Advanced Nonhematologic Malignancies
Conditions
Keywords
Drug Therapy, TAK-228, TAK-117
Brief summary
The purpose of this study was to evaluate the safety and to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and dosing schedules of oral TAK-228+TAK-117. It also evaluated the single- and multiple-dose plasma pharmacokinetics (PK) of TAK-228+TAK-117 in participants with advanced nonhematologic malignancies.
Detailed description
The drug being tested in this study was TAK-228. TAK-228 was tested to evaluate the safety, pharmacokinetics and efficacy, of TAK-228 in combination with TAK-117 when administered to adult participants with advanced nonhematologic malignancies. The study enrolled 101 patients. The study consisted of 2 phases: an escalation stage followed by an expansion stage. Participants in escalation stage were assigned to the following treatment arms: * Dose escalation treatment arm A: TAK-228 2 or 4 mg capsule * Dose escalation treatment arm B: TAK-228 3, 4, 6 or 8 mg capsule * Dose escalation treatment arm C: TAK-228 3 mg capsule Upon completion of the escalation stage, 1 combination treatment regimen was selected for further safety, tolerability, pharmacokinetics, and mutual drug-drug interaction characterization in the expansion stage. During treatment, participants in both stages received TAK-228 and TAK-117 capsules at prespecified doses in repeated 28-day cycles. This multi-center trial conducted in the United States, United Kingdom and Spain. The overall time to participate in this study was approximately 68 weeks. Participants made multiple visits to the clinic, and a final visit after 30 days after last dose of study drug.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants 18 years or older * Participants must have a diagnosis and documented disease progression of a solid tumor malignancy, excluding primary brain tumor, for which standard, curative, or life prolonging treatment does not exist or is no longer effective * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Female participants who are postmenopausal for at least 1 year prior to screening. For women of child-bearing potential agree to practice 2 effective methods of contraception or agree to practice true abstinence * Male participants must agree to practice effective barrier contraception during the entire study treatment period and through 30 days after last dose of study drug or practice true abstinence * Voluntary written consent * Suitable venous access * Participants must have a block of banked tumor tissue and/or fresh tumor tissue or at least 10 unstained slides available to be sent to the central laboratory * Clinical laboratory values as specified in the protocol * Participants must have radiographically or clinically evaluable tumor
Exclusion criteria
* 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 * Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment * Treatment with any investigational products within 30 days before the first dose of study drug * Previous treatment with TAK-117 and/or TAK-228; previous treatment with dual mTORC1/2 or dual PI3K-mTOR inhibitors * Failed to have recovered from the reversible effects of previous anticancer therapies * Have received systemic corticosteroid (inhalers are allowed) within 7 days before the first administration of study drug * Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug * Diagnosis of diabetes mellitus * Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection * Known human immunodeficiency virus (HIV) infection * Cardiovascular conditions as defined in the protocol * A requirement for positive inotropic support (excluding digoxin) or serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year before screening * Participants who are taking proton pump inhibitors within 7 days of the first dose or who require treatment with proton pump inhibitors during the trial or those who are taking histamine-2 (H2) receptor antagonists within 24 hours of the first dose * Participants who received previous therapy with PI3K inhibitors or rapalogs will be allowed in the study if all other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose | — |
| CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | From Baseline to 30 days after the last dose of study drug (Up to approximately 68 weeks) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above-mentioned criteria. |
| Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) \[Cycle 1 Day 24\]/ AUC(0-24) \[Cycle1 Day 1\]. |
| Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) \[Cycle 1 Day 24\]/ AUC(0-24) \[Cycle1 Day 1\]. |
| Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose | — |
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose | — |
| CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose | — |
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks) | The DOR is defined as the time from the date of first documented response of CR/PR to the first documented progressive disease (PD), or censored at the last response assessment date that is SD or better for a participant that has not progressed. CR was defined as the disappearance of all target lesions and for non-target lesions, the disappearance of all non-target lesions and normalization of tumor marker level. PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. |
| Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks) | ORR defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT or MRI. CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter (LD) of target lesions. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since the treatment started. |
Countries
Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in Spain, United Kingdom and United States from 28 June 2013 to 30 April 2018.
