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

Study Overview
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Brief Summary
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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.

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

Conditions
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Metastatic Solid Tumors

Intervention / Treatment
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* Drug: TAK-117


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects have had their PIK3CA gene mutation status assessed prior to enrolling into the study Subjects must have documented disease progression prior to enrolling into the study locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy. Age greater than or equal to (>=) 18 years, including males and females; Eastern cooperative oncology group (ECOG) performance status (PS) 0-1; Adequate organ function; Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration; Ability to swallow oral medications; Ability to understand and willingness to sign informed consent prior to initiation of any study procedures; For women of child-bearing potential, negative serum pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to the first study drug administration to 30 days following the last study drug administration Exclusion Criteria: Diagnosis of primary brain tumor; untreated brain metastasis or history of leptomeningeal disease or spinal cord compression; Received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug; Have received a systemic corticosteroid within one week prior to the first administration of study drug; Clinically significant cardiac disease; Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug; Malabsorption ; Poorly controlled diabetes mellitus; Pregnancy (positive serum or urine pregnancy test) or breast feeding; Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression; Failed to recover from the reversible effects of prior anticancer therapies; Have received a selective phosphoinositide-3-kinase alpha isoform (PI3K-alpha) inhibitor Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system (CNS) disease, active infection, or any other condition that could compromise the subject's participation in the study Known human immunodeficiency virus (HIV) infection Have a secondary malignancy within the last 3 years prior to first dose of study drug, excluding treated non-melanoma skin cancer, carcinoma in situ, or locally-treated prostate cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>TAK-117 administered once a day orally | Drug: TAK-117<br>* oral administration of TAK-117, daily and intermittent schedules.<br>|
| Experimental: Arm B<br>TAK-117 administered orally intermittently, once every other day (Monday, Wednesday, and Friday) each week | Drug: TAK-117<br>* oral administration of TAK-117, daily and intermittent schedules.<br>|
| Experimental: Arm C<br>TAK-117 administered orally intermittently, once a day for 3 consecutive days (Monday, Tuesday, and Wednesday) each week | Drug: TAK-117<br>* oral administration of TAK-117, daily and intermittent schedules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of TAK-117 | 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. | Baseline up to Cycle 1 Day 21 | 
| 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 |  | Baseline up to Cycle 27 Day 45 | 
| Number of Participants With Highest Level of TEAEs Severity | 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). | Baseline up to Cycle 27 Day 45 | 
| Number of Participants With Clinically Meaningful Changes in Laboratory Values |  | Baseline up to Cycle 27 Day 45 | 
| Number of Participants With Clinically Meaningful Changes in Vital Signs |  | Baseline up to Cycle 27 day 45 | 
| Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG) |  | Baseline up to Cycle 27 Day 45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | 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). | Cycle 1 Day 8 up to Cycle 27 Day 1 or disease progression or death | 
| Duration of Objective Response | 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. | Cycle 1 Day 8 up to Cycle 27 Day 1 or disease progression or death | 
| Clinical Benefit Rate (CBR) | 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. | Cycle 1 Day 8 up to Cycle 27 Day 1 or disease progression or death | 
| Cmax: Maximum Observed Plasma Concentration for TAK-117 |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| Ctrough: Observed Concentration at the End of Dosing Interval for TAK-117 |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-117 |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| T 1/2z: Terminal Disposition Phase Half-life for TAK-117 |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-117 |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-117 |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| %AUC Extrapolated: Percentage of Area Under Concentration-extrapolated |  | Process A: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 24 hrs) post-dose; Process B: Cycle 1 Day 1 pre-dose and at multiple timepoints (up to 48 hrs) post-dose | 
| Percent Change From Baseline in Pharmacodynamic Markers | 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). | Cycle 1 Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INK1117, PIK3CA, KINASE, TUMOR, CANCER, Locally advanced or metastatic solid tumors, not eligible for standard of care therapy