Study of D07001-Softgel Capsules in Subjects With Gastrointestinal Cancer in Dose-Escalation Phase and in Subjects With Biliary Tract Cancer in Dose-Expansion Phase

Study Overview
=================
Brief Summary
-----------------
Part 1: Dose-Escalation Phase (Phase 1b) The primary objective is to assess the safety and tolerability of increasing doses of D07001 softgel in patients with unresectable locally advanced or metastatic gastrointestinal (GI) cancer. Part 2: Dose-Expansion Phase (Phase 2) The primary objective is to assess the safety and tolerability of D07001 softgel in patients who have achieved stable disease or better following first line chemotherapy or combined chemoradiotherapy (CCRT) for unresectable metastatic or locally advanced biliary tract cancer (BTC)

Detailed Description
-----------------
This open label, multicenter study will be conducted in 2 parts: a dose-escalation phase (Part 1) and a dose-expansion phase (Part 2). In both Part 1 and Part 2, 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). Part 1: Dose Escalation Phase (Phase 1b) Part 1 of the study will follow a 3+3 dose escalation scheme at predefined dose levels. There will be sequential cohorts of 3 to 6 patients each with increasing doses of 40 mg, 60 mg, 80 mg, 120 mg, and 160 mg per cohort. There will be no intra patient dose escalation. Cycle 1 (21 days) is defined as the dose limiting toxicity (DLT) assessment period. Part 2: Dose Expansion Phase (Phase 2) In Part 2 of the study, eligible patients will be randomized in a 1:1 ratio to receive D07001-softgel in an open label manner at 1 of the 2 dose levels selected for expansion. Twenty (20) patients will be enrolled to each dose expansion cohort. Patients will be treated until withdrawal from treatment due to disease progression according to RECIST v1.1, withdrawn consent, or when another treatment discontinuation criterion is met. Patients who are discontinued from study drug for reasons other than disease progression or toxicity in the first 2 cycles of Part 2 will be replaced.

Official Title
-----------------
Open-Label, Multicenter Study of D07001-Softgel Capsules (Oral Gemcitabine Hydrochloride) in Subjects With Unresectable, Metastatic or Locally Advanced Gastrointestinal (GI) Cancer in Dose-Escalation Phase and in Subjects With Advanced Biliary Tract Cancer (BTC) Following Primary Chemotherapy or Combined Chemoradiotherapy (CCRT) in Dose-Expansion Phase

