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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1203-6359 | Other Identifier | WHO |
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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.
This is a single arm Phase I study with multiple dosing cohorts as noted below:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Schedule A: MLN7243 1 mg | Experimental | 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: MLN7243 2 mg | Experimental | 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: MLN7243 4 mg | Experimental | 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: MLN7243 8 mg | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MLN7243 | Drug | 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). |
| 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) |
| 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 |
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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:
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.
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| Name | Affiliation | Role |
|---|---|---|
| Medical Monitor | Millennium Pharmaceuticals, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston | Massachusetts | United States | ||||
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 took part in the study at 7 investigative sites in the United States from 31 January 2014 to 09 November 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | Schedule A: TAK-243 1 mg | 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. |
| FG001 | Schedule A: TAK-243 2 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. |
| FG002 | Schedule A: TAK-243 4 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. |
| FG003 | Schedule A: TAK-243 8 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. |
| FG004 | Schedule A: TAK-243 12 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. |
| FG005 | Schedule A: TAK-243 18 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. |
| FG006 | Schedule A: TAK-243 Homozygous Mutant 4 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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The safety population included all participants who received at least 1 dose of TAK-243.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | The safety population included all participants who received at least 1 dose of TAK-243. | Posted | Number | participants | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) |
|
Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days (Cycle 10 Day 41) after the last dose of study drug
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Schedule A: TAK-243 1 mg | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (19.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Takeda | +1-877-825-3327 | trialdisclosures@takeda.com |
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| ID | Term |
|---|---|
| C000622638 | TAK-243 |
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| Schedule A: MLN7243 12 mg | Experimental | 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: MLN7243 18 mg | Experimental | 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: MLN7243 Homozygous Mutant 4 mg | Experimental | 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. |
|
|
|
| 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) |
| St Louis |
| Missouri |
| United States |
| Cleveland | Ohio | United States |
| Philadelphia | Pennsylvania | United States |
| Charleston | South Carolina | United States |
| Nashville | Tennessee | United States |
| San Antonio | Texas | United States |
| Progressive Disease |
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| Withdrawal by Subject |
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| Adverse Event |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Height | Mean | Standard Deviation | centimeter (cm) |
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| Weight | Mean | Standard Deviation | kilogram (kg) |
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| Body Surface Area | Mean | Standard Deviation | square meter (m^2) |
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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.
| OG002 | Schedule A: TAK-243 4 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. |
| OG003 | Schedule A: TAK-243 8 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. |
| OG004 | Schedule A: TAK-243 12 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. |
| OG005 | Schedule A: TAK-243 18 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. |
| OG006 | Schedule A: TAK-243 Homozygous Mutant 4 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. |
|
|
| Primary | Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) | The safety population included all participants who received at least 1 dose of TAK-243. | Posted | Number | participants | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) |
|
|
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| Primary | Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) | The safety population included all participants who received at least 1 dose of TAK-243. | Posted | Number | participants | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) |
|
|
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| Primary | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | The safety population included all participants who received at least 1 dose of TAK-243. | Posted | Number | participants | Cycle 1 Day 1 up to Cycle 1 Day 11 |
|
|
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| Primary | Number of Participants With Clinically Significant Echocardiogram Abnormalities | The safety population included all participants who received at least 1 dose of TAK-243. | Posted | Number | participants | Cycle 1 Day 2 up to 30 days after last dose of study drug (Cycle 10 Day 41) |
|
|
|
| Primary | Number of Participants With TEAEs Related to Tropinin I and T | The safety population included all participants who received at least 1 dose of TAK-243. | Posted | Number | participants | Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) |
|
|
|
| Secondary | Ceoi: Plasma Concentration at the End of Infusion for TAK-243 | 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. | Posted | Geometric Mean | Standard Deviation | nanogram per milliliter (ng/mL) | Cycle 1 Day 1 and 11: pre-infusion to end of infusion (up to 10 minutes) |
|
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| Secondary | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration 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. | Posted | Mean | Standard Deviation | nanogram hours per milliliter (ng*hr/mL) | 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 |
|
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| Secondary | AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval 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. | Posted | Mean | Standard Deviation | ng*hr/mL | 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 |
|
