Advanced Malignant Solid Tumors
Conditions
Keywords
Drug therapy
Brief summary
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
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
Interventions
DRUGMLN7243
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).
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each participant must meet all of the following inclusion criteria to be enrolled in the study: 1. Male or female participants 18 years or older. 2. 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. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Participants with adequate hematologic and organ function. 5. All participants must have radiographically detectable tumors with measurable disease as defined by RECIST (version 1.1). 6. Participants undergoing a biopsy procedure must have accessible lesions which are safe to biopsy. 7. Recovered (that is, less than or equal to (\<=) Grade 1 toxicity) from the reversible effects of prior antineoplastic therapy, except alopecia. 8. 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. 9. Suitable venous access for the study-required blood sampling including PK sampling.
Exclusion criteria
Participants meeting any of the following
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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) | — |
| Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline and Cycle 1 Day 12 | 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. |
| Percentage of Participants With Best Overall Response | Baseline up to end of study (approximately 7 months) | 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 Response | Baseline up to end of study (approximately 7 months) | 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. |
| Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Baseline and Cycle 1 Day 12 | 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. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 7 investigative sites in the United States from 31 January 2014 to 09 November 2016.
Pre-assignment details
Participants with diagnosis of advanced malignant solid tumors were enrolled in Schedule A of dose escalation phase to receive TAK-243 (MLN7243). The study was terminated prior to start of Schedule B of dose escalation phase and planned expansion because of realignment of the sponsor's pipeline program.
Participants by arm
| Arm | Count |
|---|---|
| Schedule A: TAK-243 Total 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. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 0 | 0 | 2 | 0 |
| Overall Study | Other | 0 | 0 | 1 | 0 | 0 | 2 | 0 |
| Overall Study | Progressive Disease | 3 | 3 | 2 | 4 | 2 | 4 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Schedule A: TAK-243 Total |
|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 9.27 |
| Body Surface Area | 1.936 square meter (m^2) STANDARD_DEVIATION 0.2364 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Height | 170.88 centimeter (cm) STANDARD_DEVIATION 12.101 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment United States | 29 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 17 Participants |
| Weight | 79.69 kilogram (kg) STANDARD_DEVIATION 16.829 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 4 / 4 | 4 / 4 | 3 / 5 | 8 / 8 | 1 / 1 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 | 2 / 4 | 2 / 4 | 1 / 5 | 4 / 8 | 0 / 1 |
Outcome results
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
Population: The safety population included all participants who received at least 1 dose of TAK-243.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Schedule A: TAK-243 1 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 3 participants |
| Schedule A: TAK-243 1 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Schedule A: TAK-243 2 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 4 participants |
| Schedule A: TAK-243 2 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Schedule A: TAK-243 4 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 4 participants |
| Schedule A: TAK-243 4 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Schedule A: TAK-243 8 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 4 participants |
| Schedule A: TAK-243 8 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Schedule A: TAK-243 12 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 4 participants |
| Schedule A: TAK-243 12 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Schedule A: TAK-243 18 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 8 participants |
| Schedule A: TAK-243 18 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 4 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 1 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Primary
Number of Participants With Clinically Significant Echocardiogram Abnormalities
Time frame: Cycle 1 Day 2 up to 30 days after last dose of study drug (Cycle 10 Day 41)
Population: The safety population included all participants who received at least 1 dose of TAK-243.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Schedule A: TAK-243 1 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Clinically Significant Echocardiogram Abnormalities | 0 participants |
Primary
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
Time frame: Cycle 1 Day 1 up to Cycle 1 Day 11
Population: The safety population included all participants who received at least 1 dose of TAK-243.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Schedule A: TAK-243 1 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
Primary
Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC)
Time frame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
Population: The safety population included all participants who received at least 1 dose of TAK-243.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Schedule A: TAK-243 1 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 1 participants |
| Schedule A: TAK-243 1 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 1 participants |
| Schedule A: TAK-243 1 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 1 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 1 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 1 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 1 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 1 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 1 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 2 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 0 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 3 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 2 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 1 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 0 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 4 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 4 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 1 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Investigations | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Blood and lymphatic system disorders | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | Metabolism and nutrition disorders | 1 participants |
Primary
Number of Participants With TEAEs Related to Tropinin I and T
Time frame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
Population: The safety population included all participants who received at least 1 dose of TAK-243.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Schedule A: TAK-243 1 mg | Number of Participants With TEAEs Related to Tropinin I and T | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With TEAEs Related to Tropinin I and T | 0 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With TEAEs Related to Tropinin I and T | 1 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With TEAEs Related to Tropinin I and T | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With TEAEs Related to Tropinin I and T | 0 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With TEAEs Related to Tropinin I and T | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With TEAEs Related to Tropinin I and T | 0 participants |
Primary
Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT)
Time frame: Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
Population: The safety population included all participants who received at least 1 dose of TAK-243.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Schedule A: TAK-243 1 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 0 participants |
| Schedule A: TAK-243 1 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 0 participants |
| Schedule A: TAK-243 1 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 0 participants |
| Schedule A: TAK-243 1 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 0 participants |
| Schedule A: TAK-243 2 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 0 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 0 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 1 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 0 participants |
| Schedule A: TAK-243 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 1 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 0 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 0 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 0 participants |
| Schedule A: TAK-243 8 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 0 participants |
| Schedule A: TAK-243 12 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 0 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 2 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 1 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 1 participants |
| Schedule A: TAK-243 18 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 1 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea exertional | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Pyrexia | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Dyspnoea | 0 participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | Hypertension | 0 participants |
Secondary
Aet: Amount of TAK-243 Excreted Unchanged in Urine
Time frame: Cycle 1 Day 1; Cycle 1 Day 11
Population: No data were collected as no participant was analyzed since study was terminated before the planned expansion phase.
