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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| DS7423 | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| DS-7423 | Drug | oral capsule 1mg, 8mg, 48mg, and 80mg strengths administered once daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events | All adverse events will be graded according to the NCI-CTCAE, version 4.0 | 30 days after last dose |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma pharmacokinetics of DS-7423 | The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-7423 using non-compartmental analyses. | Cycle 1 - days 1, 2, 8, and 15; Cycle 2 - day 1; end of study |
| Effects of DS-7423 on glucose metabolism |
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Inclusion Criteria:
Platelet count >= 100 X 10^9/L Hemoglobin (Hb) level >= 9.0 g/dL ANC >= 1.5 X 10^9/L - Have adequate renal function, defined as: Creatinine clearance >= 60 mL/min, as calculated using the modified Cockroft Gault equation, ([{140 - age in yrs} x {actual weight in kg}] divided by [{72 x serum creatinine in mg/dL} multiply by 0.85 if female]), or creatinine =< 1.5 X ULN
- Have adequate hepatic function, defined as: AST/ALT levels =< 3 X ULN (if liver metastases are present, =< 5 X ULN) Bilirubin =< 1.5 X ULN
- Have adequate blood clotting function, defined as: Prothrombin time and activated partial thromboplastin time =< 1.5 X ULN
Additional Inclusion Criteria for Part 2 (Dose Expansion)
Exclusion Criteria:
Additional Exclusion Criteria for Part 2 (Dose Expansion)
- Prior treatment with a dual PI3K/ mTOR inhibitor (including, but not limited to, BEZ-235, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384)
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Karmanos Cancer Institute | Detroit | Michigan | 48201 | United States | ||
| Memorial Sloan-Kettering Cancer Center |
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| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D016889 | Endometrial Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
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| ID | Term |
|---|---|
| C000623192 | DS7423 |
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The effects of DS-7423 on glucose metabolism will be determined by measuring glucose and C-peptide levels |
| 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 | 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 | 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 | 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 | Baseline and Cycle 1 Day 15 |
| New York |
| New York |
| 10065 |
| United States |
| Sarah Cannon Research Institute | Nashville | Tennessee | 37203 | United States |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D014594 | Uterine Neoplasms |
| D005833 | Genital Neoplasms, Female |
| D014565 | Urogenital Neoplasms |
| D014591 | Uterine Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |