Study of Combination Therapy of D07001-Softgel Capsules and Xeloda/TS-1 in Subjects With Advanced Biliary Tract Cancer

Study Overview
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Brief Summary
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The primary objective are: To assess the safety and tolerability of the combination of D07001-softgel capsules and Xeloda/TS-1. To evaluate the efficacy of the combination of D07001-softgel capsules and Xeloda/TS-1, as assessed by disease control rate (DCR).

Detailed Description
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This open label, multicenter study will be conducted in 2 stages: a dose-finding stage (Phase IIa) and a dose-expansion stage (Phase IIb/III). In phase IIa, eligible patients will be assigned to receive oral D07001-softgel on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 of a 21-day cycle (9 doses per cycle) and Xeloda (or TS-1) twice daily on Day 1-14 of a 21-day cycle. A modified 3+3 dose-finding design method will be applied to identify dose-limiting toxicities (DLTs) and establish the selected dose of D07001-softgel capsules plus Xeloda (or TS-1). In phase IIb/III,the first 40 subjects (20 subjects per arm) will be randomly allocated in a 1:1 ratio in two arms. Arm A will receive active symptom control (ASC) with the selected dose from dose-finding stage of D07001-softgel capsules and Xeloda (or TS-1), in 21-day cycles. In arm B, subjects will receive ASC with mFOLFOX treatment. After the last subject of first 40 subjects will be completed the visit in the end of treatment, an adaptive interim analysis will be planned to re-estimate the required sample size based on the result of DCR if needed. The sponsor team will determine whether the study will be continued or stopped for futility. If the study continues to proceed, the total subject number will be based on the decision from the results of interim study. The rest of subjects will be randomized to receive the combination of study drug or active-control drug with the same allocation in two arms. Both groups will continue the therapy until disease progression, withdrawn consent, or when another treatment discontinuation criterion is met.

Official Title
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Open-Label, Multicenter, Phase II/III Study of Combination Therapy of D07001-Softgel Capsules and Xeloda/TS-1 in Subjects With Advanced Biliary Tract Cancer After Gemcitabine and Cisplatin-Based Treatment Failure

Conditions
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Biliary Tract Cancer

Intervention / Treatment
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* Drug: D07001-softgel capsules + Xeloda (or TS-1)
* Drug: mFOLFOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 years or older at screening (aged 20 years or older in Taiwan) Histopathological or cytologic diagnosis of unresectable metastatic or locally advanced BTC (cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma) Subject must have failed from first line gemcitabine and cisplatin-based chemotherapy Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1 Life expectancy is >12 weeks Adequate bone marrow function, demonstrated by: Absolute neutrophil count (ANC) ≥1,500 cell/mm3 Platelet count ≥ 100,000 cells/mm3 Hemoglobin ≥ 9 g/dL Adequate liver function, demonstrated by: Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or ≤5.0 x ULN in the case of liver metastases Total bilirubin ≤1.5 x ULN Albumin ≥3.0 g/dL International normalized ratio (INR) <1.5 Adequate renal function, demonstrated by: Serum creatinine ≤1.5 x ULN Creatinine clearance ≥ 50mL/min calculated by Cockcroft-Gault formula or directly measured with 24hr urine collection A negative serum pregnancy test at screening and is not breastfeeding in woman of childbearing potential Women of childbearing potential or male subjects must use a medically acceptable form of contraception as 2 barrier methods (e.g., combination of condom, diaphragm, or intrauterine device), hormonal contraception (estrogen or progesterone agents) or 1 barrier method in combination with spermicide. Birth control is required 1 month prior to screening, for the duration of their study participation, and for 1 month after the end of the study; female partners of male subjects must adhere to the same birth control methods. Provision of a signed and dated written Informed Consent Form (ICF) prior to any study specific procedures Subject is willing to comply with protocol-required visit schedule and visit requirements No more than 60 days have elapsed between completion of the prior line of chemotherapy or CCRT and enrollment Subject has not received other chemotherapy since first-line treatment Exclusion Criteria: Have prior chemotherapy regimen other than first line gemcitabine and cisplatin-based therapy for unresectable metastatic or locally advanced BTC Note: prior fluoropyrimidine chemotherapy are allowed as postsurgical adjuvant therapy. Diagnosis of active malignancy other than BTC within the past 2 years, except nonmelanoma skin carcinoma and carcinoma-in-situ of uterine cervix treated with curative intent Prior discontinuation of gemcitabine because of pulmonary or hepatic toxicity or hemolytic uremic syndrome (HUS) or hypersensitivity, allergic reaction, or intolerance Known or suspected hypersensitivity to capecitabine, tegafur, gimeracil, oteracil potassium, oxaliplatin or other platinum compounds, leucovorin products, folic acid or folinic acid, 5-fluorouracil or their excipients. Prior discontinuation of fluoropyrimidine because of any unexpected or severe reaction. Treatment with brivudine, sorivudine, or its chemically-related analogs ≤ 28 days prior to the date of enrollment. Under flucytosine treatment. Residual toxicity from prior chemotherapy or CCRT that is Grade ≥2 (residual Grade 2 neuropathy and alopecia are permitted) Any GI disorder which would significantly impede absorption of an oral agent Known brain or leptomeningeal metastases Major surgery or definitive ablation-intent (excluding palliative radiotherapy for bone metastasis) radiation therapy within the past 28 days Any active disease or condition that would not permit compliance with the protocol Clinically significant cardiovascular disease (e.g., uncontrolled hypertension, unstable angina, congestive heart failure, or New York Heart Association [NYHA] Grade 2 or greater), or uncontrolled serious cardiac arrhythmia Have documented cerebrovascular disease Have a seizure disorder not controlled on medication (based on decision of Investigator) Received an investigational agent within 28 days of enrollment Have an uncontrolled active viral, bacterial, or systemic fungal infection Known human immunodeficiency virus (HIV) infection Have HBsAg positive with HBV-DNA≥2000 copies/ml, and/or anti-HCV antibody positive with HCV-RNA positive. Received yellow fever vaccine or other live attenuated vaccine(s) within the 4 weeks prior to screening History of drug or alcohol abuse within last year Have any other serious medical condition that, in the Investigator's medical opinion, would preclude safe participation in, and compliance with, a clinical trial