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| Secondary | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity 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. | Posted | Mean | Standard Deviation | ng*hr/mL | 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 |
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| Secondary | CL: Total Clearance After Intravenous Administration 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. | Posted | Mean | Standard Deviation | liter per hour (L/hr) | 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 |
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| Secondary | Vss: Volume of Distribution at Steady State 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. | Posted | Mean | Standard Deviation | liter | 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 |
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| Secondary | Aet: Amount of TAK-243 Excreted Unchanged in Urine | No data were collected as no participant was analyzed since study was terminated before the planned expansion phase. | Posted | Cycle 1 Day 1; Cycle 1 Day 11 |
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| Secondary | Fet: Percentage of TAK-243 Excreted Unchanged in Urine | No data were collected as no participant was analyzed since study was terminated before the planned expansion phase. | Posted | Cycle 1 Day 1; Cycle 1 Day 11 |
|
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| Secondary | Terminal Phase Elimination Half-life (T1/2) 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. | Posted | Mean | Standard Deviation | hour | 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 |
|
|
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| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline and Cycle 1 Day 12 |
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| 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. | 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. | Posted | Mean | Standard Deviation | percentage of cell | Baseline and Cycle 1 Day 12 |
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| 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. | 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. | Posted | Number | percentage of participants | Baseline up to end of study (approximately 7 months) |
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| 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. | 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. | Posted | Median | Full Range | months | Baseline up to end of study (approximately 7 months) |
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| 1 |
| 3 |
| 3 |
| 3 |
| EG001 | Schedule A: TAK-243 2 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. | 1 | 4 | 4 | 4 |
| EG002 | Schedule A: TAK-243 4 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. | 2 | 4 | 4 | 4 |
| EG003 | Schedule A: TAK-243 8 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. | 2 | 4 | 4 | 4 |
| EG004 | Schedule A: TAK-243 12 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. | 1 | 5 | 3 | 5 |
| EG005 | Schedule A: TAK-243 18 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. | 4 | 8 | 8 | 8 |
| EG006 | Schedule A: TAK-243 Homozygous Mutant 4 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. | 0 | 1 | 1 | 1 |
| Escherichia bacteraemia | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Viraemia and fungaemia not elsewhere classified (NEC) | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Duodenal and small intestinal stenosis and obstruction | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Small intestinal obstruction | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Flatulence, bloating and distension | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Breathing abnormalities | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Mesothelioma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.0) | Systematic Assessment |
|
| Non-small cell lung cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.0) | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Acute myocardial infarction | Cardiac disorders | MedDRA (19.0) | Systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Sinus bradycardia | Cardiac disorders | MedDRA (19.0) | Systematic Assessment |
|
| Ear pain | Ear and labyrinth disorders | MedDRA (19.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Proctalgia | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Infusion site erythema | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Injection site erythema | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Medical device site bruise | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Medical device site phlebitis | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Abscess oral | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Furuncle | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Ligament sprain | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Upper limb fracture | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Liver function test increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Amylase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Lipase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Transaminases increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Troponin T increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hyperlipasaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Pain in jaw | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Aphasia | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Neuropathy peripheral | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA (19.0) | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (19.0) | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (19.0) | Systematic Assessment |
|
| Irritability | Psychiatric disorders | MedDRA (19.0) | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | MedDRA (19.0) | Systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA (19.0) | Systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA (19.0) | Systematic Assessment |
|
| Pelvic pain | Reproductive system and breast disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Skin fissures | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (19.0) | Systematic Assessment |
|
| Embolism | Vascular disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA (19.0) | Systematic Assessment |
|
In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
| Blood and lymphatic system disorders |
|
| Investigations |
|
| Dyspnoea |
|
| Dyspnoea exertional |
|
| Hypertension |
|
|
| Cycle 1 Day 11 |
|
|
|
| Cycle 1 Day 11 |
|
|
|
| Cycle 1 Day 11 |
|
|
|
| Cycle 1 Day 11 |
|
|
|
| Cycle 1 Day 11 |
|
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|
| Cycle 1 Day 11 |
|
|
|
| Cycle 1 Day 11 |
|
|
| Change at C1D12: Polyubiquitin H-score |
|
| Baseline: Ub-histone H2B H-score |
|
| Change at C1D12: Ub-histone H2B H-score |
|
| Change at C1D12: Polyubiquitin Positive Index |
|
| Baseline: Ub-histone H2B Positive Index |
|
| Change at C1D12: Ub-histone H2B Positive Index |
|
| PR |
|
| SD |
|
| PD |
|