Nonhematologic Neoplasms, Advanced
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of TAK-931 in participants with advanced nonhematologic tumors.
Detailed description
The drug being under investigation in this study is called TAK-931. The effect of TAK-931 is being evaluated in up to 100 participants who have nonhematologic (solid) neoplasms. This study will look at the safety, tolerability, and PK to determine the maximum tolerated dose (MTD) of TAK-931. This multi-center trial will be conducted in Japan. The overall study duration is approximately 42 months for total of dose escalation cohorts and the safety expansion cohort. Participants will make multiple visits to the clinic with final visit approximately 30-40 days after last dose of study drug for a follow-up assessment.
Interventions
DRUGTAK-931
TAK-931 oral capsules.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed diagnosis of an advanced, nonhematologic/solid tumor (with the exception of primary brain tumor). 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 . 3. For whom no effective standard therapy is available. 4. Life expectancy of greater than or equal to (\>=3) months. 5. Female participants who: * Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, OR * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilized (example, status postvasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.) * Agree not to donate sperm during this study and for 120 days after receiving their last dose of study drug. 6. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. 7. Ability to swallow oral medications, willingness to undergo serial skin punch biopsies, and suitable venous access for the study-required PK and pharmacodynamic sampling. 8. Clinical laboratory values as specified below within 28 days before the first dose of study drug: * Bone marrow reserve consistent with absolute neutrophil count (ANC) \>=1500 per millimeter cube (/mm˄3), platelet count \>=100,000/mm˄3, and hemoglobin \>=9 per gram deciliter (g/dL). * Total bilirubin must be less than (\<) 1.5 times the upper limit of normal (ULN). * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be 3 \<=ULN. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or metastatic disease in liver. * Serum albumin \>=3.0 g/dL. * Serum creatinine \<1.5 times the institutional ULN or creatinine clearance based on the Cockcroft-Gault estimate \>=50 milliliter per minute (mL/minute) for participants with serum creatinine concentrations above institutional limits. 9. Left ventricular ejection fraction (LVEF) greater than (\>) 50 percent (%) as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of study drug. 10. Recovered (that is, \<=Grade 1 toxicity) from the reversible effects of prior anticancer therapy. Participants with ongoing toxicities at baseline may be eligible; however, any Grade 2 baseline toxicity (except for alopecia) should be discussed with the medical monitor.
Exclusion criteria
1. Who require continuous use of proton pump inhibitors (PPIs) or histamine-2 (H2) receptor antagonists and participants who are taking PPIs within 5 days before the first dose of study drug. 2. Treatment with clinically significant enzyme inducers within 14 days before the first dose of study drug. 3. Treatment with any investigational products within 30 days before the first dose of study drug. 4. 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 the first dose of study drug. 5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 6. History of any of the following within the last 3 months before administration of the first dose of study drug: * Ischemic myocardial event including angina requiring therapy and artery revascularization procedures, myocardial infarction, and unstable symptomatic ischemic heart disease. * Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures. * Thromboembolic events (example, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events). * Significant, uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia). * Use of rate control drugs for arrhythmias (including beta blockers \[such as metoprolol\],acetylcholine, digoxin, and non-dihydropyridine calcium channel blockers diltiazem and verapamil). * Placement of a pacemaker for control of cardiac rhythm. * Requirement for inotropic support (including digoxin). * New York Heart Association (NYHA) Class II to IV heart failure. * Any other cardiac condition that in the opinion of the investigator could pose an additional risk for the participation in the study (example, pericardial effusion or restrictive cardiomyopathy). * Baseline prolongation of the rate-corrected QT interval (QTc; example, repeated demonstration of QTc interval \>480 millisecond (msec), or history of congenital, long QT syndrome, or torsades de pointes). 7. With any of the following blood pressure conditions: * History of orthostatic hypotension or syncope that required medical intervention. Orthostatic hypotension is defined as a 20 millimeter of mercury (mmHg) fall in systolic blood pressure and/or a 10 mmHg fall in diastolic blood pressure within 2 to 5 minutes of quiet standing immediately after a 5-minute period of supine rest. * Postural orthostatic tachycardia syndrome (POTS) or postural tachycardia syndrome (defined as an increase in heart rate of \>30 beats per minute over baseline after 10 minutes of quiet standing). * Hypertension that is unstable or not controlled by medication. 8. Seizures requiring antiepileptic treatment. 9. History of uncontrolled brain metastasis unless: * Previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery. * Stable disease for ≥60 days, without steroid use (or stable steroid dose established for ≥28 days before the first dose of TAK-931). 10. Symptomatic and/or progressive central nervous system (CNS) metastases. 