All Drugs and Chemicals

Serabelisib

Enzyme Inhibitors

TAK-117 administered orally intermittently, once every other day (Monday, Wednesday, and Friday) each week

TAK-117 administered orally intermittently, once a day for 3 consecutive days (Monday, Tuesday, and Wednesday) each week

oral administration of TAK-117, daily and intermittent schedules.

TAK-117

Medical Monitor

The purpose of this study is to determine the maximum tolerated dose (MTD) and/or optimal biologic dose(OBD), safety and tolerability, dose-limiting toxicity (DLT) of TAK-117 when administered orally in subjects with advanced solid malignancies.

Dose Escalation Study of TAK-117 (MLN1117) in Subjects With Advanced Cancer

A Phase I, Dose Escalation Study of MLN1117 in Subjects With Advanced Solid Malignancies Followed by Expansion in Subjects With Measurable Disease

MTD is highest dose level of TAK-117 at which no more than 1 out of 6 participants had a dose limiting toxicity (DLT) during first cycle. DLT was any 1 of following events occurring within first 21 days of Cycle 1 of TAK-117 administration, Grade 2: fasting hyperglycemia for \>14 days. Grade 3: nausea and/or vomiting/diarrhea for \>7 days; rash for \>7 days; thrombocytopenia with bleeding; fasting hyperglycemia for \>24 hours(hr). Grade \>=3:nonhematologic toxicity considered clinically significant by investigator. Grade 4:neutropenia (absolute neutrophil count \<=0.5\*10\^9per liter\[/L\]) for \>7 days in absence of growth factor support; neutropenia of any duration accompanied with fever \>=38.5 degree Celsius and/or systemic infection. Grade \>=4:hematologic toxicity. Inability to administer at least 75% of planned doses of TAK-117 within Cycle 1 due to its related toxicity;Any clinically significant occurrence that investigators and sponsor agreed would place participants at undue safety risk.

Severity of AEs was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 as follow: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening); Grade 5 (fatal).

The estimate of the ORR is calculated as crude percentage of participants who's best overall response is complete response (CR) or partial response (PR). Objective response (CR and PR) as determined by the participants best tumor response was assessed using response evaluation criteria in solid tumors (RECIST) version 1.1. As per RECIST version 1.1, CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 millimeter \[mm\]). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease was defined as not qualifying for CR, PR, and progressive disease (PD).

Duration of response was to be calculated for participants who achieved CR or PR. Duration of objective response was defined as the number of days from the start date of PR or CR (whichever response was achieved first) to the first date that PD or disease progression was objectively documented. The duration of objective response was to be right-censored for participants who achieved CR or PR and met 1 of the following conditions: Non-protocol anticancer treatment started before documentation of PD; Documented PD after more than 1 missed disease assessment visit; Alive and did not have documentation of PD before a data analysis cutoff date.

Clinical benefit rate was defined as the participants who achieved stable disease (SD) for at least 15 weeks, CR, or PR. The estimate of the CBR was calculated as crude percentage of participants whose best ORR was CR, PR or SD for at least 90 days.

Pharmacodynamic markers included phosphorylated ribosomal protein S6 (PS6), phosphorylated eukaryotic initiation factor 4E-binding protein 1 (P4EBP1), phosphorylated N-myc downstream regulated gene 1 (PNDRG1), phosphorylated proline-rich AKT substrate of 40 kilodaltons (PPRAS40), and phosphorylated serine/threonine protein kinase AKT (PAKT). Analysis population (n) for each skin biopsy biomarker is as follow: P4EBP1 (n=6,6,6,2,2,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PAKT and PNDRG1 (n=6,6,7,2,2,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PPRAS40 (n= 6,0,6,2,2,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PS6 (n=6,6,7,2,2,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0)."n" for each tumor tissue biomarkers is as follow: P4EBP1, PAKT, PNDRG1, and PS6 (n=1,1,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0); PPRAS40 (n= 1,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0).

Millennium Pharmaceuticals, Inc.