Pre-assignment details
Participants with a diagnosis of advanced nonhematologic malignancies were enrolled. A total of 101 participants were enrolled, out of which 81 entered the escalation phase, and 20 entered the expansion phase.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A TAK-228 2 mg, capsule (unmilled), orally, once daily every day (QD), and TAK-117 100 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 4 cycles (each cycle was 28 days), up to 16 weeks. | 7 |
| Dose Escalation Treatment Arm A: Cohort 2A TAK-228 4 mg, capsule (unmilled), orally, once daily every day (QD), and TAK-117 100 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 3 cycles (each cycle was 28 days), up to 10.4 weeks. | 3 |
| Dose Escalation Treatment Arm A: Cohort 3A TAK-228 2 mg, capsule (unmilled), orally, once daily every day (QD), and TAK-117 200 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 5 cycles (each cycle was 28 days), up to 21.0 weeks. | 7 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) TAK-228 2 mg, capsule (milled), orally, once daily every day (QD), and TAK-117 200 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 2 cycles (each cycle was 28 days), up to 6.1 weeks. | 3 |
| Dose Escalation Treatment Arm A: Cohort 4A TAK-228 2 mg, capsule (unmilled), orally, once daily every day (QD), and TAK-117 300 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 13 cycles (each cycle was 28 days), up to approximately 52 weeks. | 6 |
| Dose Escalation Treatment Arm B: Cohort 1B TAK-228 3 mg, capsule (unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 100 mg, capsule, orally, once on MTuW QW for up to 6 cycles (each cycle was 28 days), up to 23.4 weeks. | 3 |
| Dose Escalation Treatment Arm B: Cohort 2B TAK-228 3 mg, capsule (unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 200 mg, capsule, orally, once on MTuW QW for up to 6 cycles (each cycle was 28 days), up to 21.3 weeks. | 3 |
| Dose Escalation Treatment Arm B: Cohort 3B TAK-228 6 mg, capsule (unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 200 mg, capsule, orally, once on MTuW QW for up to 5 cycles (each cycle was 28 days), up to 19.4 weeks. | 3 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) TAK-228 6 mg, capsule (milled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 200 mg, capsule, orally, once on MTuW QW for up to 4 cycles (each cycle was 28 days), up to 15.4 weeks. | 6 |
| Dose Escalation Treatment Arm B: Cohort 4B TAK-228 8 mg, capsule (unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 200 mg, capsule, orally, once on MTuW QW for up to 2 cycles (each cycle was 28 days), up to 7.4 weeks. | 3 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) TAK-228 4 mg, capsule (milled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 200 mg, capsule, orally, once on MTuW QW for up to 9 cycles (each cycle was 28 days), up to 38.7 weeks. | 16 |
| Dose Escalation Treatment Arm C: Cohort 1C TAK-228 3 mg, capsule (unmilled), orally, once on MTuW QW, and TAK-117 400 mg, capsule, orally, once on MTuW QW for up to 17 cycles (each cycle was 28 days), up to 64.3 weeks. | 7 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) TAK-228 3 mg, capsule (milled), orally, once on MTuW QW, and TAK-117 300 mg, capsule, orally, once on MTuW QW for up to 11 cycles (each cycle was 28 days), up to 43.4 weeks. | 14 |
| Drug-Drug Interaction (DDI) Expansion Cohort (Milled) TAK-228 4 mg, capsule (milled), orally, once on MTuW QW except on Days 15, 16 and 17 of Cycle 1, and TAK-117 200 mg, capsule, orally, once on MTuW QW except on Days 1, 2 and 3 of Cycle 1 for up to 8 cycles (each cycle was 28 days), up to approximately 31.4 weeks. | 20 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 3 | 1 | 1 | 1 | 0 | 2 | 0 | 3 | 1 | 2 | 2 |
| Overall Study | Progressive Disease | 4 | 0 | 3 | 0 | 3 | 1 | 1 | 1 | 4 | 3 | 12 | 5 | 8 | 17 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Symptomatic Deterioration | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Unsatisfactory Therapeutic Response | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Dose Escalation Treatment Arm A: Cohort 1A | Dose Escalation Treatment Arm A: Cohort 2A | Dose Escalation Treatment Arm A: Cohort 3A | Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Dose Escalation Treatment Arm A: Cohort 4A | Dose Escalation Treatment Arm B: Cohort 1B | Dose Escalation Treatment Arm B: Cohort 2B | Dose Escalation Treatment Arm B: Cohort 3B | Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Dose Escalation Treatment Arm B: Cohort 4B | Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Dose Escalation Treatment Arm C: Cohort 1C | Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Drug-Drug Interaction (DDI) Expansion Cohort (Milled) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.9 years STANDARD_DEVIATION 6.31 | 69.3 years STANDARD_DEVIATION 5.13 | 50.6 years STANDARD_DEVIATION 14.05 | 66.7 years STANDARD_DEVIATION 5.86 | 48.7 years STANDARD_DEVIATION 11.66 | 74.3 years STANDARD_DEVIATION 5.13 | 69.3 years STANDARD_DEVIATION 14.15 | 68.3 years STANDARD_DEVIATION 9.24 | 58.0 years STANDARD_DEVIATION 7.72 | 68.3 years STANDARD_DEVIATION 4.16 | 56.6 years STANDARD_DEVIATION 9.69 | 53.3 years STANDARD_DEVIATION 14.36 | 56.5 years STANDARD_DEVIATION 6.97 | 63.4 years STANDARD_DEVIATION 9.1 | 59.4 years STANDARD_DEVIATION 10.96 |
| Body Mass Index (BMI) | 23.7 kg/m^2 STANDARD_DEVIATION 2.8 | 28.8 kg/m^2 STANDARD_DEVIATION 2.09 | 26.7 kg/m^2 STANDARD_DEVIATION 5.65 | 19.9 kg/m^2 STANDARD_DEVIATION 5.06 | 27.3 kg/m^2 STANDARD_DEVIATION 5.09 | 23.2 kg/m^2 STANDARD_DEVIATION 3.36 | 25.4 kg/m^2 STANDARD_DEVIATION 7.18 | 26.2 kg/m^2 STANDARD_DEVIATION 6.76 | 27.2 kg/m^2 STANDARD_DEVIATION 4.6 | 27.9 kg/m^2 STANDARD_DEVIATION 3.11 | 25.2 kg/m^2 STANDARD_DEVIATION 4.3 | 24.3 kg/m^2 STANDARD_DEVIATION 3.27 | 27.0 kg/m^2 STANDARD_DEVIATION 5.74 | 24.1 kg/m^2 STANDARD_DEVIATION 4.06 | 25.4 kg/m^2 STANDARD_DEVIATION 4.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 2 Participants | 7 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 2 Participants | 5 Participants | 2 Participants | 13 Participants | 7 Participants | 13 Participants | 9 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 7 Participants | 12 Participants |
| Height | 164.0 cm STANDARD_DEVIATION 3.84 | 165.1 cm STANDARD_DEVIATION 5.08 | 161.6 cm STANDARD_DEVIATION 3.26 | 159.4 cm STANDARD_DEVIATION 7.73 | 169.8 cm STANDARD_DEVIATION 8.73 | 169.0 cm STANDARD_DEVIATION 12.86 | 157.3 cm STANDARD_DEVIATION 4.25 | 168.5 cm STANDARD_DEVIATION 15.02 | 168.3 cm STANDARD_DEVIATION 12.41 | 168.5 cm STANDARD_DEVIATION 8.3 | 168.7 cm STANDARD_DEVIATION 11.24 | 180.7 cm STANDARD_DEVIATION 9.35 | 170.7 cm STANDARD_DEVIATION 7.86 | 163.7 cm STANDARD_DEVIATION 7.64 | 167.3 cm STANDARD_DEVIATION 9.67 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black Or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 2 Participants | 7 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 13 Participants | 4 Participants | 14 Participants | 19 Participants | 90 Participants |
