Safety and Tolerability of ASLAN001 in Combination With Cisplatin and 5-FU or Cisplatin and Capecitabine

Study Overview
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Brief Summary
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This is a phase IB study to assess the safety and tolerability of ASLAN001 when given in combination with either Cisplatin and 5-Fluorouracil or Cisplatin and Capecitabine, with a view to identifying the recommended Phase II dose.

Detailed Description
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This is an open-label, Phase I, dose escalation study of ASLAN001 given in combination with Regimen A or Regimen B, in patients with metastatic solid tumors, eligible to receive the cisplatin/5-fluorouracil or cisplatin/capecitabine regimen. Dose of ASLAN001 starts from 400mg BID; then, dose escalation to 500mg BID or dose de-escalation to 300mg BID will depend on DLTs observed in cohort. Regimen A: Depends on preferred medical practice, Cohort 1A will receive ASLAN001 400 mg BID in combination with cisplatin 80 mg/m2 IV infusion and 5 fluorouracil 800 mg/m2/day IV infusion for 5 days every 3 weeks; or will receive ASLAN001 400 mg BID in combination with Cisplatin 35 mg/m2 24-hour infusion for day 1 and day 8, 5-fluorouracil 2,000 mg/m2 and Leucovorin 300mg/m2 24-hour infusion for day 1, day 8 and day 15 every 4 weeks. Regimen B: Cohort 1B will receive ASLAN001 400 mg BID in combination with cisplatin 80 mg/m2 IV infusion and oral capecitabine 1,000 mg/m2 BID for 14 days every 3 weeks.

Official Title
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Phase I Study to Evaluate the Safety and Tolerability of ASLAN001 in Combination With Cisplatin and 5-Fluorouracil or Cisplatin and Capecitabine

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: ASLAN001
* Drug: cisplatin + capecitabine
* Drug: cisplatin + 5-fluorouracil (or+ Leucovorin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients 20 years of age or older at the time written informed consent is obtained. Regimen A: Patients with metastatic solid tumors eligible for treatment with cisplatin and 5-fluorouracil. The standard dose and schedule of cisplatin and 5-fluorouracil will be according to the preference of investigators and institutions. Regimen B: Patients with metastatic solid tumors eligible for treatment with cisplatin in combination with capecitabine. Patients with a partial gastrectomy may be allowed to participate in the study as long as they can take oral medications and meet all other inclusion/exclusion criteria. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days prior to enrolment: Hematological function, as follows: Absolute neutrophil count ≥ 1.5 x 109/L. Platelet count ≥ 100 x 109/L. Hemoglobin ≥ 9 g/dL. Coagulation function, as follows: Partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 x upper limit of normal (ULN) per institutional laboratory normal range. International normalized ratio ≤ 1.5. Renal function, as follows: • Creatinine clearance ≥ 50 mL/min as calculated by Cockcroft-Gault formula. Hepatic function, as follows: Total bilirubin ≤ 1.5 x ULN. AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present). Exclusion Criteria: Patients with persistent gastric outlet obstruction, complete dysphagia or feeding jejunostomy. Patients receiving proton pump inhibitors or H2 antagonists for established, symptomatic gastro duodenal ulceration or gastroesophageal reflux disease. Patients with unresolved toxicities of grade 2 or more from prior anti-cancer therapies. Untreated or symptomatic central nervous system metastases. Patients with a history of brain metastases are eligible if definitive therapy has been administered (surgery and/or radiation therapy), there is no planned treatment for brain metastases, and the patient is clinically stable and is off corticosteroids for at least 2 weeks prior to enrolment. Major surgical procedures within 28 days prior to enrolment. Clinically significant cardiovascular diseases that are symptomatic or uncontrolled. Known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen. Pregnant or breast-feeding females. Patients who have hearing impairment, due to the potential for ototoxicity of cisplatin. Any history or presence of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease or any other condition which in the opinion of the Investigator could jeopardize the safety of the patient or the validity of the study results