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

TAK-117 100 mg, capsules (Process A), orally, QD up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: TAK-117 100 Milligram (mg), Once Daily (QD)

TAK-117 150 mg, capsules (Process A), orally, QD up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: TAK-117 150 mg, QD

TAK-117 200 mg, capsules (Process A), orally, QD up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: TAK-117 200 mg, QD

TAK-117 300 mg, capsules (Process A), orally, QD up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: TAK-117 300 mg, QD

TAK-117 200 mg, capsules (Process A), orally, once every other day on Monday, Wednesday, and Friday each week (MWF QW) up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 200 mg, MWF QW

TAK-117 300 mg, capsules (Process A), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 300 mg, MWF QW

TAK-117 400 mg, capsules (Process A), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 400 mg, MWF QW

TAK-117 600 mg, capsules (Process A), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 600 mg, MWF QW

TAK-117 900 mg, capsules (Process A), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 900 mg, MWF QW

TAK-117 1200 mg, capsules (Process A), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 1200 mg, MWF QW

TAK-117 200 mg, capsules (Process A), orally, QD for 3 consecutive days, on Monday, Tuesday, and Wednesday each week (MTW QW) up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 200 mg, MTW QW

TAK-117 400 mg, capsules (Process A), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 400 mg, MTW QW

TAK-117 600 mg, capsules (Process A), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 600 mg, MTW QW

TAK-117 900 mg, capsules (Process A), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days.

Process A: TAK-117 900 mg, MTW QW

TAK-117 600 mg, capsules (Process B), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 600 mg Process B Capsule (FM) MWF QW

TAK-117 900 mg, capsules (Process B), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 900 mg FM MWF QW

TAK-117 1200 mg, capsules (Process B), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 1200 mg FM MWF QW

TAK-117 600 mg, capsules (Process B), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 600 mg FM MTW QW

TAK-117 900 mg, capsules (Process B), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 900 mg FM MTW QW

TAK-117 1200 mg, capsules (Process B), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 1200 mg FM MTW QW

TAK-117 1500 mg, capsules (Process B), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 1500 mg FM MTW QW

TAK-117 300 mg, capsules (Process B), orally, BID every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 300 mg FM Twice Daily (BID) MWF QW

TAK-117 400 mg, capsules (Process B), orally, intermittently, BID every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 400 mg FM BID MWF QW

TAK-117 500 mg, capsules (Process B), orally, intermittently, BID every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 500 mg FM BID MWF QW

TAK-117 600 mg, capsules (Process B), orally, intermittently, BID every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycles were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 600 mg FM BID MWF QW

Total

Age, Continuous

Gender

Ethnicity (NIH/OMB)

White

Black or African American

Asian

Other

Not Reported

Race/Ethnicity, Customized

Females of Child-bearing Potential

Post-menopausal

Sterilized Females

Males (Excluded from this analysis)

Female Child Bearing Potential

Height data was available only for 119 participants as follow: n=5,6,8,2,3,2,3,3,12,3,3,3,3,11,3,3,7,3,3,3,6,4,4,9,7.

Height

Weight data was available only for 123 participants as follow: n=5,6,8,4,3,2,3,3,12,3,3,3,3,11,3,3,7,3,3,3,6,4,4,10,8.

Weight

BSA data was available only for 119 participants as follow: n=5,6,8,2,3,2,3,3,12,3,3,3,3,11,3,3,7,3,3,3,6,4,4,9,7.

Body Surface Area (BSA)

The all subjects as treated (ASaT) population included all enrolled participants who received at least 1 dose of TAK-117.

Medical Director

TAK-117 100-300 mg, capsules (Process A), orally, QD up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: Total QD TAK-117 100-300 mg

TAK-117 200-1200 mg, capsules (Process A), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: Total MWF QW 200-1200 mg

TAK-117 200-900 mg, capsules (Process A), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days.

Process A: Total MTW QW 200-900 mg

TAK-117 600-1200 mg, capsules (Process B), orally, once every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: Total FM MWF QW TAK-117 600-1200 mg

TAK-117 600-1500 mg, capsules (Process B), orally, QD for 3 consecutive days, on MTW QW up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: Total FM MTW QW 600-1500 mg

TAK-117 300-600 mg, capsules (Process B), orally, BID every other day on MWF QW up to Day 15 of each treatment cycle. Treatment cycle were repeated every 21 days. FM used drug substance manufactured by an improved synthetic process.

Process B: Total FM BID MWF QW 300-600 mg

The ASat population included all enrolled participants who received at least 1 dose of TAK-117.

Maximum Tolerated Dose (MTD) of TAK-117

TEAE

AEs leading to discontinuation of study drug

Death

DLTs in Cycle 1

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Death, Adverse Events (AEs) Leading to Discontinuation of Study Drug, and DLTs in Cycle 1

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants With Highest Level of TEAEs Severity

Number of Participants With Clinically Meaningful Changes in Laboratory Values

Number of Participants With Clinically Meaningful Changes in Vital Signs

Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG)

The full analysis set (FAS) population included participants who received at least 1 dose of TAK-117, baseline data for those analyses that required baseline data and postbaseline endpoint data subsequent to at least 1 dose of study drug.

Overall Response Rate (ORR)

The duration of objective response analysis was not performed due to change in planned analysis.