| Region of Enrollment Spain | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 5 Participants | 1 Participants | 4 Participants | 12 Participants | 31 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 11 Participants |
| Region of Enrollment United States | 7 Participants | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 8 Participants | 5 Participants | 8 Participants | 7 Participants | 59 Participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 7 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 2 Participants | 11 Participants | 2 Participants | 7 Participants | 13 Participants | 64 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 5 Participants | 5 Participants | 7 Participants | 7 Participants | 37 Participants |
| Weight | 63.8 kg STANDARD_DEVIATION 9.11 | 78.4 kg STANDARD_DEVIATION 1.34 | 69.7 kg STANDARD_DEVIATION 14.2 | 49.8 kg STANDARD_DEVIATION 8.06 | 79.5 kg STANDARD_DEVIATION 19.91 | 67.6 kg STANDARD_DEVIATION 20.33 | 62.5 kg STANDARD_DEVIATION 15.32 | 73.7 kg STANDARD_DEVIATION 17.32 | 78.2 kg STANDARD_DEVIATION 22.65 | 79.3 kg STANDARD_DEVIATION 9.11 | 71.4 kg STANDARD_DEVIATION 13 | 79.9 kg STANDARD_DEVIATION 15.19 | 78.6 kg STANDARD_DEVIATION 17.55 | 64.6 kg STANDARD_DEVIATION 12.08 | 71.4 kg STANDARD_DEVIATION 15.63 |
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 / 7 | 0 / 3 | 1 / 7 | 0 / 3 | 1 / 6 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 2 / 16 | 0 / 7 | 0 / 14 | 2 / 20 |
| other Total, other adverse events | 6 / 7 | 3 / 3 | 7 / 7 | 3 / 3 | 5 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 16 / 16 | 7 / 7 | 13 / 14 | 19 / 20 |
| serious Total, serious adverse events | 2 / 7 | 0 / 3 | 1 / 7 | 1 / 3 | 1 / 6 | 0 / 3 | 1 / 3 | 1 / 3 | 1 / 6 | 1 / 3 | 4 / 16 | 4 / 7 | 6 / 14 | 9 / 20 |
Outcome results
Primary
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 31723.844 ng*hr/mL | Standard Deviation 38363.4872 |
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 14586.139 ng*hr/mL | Standard Deviation 10434.5445 |
| Dose Escalation Treatment Arm A: Cohort 2A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 11550.908 ng*hr/mL | Standard Deviation 11672.0852 |
| Dose Escalation Treatment Arm A: Cohort 2A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 22566.251 ng*hr/mL | Standard Deviation 13562.89 |
| Dose Escalation Treatment Arm A: Cohort 3A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 50960.181 ng*hr/mL | Standard Deviation 32295.532 |
| Dose Escalation Treatment Arm A: Cohort 3A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 43948.190 ng*hr/mL | Standard Deviation 25421.3428 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 69617.994 ng*hr/mL | Standard Deviation 46233.0898 |
| Dose Escalation Treatment Arm A: Cohort 4A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 54993.211 ng*hr/mL | Standard Deviation 27446.4517 |
| Dose Escalation Treatment Arm A: Cohort 4A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 46278.615 ng*hr/mL | Standard Deviation 48171.7982 |
| Dose Escalation Treatment Arm B: Cohort 1B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 12428.783 ng*hr/mL | Standard Deviation 16745.7861 |
| Dose Escalation Treatment Arm B: Cohort 1B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 26746.78 ng*hr/mL | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 47803.262 ng*hr/mL | Standard Deviation 4758.7418 |
| Dose Escalation Treatment Arm B: Cohort 2B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 90462.795 ng*hr/mL | Standard Deviation 14090.4676 |
| Dose Escalation Treatment Arm B: Cohort 3B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 67186.097 ng*hr/mL | Standard Deviation 49493.0584 |
| Dose Escalation Treatment Arm B: Cohort 3B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 23148.610 ng*hr/mL | Standard Deviation 27836.8878 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 55908.919 ng*hr/mL | Standard Deviation 39888.9699 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 38563.109 ng*hr/mL | Standard Deviation 23484.8077 |
| Dose Escalation Treatment Arm B: Cohort 4B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 1674.23 ng*hr/mL | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 4B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 39903.517 ng*hr/mL | Standard Deviation 33243.1212 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 38224.835 ng*hr/mL | Standard Deviation 22368.0163 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 72432.560 ng*hr/mL | Standard Deviation 27615.6802 |
| Dose Escalation Treatment Arm C: Cohort 1C | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 30925.255 ng*hr/mL | Standard Deviation 15126.4913 |
| Dose Escalation Treatment Arm C: Cohort 1C | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 46164.679 ng*hr/mL | Standard Deviation 37938.0208 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 70490.572 ng*hr/mL | Standard Deviation 58515.7794 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 46451.606 ng*hr/mL | Standard Deviation 33137.8861 |
Primary
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 206.418 ng*hr/mL | Standard Deviation 169.5373 |
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 120.888 ng*hr/mL | Standard Deviation 36.1184 |
| Dose Escalation Treatment Arm A: Cohort 2A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 247.361 ng*hr/mL | Standard Deviation 156.0211 |
| Dose Escalation Treatment Arm A: Cohort 2A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 208.389 ng*hr/mL | Standard Deviation 78.6461 |
| Dose Escalation Treatment Arm A: Cohort 3A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 200.762 ng*hr/mL | Standard Deviation 56.1368 |
| Dose Escalation Treatment Arm A: Cohort 3A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 138.929 ng*hr/mL | Standard Deviation 37.3727 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 230.983 ng*hr/mL | Standard Deviation 14.6292 |
| Dose Escalation Treatment Arm A: Cohort 4A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 109.622 ng*hr/mL | Standard Deviation 45.6613 |
| Dose Escalation Treatment Arm A: Cohort 4A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 115.884 ng*hr/mL | Standard Deviation 50.7913 |
| Dose Escalation Treatment Arm B: Cohort 1B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 203.836 ng*hr/mL | Standard Deviation 120.1336 |
| Dose Escalation Treatment Arm B: Cohort 1B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 126.062 ng*hr/mL | Standard Deviation 120.8204 |
| Dose Escalation Treatment Arm B: Cohort 2B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 303.897 ng*hr/mL | Standard Deviation 152.5659 |
| Dose Escalation Treatment Arm B: Cohort 2B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 410.604 ng*hr/mL | Standard Deviation 265.8768 |
| Dose Escalation Treatment Arm B: Cohort 3B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 535.365 ng*hr/mL | Standard Deviation 256.8762 |
| Dose Escalation Treatment Arm B: Cohort 3B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 287.283 ng*hr/mL | Standard Deviation 268.7088 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 331.286 ng*hr/mL | Standard Deviation 133.7879 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 351.602 ng*hr/mL | Standard Deviation 122.6407 |
| Dose Escalation Treatment Arm B: Cohort 4B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 305.97 ng*hr/mL | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 4B | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 382.588 ng*hr/mL | Standard Deviation 250.2623 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 249.341 ng*hr/mL | Standard Deviation 128.4868 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 317.111 ng*hr/mL | Standard Deviation 151.6045 |
| Dose Escalation Treatment Arm C: Cohort 1C | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 168.408 ng*hr/mL | Standard Deviation 103.9245 |
| Dose Escalation Treatment Arm C: Cohort 1C | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 132.058 ng*hr/mL | Standard Deviation 71.7154 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 211.792 ng*hr/mL | Standard Deviation 100.9091 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 160.670 ng*hr/mL | Standard Deviation 90.6815 |
Primary
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-117 administered with TAK-228 | 61148.949 ng*hr/mL | Standard Deviation 42799.7918 |
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 17, TAK-117 administered alone | 63975.156 ng*hr/mL | Standard Deviation 53764.5716 |
Primary
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3, TAK-228 administered alone | 301.613 ng*hr/mL | Standard Deviation 123.9584 |
| Dose Escalation Treatment Arm A: Cohort 1A | AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-228 administered with TAK-117 | 390.307 ng*hr/mL | Standard Deviation 155.3378 |
Primary
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 16.993 L/hr | Standard Deviation 23.6496 |
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 13.821 L/hr | Standard Deviation 16.5047 |
| Dose Escalation Treatment Arm A: Cohort 2A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 7.18 L/hr | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 2A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 9.79 L/hr | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 3A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 17.95 L/hr | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 4A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 9.25 L/hr | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 1B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 19.7 L/hr | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 3B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 5.328 L/hr | Standard Deviation 1.2794 |
| Dose Escalation Treatment Arm B: Cohort 3B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 194.998 L/hr | Standard Deviation 258.2751 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 20.944 L/hr | Standard Deviation 16.6625 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 5.45 L/hr | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 17.879 L/hr | Standard Deviation 17.8072 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 4.803 L/hr | Standard Deviation 2.7599 |
| Dose Escalation Treatment Arm C: Cohort 1C | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 21.075 L/hr | Standard Deviation 16.4116 |
| Dose Escalation Treatment Arm C: Cohort 1C | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 11.199 L/hr | Standard Deviation 8.4334 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 67.750 L/hr | Standard Deviation 110.0873 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 32.455 L/hr | Standard Deviation 35.8687 |
Primary
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled during the dose escalation and expansion stage of the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants who were evaluable at each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 16.534 L/hour | Standard Deviation 5.4762 |
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 14.720 L/hour | Standard Deviation 4.5824 |
| Dose Escalation Treatment Arm A: Cohort 2A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 19.049 L/hour | Standard Deviation 11.8558 |
| Dose Escalation Treatment Arm A: Cohort 2A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 18.207 L/hour | Standard Deviation 4.1819 |
| Dose Escalation Treatment Arm A: Cohort 3A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 10.597 L/hour | Standard Deviation 3.9917 |
| Dose Escalation Treatment Arm A: Cohort 3A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 14.419 L/hour | Standard Deviation 7.5636 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 7.694 L/hour | Standard Deviation 0.575 |
| Dose Escalation Treatment Arm A: Cohort 4A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 15.311 L/hour | Standard Deviation 3.6762 |
| Dose Escalation Treatment Arm A: Cohort 4A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 15.683 L/hour | Standard Deviation 2.9149 |
| Dose Escalation Treatment Arm B: Cohort 1B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 9.23 L/hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 1B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 11.38 L/hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 13.58 L/hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 10.728 L/hour | Standard Deviation 6.9669 |
| Dose Escalation Treatment Arm B: Cohort 3B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 28.54 L/hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 3B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 12.817 L/hour | Standard Deviation 4.7929 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 19.060 L/hour | Standard Deviation 7.1913 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 19.999 L/hour | Standard Deviation 10.0509 |
| Dose Escalation Treatment Arm B: Cohort 4B | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 16.259 L/hour | Standard Deviation 9.3725 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 17.924 L/hour | Standard Deviation 9.5261 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 14.196 L/hour | Standard Deviation 5.3137 |
| Dose Escalation Treatment Arm C: Cohort 1C | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 22.715 L/hour | Standard Deviation 14.7252 |
| Dose Escalation Treatment Arm C: Cohort 1C | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 15.53 L/hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 16.133 L/hour | Standard Deviation 8.6701 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 13.933 L/hour | Standard Deviation 5.488 |
Primary
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-117 administered with TAK-228 | 11.797 L/hour | Standard Deviation 18.004 |
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 17, TAK-117 administered alone | 9.134 L/hour | Standard Deviation 8.7741 |
