8 mg Schedule A: MLN7243 12 mg Schedule A: MLN7243 18 mg Schedule A: MLN7243 Homozygous Mutant 4 mg

Official Title
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A Phase 1, Open-Label, Multicenter, Dose Escalation Study to Assess the Safety and Tolerability of MLN7243, an Inhibitor of Ubiquitin-Activating Enzyme (UAE), in Adult Patients With Advanced Solid Tumors

Conditions
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Advanced Malignant Solid Tumors

Intervention / Treatment
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* Drug: MLN7243


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. Participants must have a histologically confirmed diagnosis of an advanced, metastatic malignant solid tumor and must have failed or exhausted standard therapies or for which no standard therapy is available. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants with adequate hematologic and organ function. All participants must have radiographically detectable tumors with measurable disease as defined by RECIST (version 1.1). Participants undergoing a biopsy procedure must have accessible lesions which are safe to biopsy. Recovered (that is, less than or equal to (<=) Grade 1 toxicity) from the reversible effects of prior antineoplastic therapy, except alopecia. Female participants who are postmenopausal for at least 1 year before the screening visit, surgically sterile, or agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 4 months after the last dose of study drug, or agree to practice true abstinence. Male participants who agree to practice effective barrier contraception during the entire study treatment period through 4 months after the last dose of study drug or agree to practice true abstinence. Suitable venous access for the study-required blood sampling including PK sampling. Exclusion Criteria Participants meeting any of the following exclusion criteria are not to be enrolled in the study: Participants with clinically significant pre-existing cardiac impairment. Participants homozygous for the ABCG2 (BCRP) c.421C greater than (>) 1 A polymorphism will be excluded from the study until the safety of a minimum of the first 3 dose levels has been characterized and the sponsor confirms that such participants can be enrolled at doses that are at least 3-fold lower than the most recently determined safe and tolerable dose among at least 3 dose limiting toxicities (DLT)-evaluable non-homozygous participants. Participants with known active central nervous system (CNS) lesions are excluded. Systemic antineoplastic therapy or investigational agents within 21 days before the first dose of study drug. Radiotherapy within 14 days before the first dose of study drug is not allowed except for limited field radiotherapy for palliative bone pain. For participants where tumor biopsies are required or requested: Any known coagulation abnormalities that would contraindicate the tumor biopsy procedure. Ongoing therapy with any anticoagulant or antiplatelet agents (example, aspirin, clopidogrel [Plavix®], heparin, or warfarin). Major surgery within 28 days before the first dose of MLN7243. Life-threatening illness unrelated to cancer. Any evidence of active infection or antibiotic therapy within 14 days before the first dose of MLN7243. Known human immunodeficiency virus (HIV) positivity or AIDS-related illness, hepatitis B virus, and hepatitis C virus. Participants whose weight is less than (<) 40 kilogram (kg). History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

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: Schedule A: MLN7243 1 mg<br>MLN7243 1 milligram (mg), infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or disease progression (PD) or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|
| Experimental: Schedule A: MLN7243 2 mg<br>MLN7243 2 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD, or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|
| Experimental: Schedule A: MLN7243 4 mg<br>MLN7243 4 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|
| Experimental: Schedule A: MLN7243 8 mg<br>MLN7243 8 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|
| Experimental: Schedule A: MLN7243 12 mg<br>MLN7243 12 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|
| Experimental: Schedule A: MLN7243 18 mg<br>MLN7243 18 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|
| Experimental: Schedule A: MLN7243 Homozygous Mutant 4 mg<br>MLN7243 homozygous mutant 4 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. | Drug: MLN7243<br>* Dose escalation stage Schedule A: Intravenous infusion on Days 1, 4, 8, 11 for a 21-day treatment cycle. Schedule B: Intravenous infusion on Days 1, 8, 15 for a 28-day treatment cycle. Dose expansion stage: MLN7243 will be administered following schedule A (twice-weekly, 21-day dosing) and/or B (once-weekly, 28-day dosing).<br>* Other names: TAK-243;|

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 (TEAEs) and Serious Adverse Events (SAEs) |  | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) | 
| Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) |  | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) | 
| Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) |  | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities |  | Cycle 1 Day 1 up to Cycle 1 Day 11 | 
| Number of Participants With Clinically Significant Echocardiogram Abnormalities |  | Cycle 1 Day 2 up to 30 days after last dose of study drug (Cycle 10 Day 41) | 
| Number of Participants With TEAEs Related to Tropinin I and T |  | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ceoi: Plasma Concentration at the End of Infusion for TAK-243 |  | Cycle 1 Day 1 and 11: pre-infusion to end of infusion (up to 10 minutes) | 
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-243 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| CL: Total Clearance After Intravenous Administration for TAK-243 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| Vss: Volume of Distribution at Steady State for TAK-243 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| Aet: Amount of TAK-243 Excreted Unchanged in Urine |  | Cycle 1 Day 1; Cycle 1 Day 11 | 
| Fet: Percentage of TAK-243 Excreted Unchanged in Urine |  | Cycle 1 Day 1; Cycle 1 Day 11 | 
| Terminal Phase Elimination Half-life (T1/2) for TAK-243 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose | 
| Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | The pharmacodynamics IHC biomarkers included polyubiquitin marker and ubquityl (Ub)-histone H2B marker. H-score was a composite score that comprised of intensity and percentage of staining and was used for assessing the amount of protein or phospho-protein present in a biopsy sample. The composite score obtained by H-score is derived by summing the percentages of cell staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+; where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). The composite H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein. | Baseline and Cycle 1 Day 12 | 
| Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | The pharmacodynamics IHC biomarkers included polyubiquitin marker and Ub-histone H2B marker. Positive index was calculated by taking the number of positive cells over the total number of cells. | Baseline and Cycle 1 Day 12 | 
| Percentage of Participants With Best Overall Response | Best overall response for participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target and non target) must have reduction in short axis to less than (<) 10 millimeter (mm). Partial Response (PR): at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter; PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study (this includes baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least mm. The appearance of 1 or more new lesions is also considered progression. | Baseline up to end of study (approximately 7 months) | 
| Duration of Response | Duration of any response (CR or PR) was defined as the time (in both days and months) from the date of first documented response per the investigator response assessment to the date of first progressive disease after the first documented response or, if the participant discontinues treatment, the date of last disease assessment as per RECIST version 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target and non target) must have reduction in short axis to <10 mm. PR: at least 30% decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. | Baseline up to end of study (approximately 7 months) | 

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