11. Ongoing medical conditions, such as acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before receiving the first dose of study drug. 12. Known history of human immunodeficiency virus (HIV) infection. 13. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C (HCV) infection viral load. Note: Participants who have positive hepatitis B core antibody or hepatitis B surface antibody can be enrolled but must have an undetectable hepatitis B viral load. Participants who have positive hepatitis C antibody must have an undetectable hepatitis C viral load. 14. Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption of study drug, such as total gastrectomy or GI conditions that could substantially modify gastric pH.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | Toxicity was evaluated by NCI CTCAE v4.03. DLT:any of following occurred events during Cycle 1 considered by investigator to be possibly related to therapy:1)Grade4 neutropenia,2)Febrile neutropenia lasting greater(\>)1 hour,3)Grade greater than or equal to (\>=)3 neutropenia with infection,4)Grade \>=3 thrombocytopenia with bleeding,4)Grade 4 thrombocytopenia,5)delay in initiation of Cycle 2 by \>14 days,6)Grade 2:\<Grade 2 ejection fraction,7)other Grade 2 nonhematologic toxicities considered by investigator related to study drug and DLTs,8)who received \<50 percent of doses of planned TAK-931 dosing in Cycle 1 for related AEs:\<7 QD/\<14 BID doses (Schedules A,B);\<11 QD/\<21 BID doses(Schedule D),\<3 QD/\<6 BID doses for(Schedule E),9)Grade \>=3 nonhematologic toxicity except arthralgia/myalgia and fatigue, isolated \>=Grade 3 laboratory abnormalities if it is asymptomatic and resolves to \<=Grade 1 or baseline levels in \<=7 days;inadequately treated Grade 3 nausea and/or vomiting and diarrhea. |
| Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | Baseline up to 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (up to Day 499) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]) | — |
| Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days) | H-score were a composite score that comprised of intensity and percentage of staining and were used for assessing amount of protein (in this case pMCM2 \[Ser40\]) present in a tissue sample. The composite score obtained by H-score is derived by adding of the percentages of cell staining at each intensity level multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\], 3+ \[strong staining\]). The H-score has a range of 0 to 300. Lower H-scores represent lower expression of pMCM2 (Ser40) in the tissue sample, while higher scores represent stronger expression of pMCM2 (Ser40) in the tissue samples. |
| Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days) | Positive index was calculated by taking the number of cells staining positive for the marker over the total number of cells. |
| Overall Response Rate (ORR) | From date of first dose to the date of first documentation of progressive disease (PD) or death due to any cause, which ever occurred first (up to Month 45) | ORR was defined as percentage of participants who had achieved complete response (CR) and partial response (PR), as measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD. |
| Progression-free Survival (PFS) | From date of first dose to the date of first documentation of PD or death due to any cause, which ever occurred first (up to Month 45) | PFS was defined as the time from the date of first dose to the date of first documentation of PD or death due to any cause, whichever occurs first, as measured by RECIST V1.1. PD: 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method. |
| Duration of Response (DOR) | From the date of first documentation of response to the date of first documentation of PD (up to Month 45) | The DOR was defined as the time from the date of first documentation of a response (CR or PR) to the date of first documentation of PD, as measured by RECIST V 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to \<10 mm. PR: was at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. PD: 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. DOR was analyzed using the Kaplan-Meier method. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in Japan from 24 March 2016 to 21 December 2019.
Pre-assignment details
Participants with advanced nonhematological solid tumors were enrolled to receive TAK-931 in 1 of the 4 treatment schedules: Schedule A, Schedule B, Schedule D and Schedule E. Schedules C and F were not conducted due to business reasons.
Participants by arm
| Arm | Count |
|---|---|
| Schedule A: TAK-931 30 mg TAK-931 30 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 3 |
| Schedule A: TAK-931 40 mg TAK-931 40 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 3 |
| Schedule A: TAK-931 50 mg TAK-931 50 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 16 |
| Schedule A: TAK-931 60 mg TAK-931 60 mg, capsule, orally, once daily for 14 days in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 3 |
| Schedule B: TAK-931 60 mg TAK-931 60 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 3 |
| Schedule B: TAK-931 80 mg TAK-931 80 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 9 |
| Schedule B: TAK-931 100 mg TAK-931 100 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 6 |
| Schedule B: TAK-931 120 mg TAK-931 120 mg, capsule, orally, once daily or twice daily for 7 days, followed by 7 days of rest and repeated (7 days on and 7 days off treatment) in each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 6 |
| Schedule D: TAK-931 20 mg TAK-931 20 mg, capsule, orally, once daily in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 6 |
| Schedule D: TAK-931 30 mg TAK-931 30 mg, capsule, orally, once daily in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 6 |