Primary
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3, TAK-228 administered alone | 15.368 L/hour | Standard Deviation 10.9714 |
| Dose Escalation Treatment Arm A: Cohort 1A | CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-228 administered with TAK-117 | 13.359 L/hour | Standard Deviation 11.3718 |
Primary
Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2514.0 ng/mL | Standard Deviation 1597.13 |
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1800.0 ng/mL | Standard Deviation 1049.25 |
| Dose Escalation Treatment Arm A: Cohort 2A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 988.7 ng/mL | Standard Deviation 858.57 |
| Dose Escalation Treatment Arm A: Cohort 2A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2720.0 ng/mL | Standard Deviation 1286.93 |
| Dose Escalation Treatment Arm A: Cohort 3A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 3438.3 ng/mL | Standard Deviation 1687 |
| Dose Escalation Treatment Arm A: Cohort 3A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3067.1 ng/mL | Standard Deviation 1243.5 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 4950.0 ng/mL | Standard Deviation 3381.06 |
| Dose Escalation Treatment Arm A: Cohort 4A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 4136.7 ng/mL | Standard Deviation 1487.68 |
| Dose Escalation Treatment Arm A: Cohort 4A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 3624.0 ng/mL | Standard Deviation 2925.79 |
| Dose Escalation Treatment Arm B: Cohort 1B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1054.8 ng/mL | Standard Deviation 1454.94 |
| Dose Escalation Treatment Arm B: Cohort 1B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2420 ng/mL | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3836.7 ng/mL | Standard Deviation 656.07 |
| Dose Escalation Treatment Arm B: Cohort 2B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 6180.0 ng/mL | Standard Deviation 127.28 |
| Dose Escalation Treatment Arm B: Cohort 3B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4876.7 ng/mL | Standard Deviation 848.84 |
| Dose Escalation Treatment Arm B: Cohort 3B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1631.3 ng/mL | Standard Deviation 1305.25 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4477.5 ng/mL | Standard Deviation 953.88 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2711.7 ng/mL | Standard Deviation 1172.97 |
| Dose Escalation Treatment Arm B: Cohort 4B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 100 ng/mL | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 4B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2568.7 ng/mL | Standard Deviation 2107.04 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3369.4 ng/mL | Standard Deviation 1417.31 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4863.3 ng/mL | Standard Deviation 1142.54 |
| Dose Escalation Treatment Arm C: Cohort 1C | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3077.7 ng/mL | Standard Deviation 1629.05 |
| Dose Escalation Treatment Arm C: Cohort 1C | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 3755.0 ng/mL | Standard Deviation 2831.78 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4805.3 ng/mL | Standard Deviation 2893.99 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3353.0 ng/mL | Standard Deviation 1955.02 |
Primary
Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 27.78 ng/mL | Standard Deviation 6.632 |
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 24.63 ng/mL | Standard Deviation 7.355 |
| Dose Escalation Treatment Arm A: Cohort 2A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 39.73 ng/mL | Standard Deviation 7.853 |
| Dose Escalation Treatment Arm A: Cohort 2A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 53.55 ng/mL | Standard Deviation 2.192 |
| Dose Escalation Treatment Arm A: Cohort 3A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 29.45 ng/mL | Standard Deviation 9.746 |
| Dose Escalation Treatment Arm A: Cohort 3A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 25.80 ng/mL | Standard Deviation 8.188 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 28.67 ng/mL | Standard Deviation 3.702 |
| Dose Escalation Treatment Arm A: Cohort 4A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 18.26 ng/mL | Standard Deviation 8.61 |
| Dose Escalation Treatment Arm A: Cohort 4A | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 13.75 ng/mL | Standard Deviation 6.938 |
| Dose Escalation Treatment Arm B: Cohort 1B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 37.36 ng/mL | Standard Deviation 49.078 |
| Dose Escalation Treatment Arm B: Cohort 1B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 21.69 ng/mL | Standard Deviation 29.273 |
| Dose Escalation Treatment Arm B: Cohort 2B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 48.90 ng/mL | Standard Deviation 28.157 |
| Dose Escalation Treatment Arm B: Cohort 2B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 46.10 ng/mL | Standard Deviation 17.253 |
| Dose Escalation Treatment Arm B: Cohort 3B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 72.43 ng/mL | Standard Deviation 13.094 |
| Dose Escalation Treatment Arm B: Cohort 3B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 33.30 ng/mL | Standard Deviation 16.301 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 61.58 ng/mL | Standard Deviation 14.894 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 53.10 ng/mL | Standard Deviation 7.257 |
| Dose Escalation Treatment Arm B: Cohort 4B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 17.1 ng/mL | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 4B | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 53.53 ng/mL | Standard Deviation 29.788 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 42.17 ng/mL | Standard Deviation 11.495 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 50.68 ng/mL | Standard Deviation 12.055 |
| Dose Escalation Treatment Arm C: Cohort 1C | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 27.53 ng/mL | Standard Deviation 11.665 |
| Dose Escalation Treatment Arm C: Cohort 1C | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 17.75 ng/mL | Standard Deviation 4.865 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 35.59 ng/mL | Standard Deviation 18.415 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 26.51 ng/mL | Standard Deviation 12.788 |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-117 administered with TAK-228 | 5357.3 ng/mL | Standard Deviation 2842.4 |
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 17, TAK-117 administered alone | 5332.6 ng/mL | Standard Deviation 2955.51 |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3, TAK-228 administered alone | 60.02 ng/mL | Standard Deviation 21.808 |
| Dose Escalation Treatment Arm A: Cohort 1A | Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-228 administered with TAK-117 | 71.99 ng/mL | Standard Deviation 22.546 |
Primary
Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above-mentioned criteria.