Secondary
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 4 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 1 | 203.043 ng*hr/mL | Standard Deviation 10.06 |
| Schedule A: TAK-243 4 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 11 | 179.726 ng*hr/mL | — |
| Schedule A: TAK-243 8 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 11 | 509.785 ng*hr/mL | — |
| Schedule A: TAK-243 8 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 1 | 375.541 ng*hr/mL | Standard Deviation 11.2872 |
| Schedule A: TAK-243 12 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 1 | 579.122 ng*hr/mL | Standard Deviation 201.1755 |
| Schedule A: TAK-243 12 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 11 | 752.152 ng*hr/mL | — |
| Schedule A: TAK-243 18 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 1 | 768.728 ng*hr/mL | Standard Deviation 174.9927 |
| Schedule A: TAK-243 18 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 | Cycle 1 Day 11 | 864.533 ng*hr/mL | Standard Deviation 175.9351 |
Secondary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-243
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 1 mg | 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 11 | 30.181 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 12.8884 |
| Schedule A: TAK-243 1 mg | 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 | 32.853 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 17.3894 |
| Schedule A: TAK-243 2 mg | 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 | 52.845 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 5.6656 |
| Schedule A: TAK-243 2 mg | 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 11 | 50.337 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 8.9494 |
| Schedule A: TAK-243 4 mg | 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 11 | 178.142 nanogram hours per milliliter (ng*hr/mL) | — |
| Schedule A: TAK-243 4 mg | 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 | 312.714 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 193.3829 |
| Schedule A: TAK-243 8 mg | 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 | 368.071 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 8.2218 |
| Schedule A: TAK-243 12 mg | 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 | 867.427 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 374.18 |
| Schedule A: TAK-243 18 mg | 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 | 922.068 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 192.2359 |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | 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 11 | 228.053 nanogram hours per milliliter (ng*hr/mL) | — |
Secondary
AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 4 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 1 | 535.581 ng*hr/mL | — |
| Schedule A: TAK-243 8 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 11 | 506.693 ng*hr/mL | — |
| Schedule A: TAK-243 8 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 1 | 377.812 ng*hr/mL | — |
| Schedule A: TAK-243 12 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 1 | 1132.160 ng*hr/mL | — |
| Schedule A: TAK-243 12 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 11 | 663.176 ng*hr/mL | Standard Deviation 261.1957 |
| Schedule A: TAK-243 18 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 11 | 771.491 ng*hr/mL | Standard Deviation 181.7875 |
| Schedule A: TAK-243 18 mg | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 | Cycle 1 Day 1 | 922.059 ng*hr/mL | Standard Deviation 192.1773 |
Secondary
Ceoi: Plasma Concentration at the End of Infusion for TAK-243
Time frame: Cycle 1 Day 1 and 11: pre-infusion to end of infusion (up to 10 minutes)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 1 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 78.658 nanogram per milliliter (ng/mL) | Standard Deviation 48.2212 |
| Schedule A: TAK-243 1 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 68.073 nanogram per milliliter (ng/mL) | Standard Deviation 35.2718 |
| Schedule A: TAK-243 2 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 100.758 nanogram per milliliter (ng/mL) | Standard Deviation 24.0669 |
| Schedule A: TAK-243 2 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 129.681 nanogram per milliliter (ng/mL) | Standard Deviation 52.468 |
| Schedule A: TAK-243 4 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 473.075 nanogram per milliliter (ng/mL) | Standard Deviation 132.7667 |
| Schedule A: TAK-243 4 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 273.807 nanogram per milliliter (ng/mL) | Standard Deviation 179.4241 |
| Schedule A: TAK-243 8 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 921.804 nanogram per milliliter (ng/mL) | Standard Deviation 258.6109 |
| Schedule A: TAK-243 8 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 2299.438 nanogram per milliliter (ng/mL) | Standard Deviation 9027.742 |
| Schedule A: TAK-243 12 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 1276.684 nanogram per milliliter (ng/mL) | Standard Deviation 804.4476 |
| Schedule A: TAK-243 12 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 1271.199 nanogram per milliliter (ng/mL) | Standard Deviation 628.4555 |
| Schedule A: TAK-243 18 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 1775.470 nanogram per milliliter (ng/mL) | Standard Deviation 463.8601 |
| Schedule A: TAK-243 18 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 2316.282 nanogram per milliliter (ng/mL) | Standard Deviation 7744.9842 |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 1 | 391.000 nanogram per milliliter (ng/mL) | — |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | Cycle 1 Day 11 | 265.000 nanogram per milliliter (ng/mL) | — |
Secondary
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.