| Schedule D: TAK-931 40 mg TAK-931 40 mg, capsule, orally, once daily in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 6 |
| Schedule E: TAK-931 100 mg TAK-931 100 mg, capsule, orally, once daily on Days 1 and 2 followed by 5 days of rest and repeated weekly (2 days on and 5 days off treatment) in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 4 |
| Schedule E: TAK-931 120 mg TAK-931 120 mg, capsule, orally, once daily on Days 1 and 2 followed by 5 days of rest and repeated weekly (2 days on and 5 days off treatment) in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 3 |
| Schedule E: TAK-931 150 mg TAK-931 150 mg, capsule, orally, once daily on Days 1 and 2 followed by 5 days of rest and repeated weekly (2 days on and 5 days off treatment) in each 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. | 6 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 2 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 3 | 3 | 14 | 3 | 3 | 7 | 5 | 5 | 6 | 6 | 5 | 4 | 3 | 5 |
Baseline characteristics
| Characteristic | Schedule A: TAK-931 40 mg | Total | Schedule E: TAK-931 150 mg | Schedule E: TAK-931 120 mg | Schedule E: TAK-931 100 mg | Schedule D: TAK-931 40 mg | Schedule D: TAK-931 30 mg | Schedule D: TAK-931 20 mg | Schedule B: TAK-931 120 mg | Schedule B: TAK-931 100 mg | Schedule B: TAK-931 80 mg | Schedule A: TAK-931 30 mg | Schedule B: TAK-931 60 mg | Schedule A: TAK-931 60 mg | Schedule A: TAK-931 50 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 2.52 | 58.1 years STANDARD_DEVIATION 10.74 | 62.8 years STANDARD_DEVIATION 12.4 | 60.7 years STANDARD_DEVIATION 13.58 | 59.5 years STANDARD_DEVIATION 2.38 | 58.3 years STANDARD_DEVIATION 17.41 | 62.7 years STANDARD_DEVIATION 8.09 | 59.3 years STANDARD_DEVIATION 6.56 | 59.8 years STANDARD_DEVIATION 12.01 | 50.0 years STANDARD_DEVIATION 8.15 | 52.4 years STANDARD_DEVIATION 13.45 | 62.7 years STANDARD_DEVIATION 6.81 | 61.7 years STANDARD_DEVIATION 3.21 | 59.3 years STANDARD_DEVIATION 1.53 | 57.4 years STANDARD_DEVIATION 11.99 |
| Body Surface Area (BSA) | 1.563 square meter (m˄2) STANDARD_DEVIATION 0.0757 | 1.656 square meter (m˄2) STANDARD_DEVIATION 0.2095 | 1.637 square meter (m˄2) STANDARD_DEVIATION 0.2284 | 1.513 square meter (m˄2) STANDARD_DEVIATION 0.2501 | 1.658 square meter (m˄2) STANDARD_DEVIATION 0.2323 | 1.595 square meter (m˄2) STANDARD_DEVIATION 0.2134 | 1.485 square meter (m˄2) STANDARD_DEVIATION 0.166 | 1.620 square meter (m˄2) STANDARD_DEVIATION 0.2922 | 1.747 square meter (m˄2) STANDARD_DEVIATION 0.1904 | 1.820 square meter (m˄2) STANDARD_DEVIATION 0.151 | 1.732 square meter (m˄2) STANDARD_DEVIATION 0.2538 | 1.810 square meter (m˄2) STANDARD_DEVIATION 0.2805 | 1.617 square meter (m˄2) STANDARD_DEVIATION 0.162 | 1.473 square meter (m˄2) STANDARD_DEVIATION 0.0569 | 1.684 square meter (m˄2) STANDARD_DEVIATION 0.1513 |
| Height | 159.70 centimeter (cm) STANDARD_DEVIATION 7.076 | 163.41 centimeter (cm) STANDARD_DEVIATION 8.89 | 165.92 centimeter (cm) STANDARD_DEVIATION 8.817 | 155.90 centimeter (cm) STANDARD_DEVIATION 12.612 | 162.43 centimeter (cm) STANDARD_DEVIATION 9.28 | 163.87 centimeter (cm) STANDARD_DEVIATION 7.469 | 156.43 centimeter (cm) STANDARD_DEVIATION 8.913 | 160.08 centimeter (cm) STANDARD_DEVIATION 12.071 | 167.40 centimeter (cm) STANDARD_DEVIATION 9.586 | 168.73 centimeter (cm) STANDARD_DEVIATION 7.387 | 163.64 centimeter (cm) STANDARD_DEVIATION 9.107 | 169.67 centimeter (cm) STANDARD_DEVIATION 8.663 | 162.80 centimeter (cm) STANDARD_DEVIATION 11.012 | 155.03 centimeter (cm) STANDARD_DEVIATION 4.306 | 165.39 centimeter (cm) STANDARD_DEVIATION 6.727 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 80 Participants | 6 Participants | 3 Participants | 4 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 9 Participants | 3 Participants | 3 Participants | 3 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 3 Participants | 80 Participants | 6 Participants | 3 Participants | 4 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 9 Participants | 3 Participants | 3 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Female | 2 Participants | 32 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 48 Participants | 5 Participants | 1 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 3 Participants | 2 Participants | 0 Participants | 11 Participants |
| Weight | 55.33 kilogram (kg) STANDARD_DEVIATION 3.099 | 60.91 kilogram (kg) STANDARD_DEVIATION 12.964 | 58.55 kilogram (kg) STANDARD_DEVIATION 13.772 | 53.27 kilogram (kg) STANDARD_DEVIATION 13.25 | 61.30 kilogram (kg) STANDARD_DEVIATION 13.851 | 56.25 kilogram (kg) STANDARD_DEVIATION 13.248 | 51.08 kilogram (kg) STANDARD_DEVIATION 10.167 | 59.63 kilogram (kg) STANDARD_DEVIATION 16.675 | 65.85 kilogram (kg) STANDARD_DEVIATION 10.783 | 71.00 kilogram (kg) STANDARD_DEVIATION 10.769 | 66.51 kilogram (kg) STANDARD_DEVIATION 16.75 | 70.07 kilogram (kg) STANDARD_DEVIATION 18.269 | 58.03 kilogram (kg) STANDARD_DEVIATION 8.686 | 50.53 kilogram (kg) STANDARD_DEVIATION 3.707 | 62.06 kilogram (kg) STANDARD_DEVIATION 10.535 |
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 | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 16 | 0 / 3 | 0 / 3 | 0 / 9 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 3 | 1 / 6 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 16 / 16 | 3 / 3 | 3 / 3 | 9 / 9 | 6 / 6 | 6 / 6 | 5 / 6 | 6 / 6 | 6 / 6 | 4 / 4 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 5 / 16 | 2 / 3 | 1 / 3 | 2 / 9 | 1 / 6 | 1 / 6 | 1 / 6 | 1 / 6 | 3 / 6 | 2 / 4 | 0 / 3 | 3 / 6 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03