Time frame: From Baseline to 30 days after the last dose of study drug (Up to approximately 68 weeks)
Population: Safety population consisted of all enrolled participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| Dose Escalation Treatment Arm A: Cohort 1A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Dose Escalation Treatment Arm A: Cohort 2A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Treatment Arm A: Cohort 2A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Dose Escalation Treatment Arm A: Cohort 3A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| Dose Escalation Treatment Arm A: Cohort 3A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm A: Cohort 4A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm A: Cohort 4A | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 5 Participants |
| Dose Escalation Treatment Arm B: Cohort 1B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Dose Escalation Treatment Arm B: Cohort 1B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Treatment Arm B: Cohort 2B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Treatment Arm B: Cohort 2B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm B: Cohort 3B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Treatment Arm B: Cohort 3B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| Dose Escalation Treatment Arm B: Cohort 4B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Dose Escalation Treatment Arm B: Cohort 4B | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 16 Participants |
| Dose Escalation Treatment Arm C: Cohort 1C | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| Dose Escalation Treatment Arm C: Cohort 1C | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 14 Participants |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 6 Participants |
| Drug-Drug Interaction (DDI) Expansion Cohort (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 9 Participants |
| Drug-Drug Interaction (DDI) Expansion Cohort (Milled) | Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) | AEs | 19 Participants |
Primary
Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 10.023 ratio | Standard Deviation 9.0435 |
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 20.138 ratio | Standard Deviation 21.6013 |
| Dose Escalation Treatment Arm A: Cohort 2A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 11.256 ratio | Standard Deviation 7.1426 |
| Dose Escalation Treatment Arm A: Cohort 2A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 8.845 ratio | Standard Deviation 7.8516 |
| Dose Escalation Treatment Arm A: Cohort 3A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 2.294 ratio | Standard Deviation 0.5975 |
| Dose Escalation Treatment Arm A: Cohort 3A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 2.551 ratio | Standard Deviation 0.9673 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 2.676 ratio | Standard Deviation 0.1635 |
| Dose Escalation Treatment Arm A: Cohort 4A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 4.373 ratio | Standard Deviation 3.3285 |
| Dose Escalation Treatment Arm A: Cohort 4A | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 20.124 ratio | Standard Deviation 33.8991 |
| Dose Escalation Treatment Arm B: Cohort 1B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 3.93 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 1B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 3.931 ratio | Standard Deviation 2.4369 |
| Dose Escalation Treatment Arm B: Cohort 2B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 3.464 ratio | Standard Deviation 0.1399 |
| Dose Escalation Treatment Arm B: Cohort 2B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 3.602 ratio | Standard Deviation 0.8361 |
| Dose Escalation Treatment Arm B: Cohort 3B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 6.640 ratio | Standard Deviation 7.3746 |
| Dose Escalation Treatment Arm B: Cohort 3B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 54.242 ratio | Standard Deviation 87.1445 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 11.832 ratio | Standard Deviation 15.4766 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 6.877 ratio | Standard Deviation 8.86 |
| Dose Escalation Treatment Arm B: Cohort 4B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 1.96 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 4B | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 2.631 ratio | Standard Deviation 0.5993 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 5.482 ratio | Standard Deviation 6.7075 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 6.872 ratio | Standard Deviation 8.368 |
| Dose Escalation Treatment Arm C: Cohort 1C | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 11.494 ratio | Standard Deviation 10.943 |
| Dose Escalation Treatment Arm C: Cohort 1C | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 11.184 ratio | Standard Deviation 8.0869 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 4.664 ratio | Standard Deviation 3.9973 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 3.426 ratio | Standard Deviation 2.3804 |
Primary
Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-117 administered with TAK-228 | 7.423 ratio | Standard Deviation 7.423 |
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 17, TAK-117 administered alone | 21.357 ratio | Standard Deviation 44.3461 |
Primary
Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 12.145 ratio | Standard Deviation 6.0465 |
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 16.546 ratio | Standard Deviation 6.5659 |
| Dose Escalation Treatment Arm A: Cohort 2A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 13.588 ratio | Standard Deviation 8.3649 |
| Dose Escalation Treatment Arm A: Cohort 2A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 27.66 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 3A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 14.691 ratio | Standard Deviation 8.1076 |
| Dose Escalation Treatment Arm A: Cohort 3A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 14.553 ratio | Standard Deviation 6.8807 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 10.420 ratio | Standard Deviation 1.5662 |
| Dose Escalation Treatment Arm A: Cohort 4A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 13.983 ratio | Standard Deviation 6.6782 |
| Dose Escalation Treatment Arm A: Cohort 4A | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 9.363 ratio | Standard Deviation 6.6336 |
| Dose Escalation Treatment Arm B: Cohort 1B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 21.864 ratio | Standard Deviation 33.1541 |
| Dose Escalation Treatment Arm B: Cohort 1B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 23.757 ratio | Standard Deviation 31.1525 |
| Dose Escalation Treatment Arm B: Cohort 2B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 14.336 ratio | Standard Deviation 7.0986 |
| Dose Escalation Treatment Arm B: Cohort 2B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 9.305 ratio | Standard Deviation 4.7969 |
| Dose Escalation Treatment Arm B: Cohort 3B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 21.979 ratio | Standard Deviation 13.7911 |
| Dose Escalation Treatment Arm B: Cohort 3B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 20.212 ratio | Standard Deviation 22.0357 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 31.971 ratio | Standard Deviation 19.641 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 13.227 ratio | Standard Deviation 8.3834 |
| Dose Escalation Treatment Arm B: Cohort 4B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.8 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 4B | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 5.761 ratio | Standard Deviation 1.525 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 22.676 ratio | Standard Deviation 14.2142 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 22.555 ratio | Standard Deviation 10.4006 |
| Dose Escalation Treatment Arm C: Cohort 1C | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 15.012 ratio | Standard Deviation 6.5253 |
| Dose Escalation Treatment Arm C: Cohort 1C | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 8.805 ratio | Standard Deviation 7.3805 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 21.157 ratio | Standard Deviation 14.9668 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 10.725 ratio | Standard Deviation 2.7876 |
Primary
Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3, TAK-228 administered alone | 22.982 ratio | Standard Deviation 11.6286 |
| Dose Escalation Treatment Arm A: Cohort 1A | Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-228 administered with TAK-117 | 23.931 ratio | Standard Deviation 15.6395 |
Primary
RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort
Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) \[Cycle 1 Day 24\]/ AUC(0-24) \[Cycle1 Day 1\].