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: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In phase IIa, a modified 3+3 dose-finding design trial will be conducted to identify the selected dose of the combination of D07001-softgel capsules plus Xeloda (or TS-1). After the dose-finding stage will be completed, a phase IIb/III adaptive design, open label, multicenter, active controlled, parallel-group trial will be implemented and incorporated into a dose-expansion stage to evaluate the efficacy and safety of D07001-softgel capsules plus Xeloda.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase IIa:Dose-Finding Stage<br>Level -5: 20 mg D07001-softgel capsules plus 625 mg/m^2 Xeloda (or 20/30/40 mg TS-1). Level -4: 40 mg D07001-softgel capsules plus 625 mg/m^2 Xeloda (or 20/30/40 mg TS-1). Level -3: 60 mg D07001-softgel capsules plus 625 mg/m^2 Xeloda (or 20/30/40 mg TS-1). Level -2: 80 mg D07001-softgel capsules plus 625 mg/m^2 Xeloda (or 20/30/40 mg TS-1). Level -1 (starting dose): 100 mg D07001-softgel capsules plus 625 mg/m^2 Xeloda (or 20/30/40 mg TS-1). Level 1: 100 mg D07001-softgel capsules plus 800 mg/m^2 Xeloda (or 30/40/50 mg TS-1). Level 2: 100 mg D07001-softgel capsules plus 1000 mg/m^2 Xeloda (or 40/50/60 mg TS-1). | Drug: D07001-softgel capsules + Xeloda (or TS-1)<br>* D07001-softgel capsules: 3 times per week (on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 of a 21-day cycle, 9 doses per cycle). Xeloda (or TS-1): twice daily for 14 consecutive days followed by 7 days rest (1 treatment cycle)<br>* Other names: Treatment group;|
| Active Comparator: Phase IIb/III: Dose Expansion Stage<br>ASC+ D07001-softgel capsules plus Xeloda (or TS-1) ASC+mFOLFOX (5-FU+Oxalipatin+folinic acid) | Drug: D07001-softgel capsules + Xeloda (or TS-1)<br>* D07001-softgel capsules: 3 times per week (on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 of a 21-day cycle, 9 doses per cycle). Xeloda (or TS-1): twice daily for 14 consecutive days followed by 7 days rest (1 treatment cycle)<br>* Other names: Treatment group;Drug: mFOLFOX<br>* intravenous infusion on Day 1 for 14-day cycle<br>* Other names: Control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs)/ serious adverse event (SAEs) | AEs will be assessed via the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 | From date of informed consent to 30-day follow-up visit for each subject | 
| To assess disease control rate (DCR) | To assess DCR, the percentage of treatment patients who achieved CR, PR, or SD. | From date of randomization until the date of first documented progression, date of death from any cause, or date of withdraw the study for each subject, whichever came first, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase IIa and IIb: Pharmacokinetics (PK) of gemcitabine (dFdC), difluorodeoxyuridine (dFdU), capecitabine, 5-FU, Tegafur, Gimeracil, and Oteracil potassium | PK parameters (Peak Plasma Concentration (Cmax)) of gemcitabine and Xeloda or TS-1 will be evaluated | Cycle 1 Days 1, 8, and 12 (each cycle is 21 days) | 
| Quality of life (QOL) will be assessed using the EORTC questionnaires | To access healthrelated quality of life of cancer patients participating in clinical trial. | Cycle 1 Days 1, and date of withdraw the study (assessed up to 24 months) for each subject (each cycle is 21 days) | 
| To assess Progression-free survival (PFS) | To assess PFS, the time from treatment assignment/randomization until objective tumor progression or death | From date of randomization until the date of first documented progression, date of death from any cause, or date of withdraw the study for each subject, whichever came first, assessed up to 24 months | 
| To assess Objective response rate (ORR) | To assess ORR, the proportion of treated patients who achieved a BOR of CR or PR. | From date of randomization until the date of first documented progression, date of death from any cause, or date of withdraw the study for each subject, whichever came first, assessed up to 24 months | 
| To assess overall survival (OS) | To assess OS, the time from treatment assignment/randomization until death from any case | The survival follow-ups will follow every 6 weeks from date of discontinued study drug for up to 24 months till the death of the subject or closure of the study. |