Toxicity was evaluated by NCI CTCAE v4.03. DLT:any of following occurred events during Cycle 1 considered by investigator to be possibly related to therapy:1)Grade4 neutropenia,2)Febrile neutropenia lasting greater(\>)1 hour,3)Grade greater than or equal to (\>=)3 neutropenia with infection,4)Grade \>=3 thrombocytopenia with bleeding,4)Grade 4 thrombocytopenia,5)delay in initiation of Cycle 2 by \>14 days,6)Grade 2:\<Grade 2 ejection fraction,7)other Grade 2 nonhematologic toxicities considered by investigator related to study drug and DLTs,8)who received \<50 percent of doses of planned TAK-931 dosing in Cycle 1 for related AEs:\<7 QD/\<14 BID doses (Schedules A,B);\<11 QD/\<21 BID doses(Schedule D),\<3 QD/\<6 BID doses for(Schedule E),9)Grade \>=3 nonhematologic toxicity except arthralgia/myalgia and fatigue, isolated \>=Grade 3 laboratory abnormalities if it is asymptomatic and resolves to \<=Grade 1 or baseline levels in \<=7 days;inadequately treated Grade 3 nausea and/or vomiting and diarrhea.
Time frame: Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The DLT-evaluable population was defined as all participants who received at least 75% of their planned TAK-931 doses for their first cycle of treatment (unless interrupted by study drug-related AEs) and who had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule A: TAK-931 40 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule A: TAK-931 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule A: TAK-931 60 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 2 Participants |
| Schedule B: TAK-931 60 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule B: TAK-931 80 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 2 Participants |
| Schedule B: TAK-931 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 1 Participants |
| Schedule B: TAK-931 120 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 1 Participants |
| Schedule D: TAK-931 20 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule D: TAK-931 30 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule D: TAK-931 40 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 1 Participants |
| Schedule E: TAK-931 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule E: TAK-931 120 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 0 Participants |
| Schedule E: TAK-931 150 mg | Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 | 2 Participants |
Primary
Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (up to Day 499)
Population: The safety population was defined as all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Schedule A: TAK-931 40 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Schedule A: TAK-931 50 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 16 Participants |
| Schedule A: TAK-931 60 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Schedule B: TAK-931 60 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Schedule B: TAK-931 80 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 9 Participants |
| Schedule B: TAK-931 100 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Schedule B: TAK-931 120 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Schedule D: TAK-931 20 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 5 Participants |
| Schedule D: TAK-931 30 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Schedule D: TAK-931 40 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Schedule E: TAK-931 100 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 4 Participants |
| Schedule E: TAK-931 120 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Schedule E: TAK-931 150 mg | Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
Secondary
AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 641 h*ng/mL | Geometric Coefficient of Variation 22.2 |
| Schedule A: TAK-931 40 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 1110 h*ng/mL | Geometric Coefficient of Variation 13.4 |
| Schedule A: TAK-931 50 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 1070 h*ng/mL | Geometric Coefficient of Variation 29.9 |
| Schedule A: TAK-931 60 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 1670 h*ng/mL | Geometric Coefficient of Variation 30.5 |
| Schedule B: TAK-931 60 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 1270 h*ng/mL | Geometric Coefficient of Variation 12.2 |
| Schedule B: TAK-931 80 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 1800 h*ng/mL | Geometric Coefficient of Variation 32.8 |
| Schedule B: TAK-931 100 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 1970 h*ng/mL | Geometric Coefficient of Variation 23.2 |
| Schedule B: TAK-931 120 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 2360 h*ng/mL | Geometric Coefficient of Variation 28.8 |
| Schedule D: TAK-931 20 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 431 h*ng/mL | Geometric Coefficient of Variation 49.9 |
| Schedule D: TAK-931 30 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 693 h*ng/mL | Geometric Coefficient of Variation 30.3 |
| Schedule D: TAK-931 40 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 956 h*ng/mL | Geometric Coefficient of Variation 27 |
| Schedule E: TAK-931 100 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 2280 h*ng/mL | Geometric Coefficient of Variation 23.8 |
| Schedule E: TAK-931 120 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 3110 h*ng/mL | Geometric Coefficient of Variation 42.8 |
| Schedule E: TAK-931 150 mg | AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931 | 3160 h*ng/mL | Geometric Coefficient of Variation 30.3 |
Secondary
AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 737 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 24.1 |
| Schedule A: TAK-931 40 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 1250 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 14.6 |
| Schedule A: TAK-931 50 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 1240 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 31.8 |
