This will be a Phase 1, open-label study of DS-7423 to assess its safety and tolerability, identify a RP2D, (recommended Phase 2 Dose) and assess its Pharmacokinetics (PK) (what your body does to process the drugs and how your body gets them out of your system.) and pharmacodynamics (PDy) (Pharmacodynamics is a study of what a drug does to your body) properties in subjects with advanced solid malignant tumors. This study will include 2 parts: part 1-Dose Escalation and part 2-Dose Expansion. Study Hypothesis: DS-7423 will be safe and tolerable, and will exhibit acceptable PK and PDy properties in subjects with advanced solid malignant tumors for whom standard therapy has failed or for whom no standard therapy exists.
Part 1 : Dose-escalation of DS-7423 to determine maximum tolerated dose (MTD) in subjects with advanced solid tumors Part 2 : Dose Expansion: The purpose of Part 2 of this clinical research study is to confirm the safety and tolerability of the MTD of DS-7423 identified in Part 1, and measure the effects of DS-7423 on your cancer. Part 2 will be conducted in subjects with advanced colorectal or endometrial cancer.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
42
oral capsule 1mg, 8mg, 48mg, and 80mg strengths administered once daily
Karmanos Cancer Institute
Detroit, Michigan, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Sarah Cannon Research Institute
Nashville, Tennessee, United States
Adverse Events
All adverse events will be graded according to the NCI-CTCAE, version 4.0
Time frame: 30 days after last dose
Plasma pharmacokinetics of DS-7423
The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-7423 using non-compartmental analyses.
Time frame: Cycle 1 - days 1, 2, 8, and 15; Cycle 2 - day 1; end of study
Effects of DS-7423 on glucose metabolism
The effects of DS-7423 on glucose metabolism will be determined by measuring glucose and C-peptide levels
Time frame: Cycle 1 Days 1, 2, and 15; and end-of-study
Pharmacodynamic effects of DS-7423 in surrogate tissues
The pharmacodynamic effects of DS-7423 will be determined by measuring phosphorylation of Akt in platelet-rich plasma
Time frame: Cycle 1 Days 1, 2, and 15
Pharmacodynamic effects of DS-7423 in tumors
The pharmacodynamic effects of DS-7423 will be determined by measuring tumor glucose uptake using (18F) fluorodeoxyglucose-positron emission tomography
Time frame: Baseline and Cycle 1 Day 4
Part 2 - Objective response rate in subjects with advanced colorectal and endometrial cancer
Objective response rate = the sum of complete response \[CR\] and partial response \[PR\] rates as measured using Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1
Time frame: Baseline and every 2 cycles of treatment for the first 8 cycles and then every 3 cycles thereafter until study drug discontinuation
Part 2 - Pharmacodynamic effects of DS-7423 in tumors
The pharmacodynamic effects of DS-7423 in tumors will be determined by measuring Akt, ribosomal protein S6 (S6), and proline-rich Akt substrate, 40 kDA (PRAS40) phosphorylation in pre- and posttreatment tumor biopsies
Time frame: Baseline and Cycle 1 Day 15
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