Time frame: Baseline and Cycle 1 Day 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Schedule A: TAK-243 1 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline: Ub-histone H2B Positive Index | 0.953 percentage of cell |
| Schedule A: TAK-243 1 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Change at C1D12: Polyubiquitin Positive Index | -0.01 percentage of cell |
| Schedule A: TAK-243 1 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline: Polyubiquitin Positive Index | 0.99 percentage of cell |
| Schedule A: TAK-243 1 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Change at C1D12: Ub-histone H2B Positive Index | 0.018 percentage of cell |
| Schedule A: TAK-243 2 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Change at C1D12: Polyubiquitin Positive Index | 0.00 percentage of cell |
| Schedule A: TAK-243 2 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline: Polyubiquitin Positive Index | 1.00 percentage of cell |
| Schedule A: TAK-243 2 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Change at C1D12: Ub-histone H2B Positive Index | 0.003 percentage of cell |
| Schedule A: TAK-243 2 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline: Ub-histone H2B Positive Index | 0.995 percentage of cell |
| Schedule A: TAK-243 4 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline: Polyubiquitin Positive Index | 0.99 percentage of cell |
| Schedule A: TAK-243 4 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Change at C1D12: Ub-histone H2B Positive Index | -0.003 percentage of cell |
| Schedule A: TAK-243 4 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Baseline: Ub-histone H2B Positive Index | 0.990 percentage of cell |
| Schedule A: TAK-243 4 mg | Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index | Change at C1D12: Polyubiquitin Positive Index | 0.00 percentage of cell |
Secondary
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.
Time frame: Baseline and Cycle 1 Day 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Schedule A: TAK-243 1 mg | 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 H-score | 286.00 score on a scale |
| Schedule A: TAK-243 1 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Change at C1D12: Polyubiquitin H-score | -3.60 score on a scale |
| Schedule A: TAK-243 1 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Baseline: Ub-histone H2B H-score | 269.750 score on a scale |
| Schedule A: TAK-243 1 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Change at C1D12: Ub-histone H2B H-score | 13.250 score on a scale |
| Schedule A: TAK-243 2 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Change at C1D12: Ub-histone H2B H-score | 3.250 score on a scale |
| Schedule A: TAK-243 2 mg | 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 H-score | 297.80 score on a scale |
| Schedule A: TAK-243 2 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Baseline: Ub-histone H2B H-score | 291.000 score on a scale |
| Schedule A: TAK-243 2 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Change at C1D12: Polyubiquitin H-score | -2.00 score on a scale |
| Schedule A: TAK-243 4 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Change at C1D12: Ub-histone H2B H-score | 2.000 score on a scale |
| Schedule A: TAK-243 4 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Change at C1D12: Polyubiquitin H-score | 4.20 score on a scale |
| Schedule A: TAK-243 4 mg | Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) | Baseline: Ub-histone H2B H-score | 290.750 score on a scale |
| Schedule A: TAK-243 4 mg | 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 H-score | 282.00 score on a scale |
Secondary
CL: Total Clearance After Intravenous Administration for TAK-243
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 4 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 1 | 19.724 liter per hour (L/hr) | Standard Deviation 0.9773 |
| Schedule A: TAK-243 4 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 11 | 22.162 liter per hour (L/hr) | — |
| Schedule A: TAK-243 8 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 11 | 15.789 liter per hour (L/hr) | — |
| Schedule A: TAK-243 8 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 1 | 21.312 liter per hour (L/hr) | Standard Deviation 0.6406 |
| Schedule A: TAK-243 12 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 1 | 22.749 liter per hour (L/hr) | Standard Deviation 8.8967 |
| Schedule A: TAK-243 12 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 11 | 16.194 liter per hour (L/hr) | — |
| Schedule A: TAK-243 18 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 1 | 24.379 liter per hour (L/hr) | Standard Deviation 5.6587 |
| Schedule A: TAK-243 18 mg | CL: Total Clearance After Intravenous Administration for TAK-243 | Cycle 1 Day 11 | 21.558 liter per hour (L/hr) | Standard Deviation 4.8376 |
Secondary
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.