| Schedule A: TAK-931 60 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 2000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 33.8 |
| Schedule B: TAK-931 60 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 1470 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 17.9 |
| Schedule B: TAK-931 80 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 2140 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 35.9 |
| Schedule B: TAK-931 100 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 2240 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 23.9 |
| Schedule B: TAK-931 120 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 2740 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 29.5 |
| Schedule D: TAK-931 20 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 494 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 52.5 |
| Schedule D: TAK-931 30 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 801 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.3 |
| Schedule D: TAK-931 40 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 1100 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 28.2 |
| Schedule E: TAK-931 100 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 2720 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 20 |
| Schedule E: TAK-931 120 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 3760 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 48.9 |
| Schedule E: TAK-931 150 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931 | 3870 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 35.9 |
Secondary
AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 799 h*ng/mL | Geometric Coefficient of Variation 19.3 |
| Schedule A: TAK-931 40 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 1400 h*ng/mL | Geometric Coefficient of Variation 15.4 |
| Schedule A: TAK-931 50 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 1320 h*ng/mL | Geometric Coefficient of Variation 33.6 |
| Schedule A: TAK-931 60 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 2210 h*ng/mL | Geometric Coefficient of Variation 30.5 |
| Schedule B: TAK-931 60 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 1650 h*ng/mL | Geometric Coefficient of Variation 10.4 |
| Schedule B: TAK-931 80 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 2220 h*ng/mL | Geometric Coefficient of Variation 39.8 |
| Schedule B: TAK-931 100 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 2620 h*ng/mL | Geometric Coefficient of Variation 26.8 |
| Schedule B: TAK-931 120 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 4410 h*ng/mL | Geometric Coefficient of Variation 81.8 |
| Schedule D: TAK-931 20 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 600 h*ng/mL | Geometric Coefficient of Variation 49.1 |
| Schedule D: TAK-931 30 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 958 h*ng/mL | Geometric Coefficient of Variation 46.1 |
| Schedule D: TAK-931 40 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 1140 h*ng/mL | Geometric Coefficient of Variation 41.2 |
| Schedule E: TAK-931 100 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 3760 h*ng/mL | Geometric Coefficient of Variation 28.6 |
| Schedule E: TAK-931 120 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 4830 h*ng/mL | Geometric Coefficient of Variation 55.6 |
| Schedule E: TAK-931 150 mg | AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931 | 6260 h*ng/mL | Geometric Coefficient of Variation 32.2 |
Secondary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 742 h*ng/mL | Geometric Coefficient of Variation 24.3 |
| Schedule A: TAK-931 40 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 1250 h*ng/mL | Geometric Coefficient of Variation 14.7 |
| Schedule A: TAK-931 50 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 1250 h*ng/mL | Geometric Coefficient of Variation 32 |
| Schedule A: TAK-931 60 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 2010 h*ng/mL | Geometric Coefficient of Variation 34 |
| Schedule B: TAK-931 60 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 1480 h*ng/mL | Geometric Coefficient of Variation 17.7 |
| Schedule B: TAK-931 80 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 2160 h*ng/mL | Geometric Coefficient of Variation 36 |
| Schedule B: TAK-931 100 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 2240 h*ng/mL | Geometric Coefficient of Variation 23.7 |
| Schedule B: TAK-931 120 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 2750 h*ng/mL | Geometric Coefficient of Variation 29.5 |
| Schedule D: TAK-931 20 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 491 h*ng/mL | Geometric Coefficient of Variation 53.3 |
| Schedule D: TAK-931 30 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 805 h*ng/mL | Geometric Coefficient of Variation 32.4 |
| Schedule D: TAK-931 40 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 1100 h*ng/mL | Geometric Coefficient of Variation 28.2 |
| Schedule E: TAK-931 100 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 2730 h*ng/mL | Geometric Coefficient of Variation 20.5 |
| Schedule E: TAK-931 120 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 3770 h*ng/mL | Geometric Coefficient of Variation 49.3 |
| Schedule E: TAK-931 150 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931 | 3880 h*ng/mL | Geometric Coefficient of Variation 35.8 |
Secondary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 805 h*ng/mL | Geometric Coefficient of Variation 19.4 |
| Schedule A: TAK-931 40 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 1410 h*ng/mL | Geometric Coefficient of Variation 15 |
| Schedule A: TAK-931 50 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 1330 h*ng/mL | Geometric Coefficient of Variation 33.9 |
| Schedule A: TAK-931 60 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 2220 h*ng/mL | Geometric Coefficient of Variation 30.8 |
