Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

The Initial Escalation Stage will enroll approximately 30 patients with advanced nonhematologic malignancies. TAK-733 will be administered orally in 28-day treatment cycles consisting of intermittent dosing with 21 days of continuous treatment, followed by a rest period of 7 days.

The Expansion Stage will enroll approximately 30 patients with advanced metastatic melanoma. The recommended phase 2 dose determined in the Initial Escalation Stage of TAK-733 will be administered orally in 28-day treatment cycles consisting of intermittent dosing with 21 days of continuous treatment, followed by a rest period of 7 days.

TAK-733

Medical Monitor

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics and maximum tolerated dose of TAK-733 in patients with advanced, nonhematologic tumors. The expansion stage of the study will evaluate evidence of antitumor activity of TAK-733 in patients with advanced metastatic melanoma.

Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies

A Multicenter, Open-label, Dose-escalation, Phase I Study of TAK-733, an Oral MEK Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

Millennium Pharmaceuticals, Inc.

Carcinoma

Carcinoma, Basal Cell

Neoplasms, Glandular and Epithelial

Neoplasms, Basal Cell

TAK-441 will be administered as an oral tablet as follows:

Patients enrolled in the dose escalation cohorts will receive:

* A single-dose administration on Day 1, followed by a 1-week washout period during which pharmacokinetics is assessed
* Continuous daily dosing on Days 8 through 28 in Cycle 1
* In subsequent cycles, continuous daily dosing over 21 days, repeated continuously

Patients enrolled in the expansion cohorts will receive continuous daily dosing on Days 1 through 21 of each 21-day cycle

TAK-441

This is the first study in which TAK-441 is administered to humans. The patient population will consist of adults aged 18 or older who have advanced nonhematologic malignancies and for whom standard treatment is no longer effective or does not offer curative or life-prolonging potential. Following completion of the dose escalation study, patients will be enrolled as part of 2 expansion cohorts.

A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies

A Multicenter, Open-Label, Dose-Escalation, Phase 1 Study of TAK-441, an Oral Hedgehog Signaling Pathway Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

Adverse events, serious adverse events, dose-limiting toxicities, assessments of clinical laboratory values, electrocardiogram parameters and vital sign measurements

Including but not limited to maximum plasma concentration (Cmax), first time to plasma concentration (Tmax) and area under the plasma concentration versus time curve (AUC)

Based on the investigator's assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

All Drugs and Chemicals

Serabelisib

Enzyme Inhibitors

TAK-228 2 or 4 mg, capsule (milled or unmilled), orally, once daily every day (QD), and TAK-117 100, 200 or 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.

TAK-228 3, 4, 6 or 8 mg, capsule (milled or unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 100 or 200 mg, capsule, orally, once on MTuW QW for up to 9 cycles (each cycle was 28 days), up to approximately 38.7 weeks.

TAK-228 3 mg, capsule (milled or unmilled), orally, once on MTuW QW, and TAK-117 300 or 400 mg, capsule, orally, once on MTuW QW for up to 17 cycles (each cycle was 28 days), up to approximately 64.3 weeks.

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.

TAK-228

TAK-117

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.

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.

A Safety and Pharmacokinetic Study of TAK-228 in Combination With TAK-117 in Adult Participants With Advanced Nonhematologic Malignancies

A Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced Nonhematologic Malignancies

Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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.

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) \[Cycle1 Day 1\].

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.

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.

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-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.

Dose Escalation Treatment Arm A: Cohort 1A

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.

Dose Escalation Treatment Arm A: Cohort 2A

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.

Dose Escalation Treatment Arm A: Cohort 3A

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.

Dose Escalation Treatment Arm A: Cohort 3A (Milled)

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.

Dose Escalation Treatment Arm A: Cohort 4A

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.

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-117 200 mg, capsule, orally, once on MTuW QW for up to 6 cycles (each cycle was 28 days), up to 21.3 weeks.

Dose Escalation Treatment Arm B: Cohort 2B

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.

Dose Escalation Treatment Arm B: Cohort 3B

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.

Dose Escalation Treatment Arm B: Cohort 3B (Milled)

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.

Dose Escalation Treatment Arm B: Cohort 4B

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.

Dose Escalation Treatment Arm B: Cohort 5B (Milled)

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.

Dose Escalation Treatment Arm C: Cohort 1C

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.

