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.

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.

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.

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.

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.

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.

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.

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).

MLN7243

Medical Monitor

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.

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

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

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

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.

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.

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.

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.

Millennium Pharmaceuticals, Inc.

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

TAK-243 (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.

Schedule A: TAK-243 1 mg

TAK-243 (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.

Schedule A: TAK-243 2 mg

TAK-243 (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.

Schedule A: TAK-243 4 mg

TAK-243 (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.

Schedule A: TAK-243 8 mg

TAK-243 (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.

Schedule A: TAK-243 12 mg

TAK-243 (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.

Schedule A: TAK-243 18 mg

TAK-243 (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.

Schedule A: TAK-243 Homozygous Mutant 4 mg

TAK-243 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 18 mg, and 4mg homozygous mutant, infusion, IV over 10-minutes, twice-weekly on Days 1, 4, 8, and 11 in a 21-day treatment cycle for a maximum of 12 cycles, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped.

Schedule A: TAK-243 Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Height

Weight

Body Surface Area

The safety population included all participants who received at least 1 dose of TAK-243.

Medical Director

TEAEs

SAEs

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Metabolism and nutrition disorders

Blood and lymphatic system disorders

Investigations

Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC)

Pyrexia

Dyspnoea

Dyspnoea exertional

Hypertension

Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT)

Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities

Number of Participants With Clinically Significant Echocardiogram Abnormalities

Number of Participants With TEAEs Related to Tropinin I and T

Cycle 1 Day 1

Cycle 1 Day 11

The plasma pharmacokinetic (PK) analysis population where data at specified time points was available.The plasma PK-evaluable population included all participants who have sufficient dosing and concentration-time data to reliably estimate PK parameters.

Ceoi: Plasma Concentration at the End of Infusion for TAK-243

The plasma PK analysis population where data at specified time points was available. The plasma PK-evaluable population included all participants who have sufficient dosing and concentration-time data to reliably estimate PK parameters.

AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-243

AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243

AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243

CL: Total Clearance After Intravenous Administration for TAK-243

Vss: Volume of Distribution at Steady State for TAK-243

No data were collected as no participant was analyzed since study was terminated before the planned expansion phase.

Aet: Amount of TAK-243 Excreted Unchanged in Urine

Fet: Percentage of TAK-243 Excreted Unchanged in Urine

Terminal Phase Elimination Half-life (T1/2) for TAK-243

Baseline: Polyubiquitin H-score

Change at C1D12: Polyubiquitin H-score

Baseline: Ub-histone H2B H-score

Change at C1D12: Ub-histone H2B H-score

Pharmacodynamic population:baseline,post-baseline assessments were available,including all participants who received all doses(Cycle 1),have pre-post dose paired tumor tissue biopsies taken at protocol-specified timepoints,have sufficient tumor content at both timepoints to estimate changes in Pharmacodynamic biomarker percent area positive values.

Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score)

Baseline: Polyubiquitin Positive Index

Change at C1D12: Polyubiquitin Positive Index

Baseline: Ub-histone H2B Positive Index

Change at C1D12: Ub-histone H2B Positive Index

Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index

The response-evaluable population included all participants who received at least 1 dose of TAK-243, have measurable disease at baseline, and have at least 1 post baseline disease assessment.

Percentage of Participants With Best Overall Response

The response-evaluable population where baseline and post-baseline assessments were available. The Response-evaluable population included all participants who received at least 1 dose of TAK-243, have measurable disease at baseline, and have at least 1 post baseline disease assessment.

Spots Global Cancer Trial Database for A Dose Escalation Study of MLN7243 (TAK-243) in Adult Participants With Advanced Solid Tumors

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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