| Schedule B: TAK-931 60 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 1650 h*ng/mL | Geometric Coefficient of Variation 10.4 |
| Schedule B: TAK-931 80 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 2230 h*ng/mL | Geometric Coefficient of Variation 39.8 |
| Schedule B: TAK-931 100 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 2630 h*ng/mL | Geometric Coefficient of Variation 27.4 |
| Schedule B: TAK-931 120 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 4420 h*ng/mL | Geometric Coefficient of Variation 81 |
| Schedule D: TAK-931 20 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 603 h*ng/mL | Geometric Coefficient of Variation 49.2 |
| Schedule D: TAK-931 30 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 964 h*ng/mL | Geometric Coefficient of Variation 46.4 |
| Schedule D: TAK-931 40 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 1150 h*ng/mL | Geometric Coefficient of Variation 41.3 |
| Schedule E: TAK-931 100 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 3770 h*ng/mL | Geometric Coefficient of Variation 28.7 |
| Schedule E: TAK-931 120 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 4840 h*ng/mL | Geometric Coefficient of Variation 55.8 |
| Schedule E: TAK-931 150 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931 | 6280 h*ng/mL | Geometric Coefficient of Variation 32.2 |
Secondary
Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The pharmacokinetic (PK) population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 133 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22.6 |
| Schedule A: TAK-931 40 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 229 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 14.3 |
| Schedule A: TAK-931 50 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 214 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 40.9 |
| Schedule A: TAK-931 60 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 265 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 9.8 |
| Schedule B: TAK-931 60 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 277 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 19 |
| Schedule B: TAK-931 80 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 302 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.7 |
| Schedule B: TAK-931 100 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 402 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 24.5 |
| Schedule B: TAK-931 120 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 454 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 49.2 |
| Schedule D: TAK-931 20 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 98.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| Schedule D: TAK-931 30 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 149 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39.8 |
| Schedule D: TAK-931 40 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 197 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.5 |
| Schedule E: TAK-931 100 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 462 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 36.1 |
| Schedule E: TAK-931 120 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 514 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 15.9 |
| Schedule E: TAK-931 150 mg | Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931 | 499 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.3 |
Secondary
Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Schedule A: TAK-931 30 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 133 ng/mL | Geometric Coefficient of Variation 21.8 |
| Schedule A: TAK-931 40 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 239 ng/mL | Geometric Coefficient of Variation 16.2 |
| Schedule A: TAK-931 50 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 231 ng/mL | Geometric Coefficient of Variation 28.7 |
| Schedule A: TAK-931 60 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 330 ng/mL | Geometric Coefficient of Variation 23.9 |
| Schedule B: TAK-931 60 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 218 ng/mL | Geometric Coefficient of Variation 4.4 |
| Schedule B: TAK-931 80 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 341 ng/mL | Geometric Coefficient of Variation 54 |
| Schedule B: TAK-931 100 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 380 ng/mL | Geometric Coefficient of Variation 15.6 |
| Schedule B: TAK-931 120 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 671 ng/mL | Geometric Coefficient of Variation 73.6 |
| Schedule D: TAK-931 20 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 104 ng/mL | Geometric Coefficient of Variation 53.4 |
| Schedule D: TAK-931 30 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 160 ng/mL | Geometric Coefficient of Variation 34.1 |
| Schedule D: TAK-931 40 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 193 ng/mL | Geometric Coefficient of Variation 20.7 |
| Schedule E: TAK-931 100 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 532 ng/mL | Geometric Coefficient of Variation 39.9 |
| Schedule E: TAK-931 120 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 654 ng/mL | Geometric Coefficient of Variation 40.7 |
| Schedule E: TAK-931 150 mg | Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931 | 917 ng/mL | Geometric Coefficient of Variation 22.1 |
Secondary
Duration of Response (DOR)
The DOR was defined as the time from the date of first documentation of a response (CR or PR) to the date of first documentation of PD, as measured by RECIST V 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to \<10 mm. PR: was at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. PD: 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. DOR was analyzed using the Kaplan-Meier method.