Duration of Objective Response

The FAS population included participants who received at least 1 dose of TAK-117, baseline data for those analyses that required baseline data and postbaseline endpoint data subsequent to at least 1 dose of study drug.

Clinical Benefit Rate (CBR)

Cohort 1: TAK-117 100 mg, capsules, orally, once a day (QD), continuously for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 100 mg

Cohort 2: TAK-117 150 mg, capsules, orally, QD, continuously for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 150 mg

Cohort 3: TAK-117 200 mg, capsules, orally, QD, continuously; Cohort 5: TAK-117 200 mg, capsules, orally, intermittently, once every other day on MWF QW; Cohort 11: TAK-117 200 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW. TAK-117 was administered in all 3 cohorts for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 200 mg

Cohort 4: TAK-117 300 mg, capsules, orally, QD, continuously; Cohort 6: TAK-117 300 mg, capsules, orally, intermittently, once every other day on MWF QW. TAK-117 was administered in both the cohorts for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 300 mg

Cohort 7: TAK-117 400 mg, capsules, orally, intermittently, once every other day on MWF QW; Cohort 12: TAK-117 400 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW. TAK-117 was administered in both the cohorts for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 400 mg

Cohort 8: TAK-117 600 mg, capsules, orally, intermittently, once every other day on MWF QW; Cohort 13: TAK-117 600 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW. TAK-117 was administered in both the cohorts for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 600 mg

Cohort 9: TAK-117 900 mg, capsules, orally, intermittently, once every other day on MWF QW; Cohort 14: TAK-117 200 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW. TAK-117 was administered in both the cohorts for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 900 mg

Cohort 10: TAK-117 1200 mg, capsules, orally, intermittently, once every other day on MWF QW for first 21 days of therapy (Cycle 1). Process A included participants who received original formulation of TAK-117 capsules.

Process A: TAK-117 1200 mg

Cohort 22: TAK-117 300 mg, capsules, orally, intermittently, BID every other day on MWF QW for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 300 mg

Cohort 23: TAK-117 400 mg, capsules, orally, intermittently, BID every other day on MWF QW for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 400 mg

Cohort 24: TAK-117 500 mg, capsules, orally, intermittently, BID every other day on MWF QW for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 500 mg

Cohort 15: TAK-117 600 mg, capsules, orally, intermittently, once every other day on MWF QW; Cohort 18: TAK-117 600 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW; Cohort 25: TAK-117 600 mg, capsules, orally, intermittently, BID every other day on MWF QW. TAK-117 was administered in all the 3 cohorts for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 600 mg

Cohort 16: TAK-117 900 mg, capsules, orally, intermittently, once every other day on MWF QW; Cohort 19: TAK-117 900 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW. TAK-117 was administered in both the cohorts for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 900 mg

Cohort 17: TAK-117 1200 mg, capsules, orally, intermittently, once every other day on MWF QW ; Cohort 20: TAK-117 1200 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW. TAK-117 was administered in both the cohorts for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 1200 mg

Cohort 21: TAK-117 1500 mg, capsules, orally, intermittently, QD for 3 consecutive days, on MTW QW for first 21 days of therapy (Cycle 1). Process B in the study is referred to the study design when new CTM was introduced. FM used drug substance manufactured by an improved synthetic process.

Process B: TAK-117 1500 mg

Pharmacokinetic (PK) population included all participants who took at least 1 dose of study drug and had sufficient plasma concentration-time data to calculate PK parameters.

Cmax: Maximum Observed Plasma Concentration for TAK-117

PK population included all participants who took at least 1 dose of study drug and had sufficient concentration-time data to calculate PK parameters.

Ctrough: Observed Concentration at the End of Dosing Interval for TAK-117

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-117

T 1/2z: Terminal Disposition Phase Half-life for TAK-117

AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-117

No data is reported since serum concentration of TAK-117 were below the limit of quantification.

AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-117

%AUC Extrapolated: Percentage of Area Under Concentration-extrapolated

Skin Biopsy: P4EBP1

Skin Biopsy: PAKT

Skin Biopsy: PNDRG1

Skin Biopsy: PPRAS40

Skin Biopsy: PS6

Tumor Tissue: P4EBP1

Tumor Tissue: PAKT

Tumor Tissue: PNDRG1

Tumor Tissue: PPRAS40

Tumor Tissue: PS6

Asat population where baseline and post-baseline assessments were available. The ASat population included all enrolled participants who received at least 1 dose of TAK-117.

Spots Global Cancer Trial Database for Dose Escalation Study of TAK-117 (MLN1117) in Subjects With Advanced Cancer

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

Useful links and downloads for this trial