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with evaluable data at both Days 1 and 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 0.965 ratio | Standard Deviation 0.1423 |
| Dose Escalation Treatment Arm A: Cohort 2A | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 1.33 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 3A | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 1.161 ratio | Standard Deviation 0.2506 |
| Dose Escalation Treatment Arm A: Cohort 4A | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 1.049 ratio | Standard Deviation 0.9033 |
| Dose Escalation Treatment Arm B: Cohort 1B | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 1.18 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 2.007 ratio | Standard Deviation 0.4766 |
| Dose Escalation Treatment Arm B: Cohort 3B | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 2.687 ratio | Standard Deviation 0.57 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 1.748 ratio | Standard Deviation 1.1575 |
| Dose Escalation Treatment Arm B: Cohort 4B | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 0.91 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 1.879 ratio | Standard Deviation 1.5772 |
| Dose Escalation Treatment Arm C: Cohort 1C | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 0.925 ratio | Standard Deviation 0.6281 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort | 4.183 ratio | Standard Deviation 5.806 |
Primary
RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort
Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) \[Cycle 1 Day 24\]/ AUC(0-24) \[Cycle1 Day 1\].
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with evaluable data at both Days 1 and 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 2.225 ratio | Standard Deviation 1.4576 |
| Dose Escalation Treatment Arm A: Cohort 2A | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.25 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 3A | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.495 ratio | Standard Deviation 0.1884 |
| Dose Escalation Treatment Arm A: Cohort 4A | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.219 ratio | Standard Deviation 0.3497 |
| Dose Escalation Treatment Arm B: Cohort 1B | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.569 ratio | Standard Deviation 0.4099 |
| Dose Escalation Treatment Arm B: Cohort 2B | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.712 ratio | Standard Deviation 0.265 |
| Dose Escalation Treatment Arm B: Cohort 3B | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.718 ratio | Standard Deviation 0.4329 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.015 ratio | Standard Deviation 0.1453 |
| Dose Escalation Treatment Arm B: Cohort 4B | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.58 ratio | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.172 ratio | Standard Deviation 0.3363 |
| Dose Escalation Treatment Arm C: Cohort 1C | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.213 ratio | Standard Deviation 0.1306 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort | 1.461 ratio | Standard Deviation 0.2246 |
Primary
Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 6.590 hour | Standard Deviation 3.4673 |
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 5.722 hour | Standard Deviation 3.1259 |
| Dose Escalation Treatment Arm A: Cohort 2A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 6.53 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 2A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 4.92 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 3A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 2.98 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm A: Cohort 4A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 3.2 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 1B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 8.37 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 3B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 6.233 hour | Standard Deviation 4.4813 |
| Dose Escalation Treatment Arm B: Cohort 3B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 3.839 hour | Standard Deviation 3.5498 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 7.465 hour | Standard Deviation 2.2023 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 4.61 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 4.858 hour | Standard Deviation 2.7928 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 7.717 hour | Standard Deviation 2.6428 |
| Dose Escalation Treatment Arm C: Cohort 1C | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 6.379 hour | Standard Deviation 1.5369 |
| Dose Escalation Treatment Arm C: Cohort 1C | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 5.853 hour | Standard Deviation 2.1534 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 24 | 5.984 hour | Standard Deviation 3.6558 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort | Cycle 1, Day 1 | 7.368 hour | Standard Deviation 0.3774 |
Primary
Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 5.090 hour | Standard Deviation 2.1653 |
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 5.489 hour | Standard Deviation 2.4782 |
| Dose Escalation Treatment Arm A: Cohort 2A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 5.783 hour | Standard Deviation 3.3941 |
| Dose Escalation Treatment Arm A: Cohort 2A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4.686 hour | Standard Deviation 2.1265 |
| Dose Escalation Treatment Arm A: Cohort 3A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 5.521 hour | Standard Deviation 1.6417 |
| Dose Escalation Treatment Arm A: Cohort 3A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 6.214 hour | Standard Deviation 2.6649 |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 7.450 hour | Standard Deviation 0.7368 |
| Dose Escalation Treatment Arm A: Cohort 4A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 6.975 hour | Standard Deviation 1.0108 |
| Dose Escalation Treatment Arm A: Cohort 4A | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 7.635 hour | Standard Deviation 1.1253 |
| Dose Escalation Treatment Arm B: Cohort 1B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 5.43 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 1B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 4.65 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 8.5 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 2B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 8.412 hour | Standard Deviation 1.3996 |
| Dose Escalation Treatment Arm B: Cohort 3B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 4.96 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm B: Cohort 3B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 6.808 hour | Standard Deviation 1.7326 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 6.221 hour | Standard Deviation 1.0591 |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 5.792 hour | Standard Deviation 3.4405 |
| Dose Escalation Treatment Arm B: Cohort 4B | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 6.799 hour | Standard Deviation 5.574 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 6.320 hour | Standard Deviation 1.7839 |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 5.940 hour | Standard Deviation 1.6737 |
| Dose Escalation Treatment Arm C: Cohort 1C | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 5.512 hour | Standard Deviation 2.1598 |
| Dose Escalation Treatment Arm C: Cohort 1C | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 6.42 hour | Standard Deviation 0 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 6.354 hour | Standard Deviation 1.932 |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 7.593 hour | Standard Deviation 1.1365 |
Primary
Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-117 administered with TAK-228 | 6.420 hour | Standard Deviation 2.3635 |
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 17, TAK-117 administered alone | 5.717 hour | Standard Deviation 2.3715 |
Primary
Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3, TAK-228 administered alone | 6.823 hour | Standard Deviation 2.1608 |