Time frame: Baseline up to end of study (approximately 7 months)
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Schedule A: TAK-243 1 mg | Duration of Response | 6.24 months |
Secondary
Fet: Percentage of TAK-243 Excreted Unchanged in Urine
Time frame: Cycle 1 Day 1; Cycle 1 Day 11
Population: No data were collected as no participant was analyzed since study was terminated before the planned expansion phase.
Secondary
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.
Time frame: Baseline up to end of study (approximately 7 months)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Schedule A: TAK-243 1 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 1 mg | Percentage of Participants With Best Overall Response | PD | 0 percentage of participants |
| Schedule A: TAK-243 1 mg | Percentage of Participants With Best Overall Response | SD | 67 percentage of participants |
| Schedule A: TAK-243 1 mg | Percentage of Participants With Best Overall Response | PR | 33 percentage of participants |
| Schedule A: TAK-243 2 mg | Percentage of Participants With Best Overall Response | SD | 75 percentage of participants |
| Schedule A: TAK-243 2 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 2 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Schedule A: TAK-243 2 mg | Percentage of Participants With Best Overall Response | PD | 25 percentage of participants |
| Schedule A: TAK-243 4 mg | Percentage of Participants With Best Overall Response | SD | 100 percentage of participants |
| Schedule A: TAK-243 4 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Schedule A: TAK-243 4 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 4 mg | Percentage of Participants With Best Overall Response | PD | 0 percentage of participants |
| Schedule A: TAK-243 8 mg | Percentage of Participants With Best Overall Response | PD | 100 percentage of participants |
| Schedule A: TAK-243 8 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 8 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Schedule A: TAK-243 8 mg | Percentage of Participants With Best Overall Response | SD | 0 percentage of participants |
| Schedule A: TAK-243 12 mg | Percentage of Participants With Best Overall Response | SD | 50 percentage of participants |
| Schedule A: TAK-243 12 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 12 mg | Percentage of Participants With Best Overall Response | PD | 50 percentage of participants |
| Schedule A: TAK-243 12 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Schedule A: TAK-243 18 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Schedule A: TAK-243 18 mg | Percentage of Participants With Best Overall Response | SD | 60 percentage of participants |
| Schedule A: TAK-243 18 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 18 mg | Percentage of Participants With Best Overall Response | PD | 40 percentage of participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Percentage of Participants With Best Overall Response | PD | 100 percentage of participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Schedule A: TAK-243 Homozygous Mutant 4 mg | Percentage of Participants With Best Overall Response | SD | 0 percentage of participants |
Secondary
Terminal Phase Elimination Half-life (T1/2) for TAK-243
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 4 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 1 | 7.001 hour | Standard Deviation 1.4372 |
| Schedule A: TAK-243 4 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 11 | 5.572 hour | — |
| Schedule A: TAK-243 8 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 11 | 15.212 hour | — |
| Schedule A: TAK-243 8 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 1 | 9.377 hour | Standard Deviation 4.6442 |
| Schedule A: TAK-243 12 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 1 | 5.765 hour | Standard Deviation 0.8607 |
| Schedule A: TAK-243 12 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 11 | 27.446 hour | — |
| Schedule A: TAK-243 18 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 1 | 8.296 hour | Standard Deviation 4.3573 |
| Schedule A: TAK-243 18 mg | Terminal Phase Elimination Half-life (T1/2) for TAK-243 | Cycle 1 Day 11 | 9.873 hour | Standard Deviation 6.303 |
Secondary
Vss: Volume of Distribution at Steady State for TAK-243
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-243 4 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 11 | 34.120 liter | — |
| Schedule A: TAK-243 4 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 1 | 29.806 liter | Standard Deviation 0.9494 |
| Schedule A: TAK-243 8 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 1 | 33.957 liter | Standard Deviation 5.8273 |
| Schedule A: TAK-243 8 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 11 | 39.618 liter | — |
| Schedule A: TAK-243 12 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 11 | 56.573 liter | — |
| Schedule A: TAK-243 12 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 1 | 37.596 liter | Standard Deviation 20.752 |
| Schedule A: TAK-243 18 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 11 | 51.806 liter | Standard Deviation 18.8787 |
| Schedule A: TAK-243 18 mg | Vss: Volume of Distribution at Steady State for TAK-243 | Cycle 1 Day 1 | 63.744 liter | Standard Deviation 39.5945 |