Ages Eligible for Study
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Minimum Age: 20 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: Regimen A / Amended Regimen A<br>Regimen A: Cisplatin + 5-fluorouracil ASLAN001 daily in combination with: Cisplatin 80 mg/m2 IV infusion for 1 day and 5-fluorouracil 800 mg/m2/day IV infusion for 5 days every 3 weeks for up to 6 cycles. Or Amended Regimen A: Cisplatin + 5-fluorouracil + leucovorin ASLAN001 daily in combination with: Cisplatin 35 mg/m2 24-hour infusion for day 1 and day 8, 5-fluorouracil 2,000 mg/m2 and Leucovorin 300mg/m2 24-hour infusion for day 1, day 8 and day 15 every 4 weeks for up to 6 cycles. | Drug: ASLAN001<br>* ASLAN001 400mg BID daily; ASLAN001 500mg BID daily; or ASLAN001 300mg BID daily<br>* Other names: Varlitinib;Drug: cisplatin + 5-fluorouracil (or+ Leucovorin)<br>* Cisplatin 80 mg/m2 IV infusion and 5-fluorouracil 800 mg/m2/day IV infusion for 5 days every 3 weeks; Or Cisplatin 35 mg/m2 24-hour infusion for day 1 and day 8, 5-fluorouracil 2,000 mg/m2 and Leucovorin 300mg/m2 24-hour infusion for day 1, day 8 and day 15 every 4 weeks.<br>|
| Experimental: Regimen B<br>Regimen B: Cisplatin + capecitabine ASLAN001 daily in combination with: Cisplatin 60-80 mg/m2 IV infusion on Day 1 and capecitabine 1,000 mg/m2 orally BID for 14 days every 3 weeks for up to 6 cycles. | Drug: ASLAN001<br>* ASLAN001 400mg BID daily; ASLAN001 500mg BID daily; or ASLAN001 300mg BID daily<br>* Other names: Varlitinib;Drug: cisplatin + capecitabine<br>* Cisplatin 80 mg/m2 IV infusion and capecitabine 1,000 mg/m2 orally BID for 14 days every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of ASALN001 | Safety and tolerability as evaluated with: DLTs (in first 2 cycles); Maximum tolerated dose (MTD) of ASLAN001 in combination with cisplatin/capecitabine or cisplatin/5-FU will be determined. | First 2 cycles | 
| Safety and Tolerability of ASALN001 | Safety and tolerability as evaluated with: Adverse events. | Baseline to post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary assessment of the efficacy | •To provide a preliminary assessment of the efficacy of ASLAN001 when given in combination in Regimen A or Regimen B as measured by the objective response rate (ORR). | Along the study duration | 
| Pharmacokinetics profile (AUC) of ASLAN001 | To evaluate the pharmacokinetics of ASLAN001, when given in combination with Regimen A or Regimen B. Pharmacokinetic parameters including, but not limited to area under the plasma concentration-time curve (AUC) from 0 to 6 hours (AUC0-6). | Along the study duration | 
| Pharmacokinetics profile (Cmax) of ASLAN001 | To evaluate the pharmacokinetics of ASLAN001, when given in combination with Regimen A or Regimen B. Pharmacokinetic parameters including, but not limited to maximum plasma concentration (Cmax). | Along the study duration | 
| Pharmacokinetics profile (Cmin) of ASLAN001 | To evaluate the pharmacokinetics of ASLAN001, when given in combination with Regimen A or Regimen B. Pharmacokinetic parameters including, but not limited to minimum (trough) plasma concentration (Cmin). | Along the study duration | 
| Pharmacokinetics profile (RacAUC0-6) of ASLAN001 | To evaluate the pharmacokinetics of ASLAN001, when given in combination with Regimen A or Regimen B. Pharmacokinetic parameters including, but not limited to accumulation ratio for AUC (RacAUC0-6). | Pharmacokinetic measurements will be from Cycle 1 Day 1 to Cycle 3 Day 1 (each cycle is 28 days for Amended Regimen A, and 21 days for Regimen A and B. | 
| Pharmacokinetics profile (Tmax) of ASLAN001 | To evaluate the pharmacokinetics of ASLAN001, when given in combination with | Along the study duration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASLAN001, Varlitinib