| Dose Escalation Treatment Arm A: Cohort 1A | Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-228 administered with TAK-117 | 6.546 hour | Standard Deviation 1.8351 |
Primary
Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: Pharmacokinetic (PK) population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.000 hour |
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.000 hour |
| Dose Escalation Treatment Arm A: Cohort 2A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 0.758 hour |
| Dose Escalation Treatment Arm A: Cohort 2A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.000 hour |
| Dose Escalation Treatment Arm A: Cohort 3A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.000 hour |
| Dose Escalation Treatment Arm A: Cohort 3A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.400 hour |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.050 hour |
| Dose Escalation Treatment Arm A: Cohort 4A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2.000 hour |
| Dose Escalation Treatment Arm A: Cohort 4A | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.033 hour |
| Dose Escalation Treatment Arm B: Cohort 1B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4.000 hour |
| Dose Escalation Treatment Arm B: Cohort 1B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.083 hour |
| Dose Escalation Treatment Arm B: Cohort 2B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.000 hour |
| Dose Escalation Treatment Arm B: Cohort 2B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.408 hour |
| Dose Escalation Treatment Arm B: Cohort 3B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.067 hour |
| Dose Escalation Treatment Arm B: Cohort 3B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 0.617 hour |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 0.925 hour |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.358 hour |
| Dose Escalation Treatment Arm B: Cohort 4B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.067 hour |
| Dose Escalation Treatment Arm B: Cohort 4B | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4.000 hour |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.033 hour |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.000 hour |
| Dose Escalation Treatment Arm C: Cohort 1C | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2.083 hour |
| Dose Escalation Treatment Arm C: Cohort 1C | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 0.725 hour |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 1 | 0.983 hour |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.017 hour |
Primary
Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-117 administered with TAK-228 | 1.033 hour |
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort | Cycle 1, Day 17, TAK-117 administered alone | 1.983 hour |
Primary
Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK DDI-evaluable population consisted of all participants from Expansion Phase with sufficient dosing and concentration-time PK data to reliably estimate PK parameters for statistical analyses of effect of TAK-228 on TAK-117 PK and effect of TAK-117 on TAK-228 PK. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 3, TAK-228 administered alone | 1.000 hour |
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort | Cycle 1, Day 10, TAK-228 administered with TAK-117 | 0.983 hour |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.000 hour |
| Dose Escalation Treatment Arm A: Cohort 1A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 0.800 hour |
| Dose Escalation Treatment Arm A: Cohort 2A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.000 hour |
| Dose Escalation Treatment Arm A: Cohort 2A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.025 hour |
| Dose Escalation Treatment Arm A: Cohort 3A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 4.108 hour |
| Dose Escalation Treatment Arm A: Cohort 3A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.050 hour |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.050 hour |
| Dose Escalation Treatment Arm A: Cohort 4A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3.017 hour |
| Dose Escalation Treatment Arm A: Cohort 4A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2.417 hour |
| Dose Escalation Treatment Arm B: Cohort 1B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2.000 hour |
| Dose Escalation Treatment Arm B: Cohort 1B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.97 hour |
| Dose Escalation Treatment Arm B: Cohort 2B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.000 hour |
| Dose Escalation Treatment Arm B: Cohort 2B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.408 hour |
| Dose Escalation Treatment Arm B: Cohort 3B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 0.883 hour |
| Dose Escalation Treatment Arm B: Cohort 3B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.033 hour |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 3.150 hour |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 4.008 hour |
| Dose Escalation Treatment Arm B: Cohort 4B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 7.33 hour |
| Dose Escalation Treatment Arm B: Cohort 4B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3.883 hour |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 1.925 hour |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2.000 hour |
| Dose Escalation Treatment Arm C: Cohort 1C | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 2.083 hour |
| Dose Escalation Treatment Arm C: Cohort 1C | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 2.050 hour |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 24 | 1.117 hour |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort | Cycle 1, Day 1 | 3.125 hour |
Secondary
Duration of Response (DOR)
The DOR is defined as the time from the date of first documented response of CR/PR to the first documented progressive disease (PD), or censored at the last response assessment date that is SD or better for a participant that has not progressed. CR was defined as the disappearance of all target lesions and for non-target lesions, the disappearance of all non-target lesions and normalization of tumor marker level. PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions.
Time frame: Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)
Population: Safety population consisted of all enrolled participants who received at least 1 dose of any study drug. Data for this outcome measure is reported for the participants with objective response available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Drug-Drug Interaction (DDI) Expansion Cohort (Milled) | Duration of Response (DOR) | 92 days |
Secondary
Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
ORR defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT or MRI. CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter (LD) of target lesions. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since the treatment started.
Time frame: Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)
Population: Safety population consisted of all enrolled participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Treatment Arm A: Cohort 1A | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm A: Cohort 2A | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm A: Cohort 3A | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm A: Cohort 3A (Milled) | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm A: Cohort 4A | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm B: Cohort 1B | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm B: Cohort 2B | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm B: Cohort 3B | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm B: Cohort 3B (Milled) | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm B: Cohort 4B | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm B: Cohort 5B (Milled) | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm C: Cohort 1C | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Dose Escalation Treatment Arm C: Cohort 2C (Milled) | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 0.0 percentage of participants |
| Drug-Drug Interaction (DDI) Expansion Cohort (Milled) | Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 20.0 percentage of participants |