Conditions
-----------------
Gastrointestinal Cancer, Biliary Tract Cancer

Intervention / Treatment
-----------------
* Drug: D07001-softgel capsules


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of a signed and dated written Informed Consent Form (ICF) prior to any study specific procedures 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 GI cancer (Part 1) or unresectable metastatic or locally advanced BTC (cholangiocarcinoma or gallbladder cancer; Part 2) Part 1 only: Refractory to or have relapsed from all standard therapies of advanced GI malignancy Part 2 only: Achieved stable disease or better, based on the Investigator's assessment, in response to first line systemic therapy or CCRT, with continued stable disease or better based on imaging studies obtained as part of screening Completed first line systemic therapy (with 2-8 cycles of chemotherapy with a gemcitabine based regimen) or CCRT, based on the local standard of care and preferences in the participating countries Note: No more than 30% of patients enrolled in Part 2 will have received CCRT No more than 60 days have elapsed between completion of the prior line of chemotherapy or CCRT and enrollment Part 2 only: Patient has not received intervening systemic therapy since first line treatment Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-2 in Part 1 and 0-1 in Part 2 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 ≥ 60 mL/min calculated by Cockcroft-Gault formula or directly measured with 24 hr urine collection If a woman of childbearing potential, the patient has a negative serum pregnancy test at screening and is not breastfeeding If a woman of childbearing potential, patient 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 patients must adhere to the same birth control methods. Patient is willing to comply with protocol-required visit schedule and visit requirements Exclusion Criteria: Part 2 only: More than one prior chemotherapy regimen for unresectable metastatic or locally advanced BTC Note: prior radiation (with or without radiosensitizing doses of chemotherapy) or fluoropyrimidine chemotherapy are allowed as postsurgical adjuvant therapy. Part 2 only: Received any systemic therapy (chemotherapy, biologics, immunotherapy, or investigational agents) for metastatic disease other than gemcitabine based chemotherapy or CCRT for locally advanced BTC Diagnosis of active malignancy (other than GI cancer [Part 1] or BTC [Part 2]) 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 Any GI disorder which would significantly impede absorption of an oral agent Known brain or leptomeningeal metastases Surgery or radiation therapy within the past 28 days Part 2 only: Evidence of disease progression, based on the Investigator's assessment, on the screening computed tomography (CT) scan or magnetic resonance imaging (MRI) scan Any active disease or condition that would not permit compliance with the protocol Residual toxicity from prior chemotherapy or CCRT that is Grade ≥2 (residual Grade 2 neuropathy and alopecia are permitted) 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 Patient has a history of drug or alcohol abuse within last year Patient has documented cerebrovascular disease Patient has a seizure disorder not controlled on medication (based on decision of Investigator) Patient received an investigational agent within 28 days of enrollment Patients with uncontrolled active viral, bacterial, or systemic fungal infection Patient has known human immunodeficiency virus (HIV) infection Patient has hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in medical history. If positive results are not indicative of true active or chronic infection, the patient can enter the study after discussion and agreement between the Investigator and the Clinical Research Organization (CRO) Medical Monitor Patient has received yellow fever vaccine or other live attenuated vaccine(s) within the 4 weeks prior to screening Patient has 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 of the study comprises a sequential dose escalation to identify dose-limiting toxicity (DLT) and establish the maximum tolerated dose (MTD), if any, of D07001-softgel in patients with unresectable locally advanced or metastatic GI cancer. Part 1 will follow a 3+3 dose escalation scheme at predefined dose levels. There will be sequential cohorts of 3 to 6 patients each with increasing doses of 40 mg, 60 mg, 80 mg, 120 mg, and 160 mg per cohort. In Part 2 of the study, D07001-softgel will be administered at the 2 dose levels selected for expansion from Part 1 of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1:Dose-Escalation Phase<br>40 mg D07001-softgel capsules 60 mg D07001-softgel capsules 80 mg D07001-softgel capsules 120 mg D07001-softgel capsules 160 mg D07001-softgel capsules | Drug: D07001-softgel capsules<br>* Active Ingredient:Gemcitabine hydrochloride<br>|
| Experimental: Part 2: Dose-Expansion Phase (Phase 2)<br>higher dose-expansion of D07001-softgel capsules lower dose-expansion of D07001-softgel capsules | Drug: D07001-softgel capsules<br>* Active Ingredient:Gemcitabine hydrochloride<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Establish the Maximum Tolerated Dose (MTD) | MTD will be defined based on the number of dose limiting toxicities (DLT) in subjects at each dose level. DLT definition: In Part 1 of the study, any of the following AEs occurring during Cycle 1 will be classified as DLTs, if there is a reasonable possibility that it is related to the study drug Hematologic: Grade 4 neutropenia lasting >7 days Febrile neutropenia (defined as neutropenia Grade ≥3 and a body temp ≥38.3°C) Grade ≥3 neutropenic infection Grade 4 anemia Grade ≥3 thrombocytopenia with bleeding Grade 4 thrombocytopenia Non-hematologic: o Grade ≥3 toxicities that are considered clinically significant, except those that have not been maximally treated (e.g., nausea, vomiting, diarrhea*) or can be easily treated (e.g., electrolyte abnormalities). Failure to deliver at least 6 of the planned 9 doses during Cycle 1 due to treatment-related toxicities. Upon the second occurrence of a toxicity leading to a dose hold. | During Cycle 1 of treatment (each cycle is 21 days) for each subject | 
| Part 1 : 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, an average of 10 months | 
| Part 2: Incidence of Dose Modifications, Including Dose Reduction, Interruption, or Discontinuation of Study Drug | To measure ratio of total subjects who experienced the dose modifications including dose reduction, interruption, or discontinuation of study drug due to AEs. | First dose through last dose for each subject, an average of 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Pharmacokinetics (PK)- Cmax | PK would be analyzed by maximum concentration (Cmax) of dFdC | Cycle 1 Days 1 and 15 | 
| Part 1: PK- AUC | PK would be analyzed by Area Under Curve (AUC) of dFdC | Cycle 1 Days 1 and 15 | 
| Part 2: Pharmacokinetics (PK)- Cmax | PK would be analyzed by maximum concentration (Cmax) of dFdC | Cycle 1 Days 1, 8, and 15; Cycle 1 Day 15 and Cycle 2 Day 1 for food-effect cohort only | 
| Part 2: PK- AUC | PK would be analyzed by Area Under Curve (AUC) of dFdC | Cycle 1 Days 1, 8, and 15; Cycle 1 Day 15 and Cycle 2 Day 1 for food-effect cohort only |