Dose Escalation Treatment Arm C: Cohort 2C (Milled)

Drug-Drug Interaction (DDI) Expansion Cohort (Milled)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

United Kingdom

Spain

United States

Region of Enrollment

Height

Weight

BMI was calculated as weight/\[height\^2\].

Body Mass Index (BMI)

Safety population consisted of all enrolled participants who received at least 1 dose of any study drug.

Medical Director

SAEs

Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)

Cycle 1, Day 1

Cycle 1, Day 24

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.

Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

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.

Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

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

Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

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.

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

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.

RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort

Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort

Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort

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

Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort

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

RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort

Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort

Cycle 1, Day 3, TAK-228 administered alone

Cycle 1, Day 10, TAK-228 administered with TAK-117

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.

Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort

Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort

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

Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort

Drug-Drug Interaction (DDI) Expansion Cohort (Milled))

CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort

Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort

Cycle 1, Day 10, TAK-117 administered with TAK-228

Cycle 1, Day 17, TAK-117 administered alone

Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort

Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort

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

Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort

CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort

Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort

Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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.

Duration of Response (DOR)

Overall Study

Pevonedistat

IV dose escalation for 5 consecutive days followed by a rest period of 16 days for a 21 day cycle. Treated may continue until disease progression or unacceptable toxicity develops.

MLN4924

This study is an open-label, multicenter, Phase 1, dose escalation study of MLN4924 in adult patients with nonhematologic malignancies. This study will be the first to administer MLN4924 in humans. The patient population will consist of adults with any form of nonhematologic malignancy for which standard, curative, life prolonging, or palliative treatment does not exist or is no longer effective.

Study of MLN4924 in Adult Patients With Nonhematologic Malignancies

An Open-Label, Dose Escalation, Phase I Study of MLN4924, a Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients With Nonhematologic Malignancies

TAK-733 will be administered orally once daily (QD) on Days 1 through 14 of the 21-day cycle.

Alisertib will be administered orally twice daily (BID) on Days 1 through 7 of the 21-day cycle.

TAK-733 and alisertib

This is a Multicenter, Open-label, Phase 1b Study of TAK-733 in Combination With Alisertib in Adult Patients With Advanced Nonhematologic Malignancies

Study of TAK-733 in Combination With Alisertib in Adult Patients With Advanced Nonhematologic Malignancies

A Multicenter, Open-label, Phase 1b Study of TAK-733 (an Oral MEK Inhibitor) in Combination With Alisertib (an Oral Aurora A Kinase Inhibitor) in Adult Patients With Advanced Nonhematologic Malignancies

To evaluate the safety profile and to determine DLTs, MTDs, and RP2D of oral TAK-733 + alisertib in patients with advanced nonhematologic malignancies

To characterize the single- and multiple-dose plasma PK of TAK-733 and alisertib in patients with advanced nonhematologic malignancies

To evaluate evidence of antitumor activity of TAK-733 + alisertib

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies	NCT00948467	Advanced Non-he... Advanced Metast...	TAK-733	18 Years -	Millennium Pharmaceuticals, Inc.
A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies	NCT01204073	Advanced Nonhem... Carcinoma, Basa...	TAK-441	18 Years -	Millennium Pharmaceuticals, Inc.
A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies	NCT01204073	Advanced Nonhem... Carcinoma, Basa...	TAK-441	18 Years -	Millennium Pharmaceuticals, Inc.
Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies	NCT00948467	Advanced Non-he... Advanced Metast...	TAK-733	18 Years -	Millennium Pharmaceuticals, Inc.
A Safety and Pharmacokinetic Study of TAK-228 in Combination With TAK-117 in Adult Participants With Advanced Nonhematologic Malignancies	NCT01899053	Advanced Nonhem...	TAK-228 TAK-117	18 Years -	Takeda
Study of MLN4924 in Adult Patients With Nonhematologic Malignancies	NCT00677170	Advanced Nonhem...	MLN4924	18 Years -	Millennium Pharmaceuticals, Inc.
Study of TAK-733 in Combination With Alisertib in Adult Patients With Advanced Nonhematologic Malignancies	NCT01613261	Advanced Nonhem...	TAK-733 and ali...	18 Years -	Millennium Pharmaceuticals, Inc.
Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies	NCT00948467	Advanced Non-he... Advanced Metast...	TAK-733	18 Years -	Millennium Pharmaceuticals, Inc.

Spots Global Cancer Trial Database for advanced nonhematologic malignancies