Urothelial cancer with HER2 or HER3 mutation Biliary tract cancer with HER2 or HER3 mutation Breast cancer with HER2 or HER3 mutation Breast cancer with HER2 amplification/overexpression as per ASCO-CAP 2013 guidelines Non-small cell lung cancer (NSCLC) with HER2 or HER3 mutation Colorectal cancer (CRC) with HER2 mutation or amplification Other tumors with HER2 or HER3 mutation, amplification, or ove
Conditions
Sponsors
Taiho Oncology, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or females with an age = 18 years. 2. Subjects with histological-confirmed, advanced cancer, who have progressed on (or not been able to tolerate) standard therapy or for whom no standard anticancer therapy exists. Subjects may have received two different forms of specific anti-HER2 therapy for their cancer except for breast cancer where receipt of up to four lines of anti-HER2 therapy is allowed prior to enrollment. a. For Phase 1, only subjects with measureable or evaluable disease and one of the following molecular/genetic alterations will be enrolled: i. HER2+ determined by local laboratory, for example: immunohistochemistry (IHC) 3+ and/or fluorescence in situ hybridization (FISH)+ by an accurate and validated assay, or potentially actionable HER2 or HER3 mutation or amplification by next generation sequencing. b. For Phase 2, only subjects with one of the following tumor types will be enrolled as determined by local laboratory: i. Urothelial cancer with HER2 or HER3 mutation ii. Biliary tract cancer with HER2 or HER3 mutation iii. Breast cancer with HER2 or HER3 mutation iv. Breast cancer with HER2 amplification or overexpression as per ASCO-CAP 2013 guidelines v. NSCLC with HER2 or HER3 mutation vi. CRC with HER2 mutation or amplification vii. Other tumors with HER2 mutation/amplification/overexpression or HER3 mutation (gastric/GEJ, endometrial). c. For Phase 2a, subjects should also meet the following criteria: i. Radiological progression on the last line of therapy before entering this trial must be documented ii. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Subjects must have the following laboratory values: a. ANC = 1.5 × 109/L b. Hemoglobin = 8.0 g/dL c. Platelet count = 75 × 109/L d. Albumin = 3 g/dL e. Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within institutional normal limits f. AST/serum glutamic-oxaloacetic transaminase and ALT/serum glutamic-pyruvic transaminase = 3 × (ULN) or = 5.0 × ULN if liver metastases are present g. Total serum bilirubin = 1.5 × ULN h. Serum creatinine = 1.4 × ULN or 24-hour or calculated creatinine clearance (Ccr) = 50 mL/min (according to Cockcroft Gault formula).* For subjects in Phase 2a with urothelial cancer, a creatinine clearance of = 40 mL/min is acceptable. *For a calculated Ccr value, the eligibility should be determined using the Cockcroft Gault formula: Male Ccr (mL/min) = Body weight (kg) × (140 – age)/[72 × serum creatinine (mg/dL)] Female Ccr (mL/min) = male Ccr × 0.85. 5. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval. Female subjec
Exclusion criteria
Exclusion criteria: Disease exclusions 1. Subjects with a history of brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases. Subjects with treated brain metastases that are asymptomatic and have been clinically stable for at least 4 weeks will be eligible. Medical condition exclusions 2. Subjects who have a history of another primary malignancy, other than: a. carcinomas in situ, eg, breast, cervix, and prostate (subjects with early-stage prostate cancer not requiring therapy are eligible) b. locally excised nonmelanoma skin cancer c. A subject who has had no evidence of disease from another primary cancer for 2 or more years. 3. Any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase the risk associated with study drug administration, or may interfere with the interpretation of study results such as, but not limited to: a. Uncontrolled diabetes mellitus b. Liver disease such as decompensated liver disease c. Life-threatening autoimmune disease. 4. Diseases that significantly affect GI absorption of the compound. 5. Subjects who have impaired cardiac function or clinically significant cardiac disease, including any of the following: a. Baseline corrected QT level using Fridericia formula (QTcF) > 480 ms or congenital QT syndrome b. History or presence of serious uncontrolled ventricular arrhythmias c. Any New York Heart Association Classification of Heart Failure = Class II Severe/unstable angina, New York Heart Association classification 4 Congestive Heart Failure (Appendix 1) d. Echocardiogram or multiple grated acquisition under 50% ejection fraction. Prior therapy exclusions 6. Chemotherapy, biologic therapy, targeted therapy, immunotherapy, extended-field radiotherapy, or investigational agents within 5 half-lives or within 4 weeks (whichever is shorter) prior to administration of first dose of study drug on Day 1 or unresolved clinically significant toxicities (as assessed by the investigator) attributed to any prior therapy 7. Major surgery/surgical therapy for any cause within 4 weeks of first dose.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: For phase I (dose escalation): To determine the maximum-tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of TAS0728 when administered orally twice daily (BID) in 21-day cycles to adult subjects with advanced solid tumors harboring human epidermal growth factor receptor (HER) 2 or HER3 overexpression, amplification, or mutation. For phase IIa (proof of concept): To evaluate the preliminary efficacy of TAS0728 as measured by objective response rate (ORR) in subjects with the following tumor types with HER2 or HER3 mutation: Urothelial cancer Biliary tract cancer Breast cancer with Breast cancer with Non-small cell lung cancer (NSCLC) Colorectal cancer (CRC) ; Secondary Objective: Phase 1 Dose Escalation • To evaluate the ORR in subjects receiving TAS0728 • To assess the safety and tolerability of TAS0728 • To investigate the clinical pharmacokinetics (PK) of TAS0728 Phase 2a Proof of Concept • To assess the safety and tolerability of TAS0728 •To evaluate the preliminary efficacy of TAS0728 as measured by DOR, DCR, PFS, and OS ; Primary end point(s): Phase 1 Dose Escalation • Incidence rate of dose-limiting toxicities (first cycle only) at each dose level Phase 2a Proof of Concept • ORR according to Response Evaluation Criteria in Solid Tumors (RECIST guidelines (Version 1.1, 2009) for each tumor type. Objective response rate is defined as the proportion of subjects who had best overall response (BOR) of complete response (CR) or partial response (PR) ;Timepoint(s) of evaluation of this end point: See table 1, pg 12-14 in Protocol, Schedule of Events | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Safety: Type, frequency and severity of adverse drug reactions according to National Cancer Institute NCI/ Common Terminology Criteria for Adverse Events (CTCAE) (Version 5.0) • Disease control rate is defined as the proportion of subjects who achieve a response of CR, PR, or stable disease • Progression-free survival is defined as the time from the first dose date to objectively documented disease progression or death • Duration of response defined as the time between the date of first response and the subsequent date of objectively documented disease progression or death • Overall survival is defined as the time between the first dosing date and the date of death •Pharmacokinetics (Phase 1 – dose escalation only): TAS0728 plasma concentrations, urinary concentrations and basic PK parameters ;Timepoint(s) of evaluation of this end point: See table 1, pg 12-14 in Protocol, Schedule of Events | — |
Countries
Australia, France, Spain, United Kingdom, United States
Contacts
Public ContactAlan Braunton
Taiho Pharma Europe, Ltd. (TPEL)
Outcome results
None listed