Time frame: From the date of first documentation of response to the date of first documentation of PD (up to Month 45)
Population: The response-evaluable population is defined as participants who receive at least 1 dose of study drug, have measurable disease at baseline, and at least 1 post-baseline response assessment. Responders without documentation of PD were censored at the date of last response assessment that is stable disease or better.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Duration of Response (DOR) | 2.1 months |
| Schedule A: TAK-931 50 mg | Duration of Response (DOR) | 2.7 months |
| Schedule A: TAK-931 60 mg | Duration of Response (DOR) | 2.2 months |
| Schedule B: TAK-931 100 mg | Duration of Response (DOR) | 4.2 months |
| Schedule B: TAK-931 120 mg | Duration of Response (DOR) | 0.0 months |
Secondary
Overall Response Rate (ORR)
ORR was defined as percentage of participants who had achieved complete response (CR) and partial response (PR), as measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
Time frame: From date of first dose to the date of first documentation of progressive disease (PD) or death due to any cause, which ever occurred first (up to Month 45)
Population: The response-evaluable population is defined as participants who receive at least 1 dose of study drug, have measurable disease at baseline, and at least 1 post-baseline response assessment. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Overall Response Rate (ORR) | 33 percentage of participants |
| Schedule A: TAK-931 40 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule A: TAK-931 50 mg | Overall Response Rate (ORR) | 7 percentage of participants |
| Schedule A: TAK-931 60 mg | Overall Response Rate (ORR) | 33 percentage of participants |
| Schedule B: TAK-931 60 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule B: TAK-931 80 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule B: TAK-931 100 mg | Overall Response Rate (ORR) | 17 percentage of participants |
| Schedule B: TAK-931 120 mg | Overall Response Rate (ORR) | 17 percentage of participants |
| Schedule D: TAK-931 20 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule D: TAK-931 30 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule D: TAK-931 40 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule E: TAK-931 100 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule E: TAK-931 120 mg | Overall Response Rate (ORR) | 0 percentage of participants |
| Schedule E: TAK-931 150 mg | Overall Response Rate (ORR) | 0 percentage of participants |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from the date of first dose to the date of first documentation of PD or death due to any cause, whichever occurs first, as measured by RECIST V1.1. PD: 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method.
Time frame: From date of first dose to the date of first documentation of PD or death due to any cause, which ever occurred first (up to Month 45)
Population: The safety population was defined as all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Progression-free Survival (PFS) | 4.2 months |
| Schedule A: TAK-931 40 mg | Progression-free Survival (PFS) | 2.1 months |
| Schedule A: TAK-931 50 mg | Progression-free Survival (PFS) | 2.0 months |
| Schedule A: TAK-931 60 mg | Progression-free Survival (PFS) | 4.8 months |
| Schedule B: TAK-931 60 mg | Progression-free Survival (PFS) | 3.1 months |
| Schedule B: TAK-931 80 mg | Progression-free Survival (PFS) | 2.8 months |
| Schedule B: TAK-931 100 mg | Progression-free Survival (PFS) | 2.1 months |
| Schedule B: TAK-931 120 mg | Progression-free Survival (PFS) | 4.2 months |
| Schedule D: TAK-931 20 mg | Progression-free Survival (PFS) | 1.9 months |
| Schedule D: TAK-931 30 mg | Progression-free Survival (PFS) | 3.9 months |
| Schedule D: TAK-931 40 mg | Progression-free Survival (PFS) | 2.1 months |
| Schedule E: TAK-931 100 mg | Progression-free Survival (PFS) | 1.9 months |
| Schedule E: TAK-931 120 mg | Progression-free Survival (PFS) | 1.9 months |
| Schedule E: TAK-931 150 mg | Progression-free Survival (PFS) | 2.6 months |
Secondary
Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931
H-score were a composite score that comprised of intensity and percentage of staining and were used for assessing amount of protein (in this case pMCM2 \[Ser40\]) present in a tissue sample. The composite score obtained by H-score is derived by adding of the percentages of cell staining at each intensity level multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\], 3+ \[strong staining\]). The H-score has a range of 0 to 300. Lower H-scores represent lower expression of pMCM2 (Ser40) in the tissue sample, while higher scores represent stronger expression of pMCM2 (Ser40) in the tissue samples.
Time frame: Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days)
Population: Pharmacodynamics population: all participants who received at least the first dose of TAK-931, had a baseline skin punch biopsy sample, and had at least 1 additional postbaseline skin punch biopsy sample. Overall number analyzed N: participants who were evaluable for the outcome measure. Number analyzed n: participants who were evaluable for this outcome measure for given categories. Data for this outcome measure was not collected and analyzed for Schedule E Cohorts due to business reasons.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -7.533 score on a scale | Standard Deviation 2.928 |
| Schedule A: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 18.467 score on a scale | Standard Deviation 8.4506 |
| Schedule A: TAK-931 40 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -6.667 score on a scale | Standard Deviation 10.5078 |
| Schedule A: TAK-931 40 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 19.533 score on a scale | Standard Deviation 3.7754 |
| Schedule A: TAK-931 50 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 10.500 score on a scale | Standard Deviation 5.8477 |
| Schedule A: TAK-931 50 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -6.743 score on a scale | Standard Deviation 8.7444 |
| Schedule A: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -9.933 score on a scale | Standard Deviation 2.203 |
| Schedule A: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 10.933 score on a scale | Standard Deviation 1.9425 |
| Schedule B: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 4.400 score on a scale | Standard Deviation 2.9597 |
| Schedule B: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule B: Change at Cycle 1 Day 7 | -3.733 score on a scale | Standard Deviation 3.177 |
| Schedule B: TAK-931 80 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule B: Change at Cycle 1 Day 7 | -9.180 score on a scale | Standard Deviation 7.2589 |
| Schedule B: TAK-931 80 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 12.720 score on a scale | Standard Deviation 2.0229 |
| Schedule D: TAK-931 20 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule D: Change at Cycle 1 Day 12 | -67.100 score on a scale | — |
| Schedule D: TAK-931 20 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 22.050 score on a scale | Standard Deviation 24.5239 |
| Schedule D: TAK-931 20 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -5.900 score on a scale | Standard Deviation 4.2379 |
| Schedule D: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -26.883 score on a scale | Standard Deviation 24.5978 |
| Schedule D: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931 | Baseline | 33.317 score on a scale | Standard Deviation 23.4266 |
Secondary
Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931
Positive index was calculated by taking the number of cells staining positive for the marker over the total number of cells.
Time frame: Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days)
Population: Pharmacodynamics population: all participants who received at least the first dose of TAK-931, had a baseline skin punch biopsy sample, and had at least 1 additional postbaseline skin punch biopsy sample. Overall number analyzed N: participants who were evaluable for the outcome measure. Number analyzed n: participants who were evaluable for this outcome measure for given categories. Data for this outcome measure was not collected and analyzed for Schedule E Cohorts due to business reasons.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Schedule A: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -0.03037 percentage of cell | Standard Deviation 0.014191 |
| Schedule A: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.08600 percentage of cell | Standard Deviation 0.03995 |
| Schedule A: TAK-931 40 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.08533 percentage of cell | Standard Deviation 0.019425 |
| Schedule A: TAK-931 40 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -0.02386 percentage of cell | Standard Deviation 0.046889 |
| Schedule A: TAK-931 50 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.04429 percentage of cell | Standard Deviation 0.02178 |
| Schedule A: TAK-931 50 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -0.02643 percentage of cell | Standard Deviation 0.033014 |
| Schedule A: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -0.04125 percentage of cell | Standard Deviation 0.008245 |
| Schedule A: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.04800 percentage of cell | Standard Deviation 0.006928 |
| Schedule B: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.02000 percentage of cell | Standard Deviation 0.013856 |
| Schedule B: TAK-931 60 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule B: Change at Cycle 1 Day 7 | -0.01667 percentage of cell | Standard Deviation 0.015144 |
| Schedule B: TAK-931 80 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.05080 percentage of cell | Standard Deviation 0.007694 |
| Schedule B: TAK-931 80 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule B: Change at Cycle 1 Day 7 | -0.01916 percentage of cell | Standard Deviation 0.063995 |
| Schedule D: TAK-931 20 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -0.02150 percentage of cell | Standard Deviation 0.01893 |
| Schedule D: TAK-931 20 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule D: Change at Cycle 1 Day 12 | -0.33900 percentage of cell | — |
| Schedule D: TAK-931 20 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.10217 percentage of cell | Standard Deviation 0.126757 |
| Schedule D: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Schedule A and D: Change at Cycle 1 Day 8 | -0.12436 percentage of cell | Standard Deviation 0.13441 |
| Schedule D: TAK-931 30 mg | Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931 | Baseline | 0.15200 percentage of cell | Standard Deviation 0.128829 |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 0.97 hours |
| Schedule A: TAK-931 40 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.05 hours |
| Schedule A: TAK-931 50 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.93 hours |
| Schedule A: TAK-931 60 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 3.88 hours |
| Schedule B: TAK-931 60 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.00 hours |
| Schedule B: TAK-931 80 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 4.00 hours |
| Schedule B: TAK-931 100 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.36 hours |
| Schedule B: TAK-931 120 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.05 hours |
| Schedule D: TAK-931 20 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.00 hours |
| Schedule D: TAK-931 30 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 2.13 hours |
| Schedule D: TAK-931 40 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 1.92 hours |
| Schedule E: TAK-931 100 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 2.00 hours |
| Schedule E: TAK-931 120 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 3.82 hours |
| Schedule E: TAK-931 150 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931 | 2.07 hours |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Population: The PK population was defined as all participants for whom there were sufficient dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Schedule A: TAK-931 30 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 2.02 hours |
| Schedule A: TAK-931 40 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.00 hours |
| Schedule A: TAK-931 50 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.91 hours |
| Schedule A: TAK-931 60 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.95 hours |
| Schedule B: TAK-931 60 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 2.00 hours |
| Schedule B: TAK-931 80 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 2.01 hours |
| Schedule B: TAK-931 100 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.90 hours |
| Schedule B: TAK-931 120 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.92 hours |
| Schedule D: TAK-931 20 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.50 hours |
| Schedule D: TAK-931 30 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 2.00 hours |
| Schedule D: TAK-931 40 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.08 hours |
| Schedule E: TAK-931 100 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 1.49 hours |
| Schedule E: TAK-931 120 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 2.07 hours |
| Schedule E: TAK-931 150 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931 | 2.08 hours |