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

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

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)

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 Patients will be treated until withdrawal from treatment due to disease progression according to RECIST v1.1, withdrawn consent, or when another treatment discontinuation criterion is met.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.

Inclusion Criteria:

1. Provision of a signed and dated written Informed Consent Form (ICF) prior to any study specific procedures

2. Male or female patients aged 18 years or older at screening (aged 20 years or older in Taiwan)

3. 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)

4. Part 1 only: Refractory to or have relapsed from all standard therapies of advanced GI malignancy

5. Part 2 only:

   1. 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
   2. 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

6. No more than 60 days have elapsed between completion of the prior line of chemotherapy or CCRT and enrollment

7. Part 2 only: Patient has not received intervening systemic therapy since first line treatment

8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-2 in Part 1 and 0-1 in Part 2

9. Life expectancy is >12 weeks

10. Adequate bone marrow function, demonstrated by:

    1. Absolute neutrophil count (ANC) ≥1,500 cell/mm3
    2. Platelet count ≥100,000 cells/mm3
    3. Hemoglobin ≥9 g/dL

11. Adequate liver function, demonstrated by:

    1. 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
    2. Total bilirubin ≤1.5 x ULN
    3. Albumin ≥3.0 g/dL
    4. International normalized ratio (INR) <1.5

12. Adequate renal function, demonstrated by:

    1. Serum creatinine ≤1.5 x ULN
    2. Creatinine clearance ≥ 60 mL/min calculated by Cockcroft-Gault formula or directly measured with 24 hr urine collection

13. If a woman of childbearing potential, the patient has a negative serum pregnancy test at screening and is not breastfeeding

14. 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.

15. Patient is willing to comply with protocol-required visit schedule and visit requirements

Exclusion Criteria:

1. 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.
2. 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
3. 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
4. Prior discontinuation of gemcitabine because of pulmonary or hepatic toxicity or hemolytic uremic syndrome (HUS) or hypersensitivity, allergic reaction, or intolerance
5. Any GI disorder which would significantly impede absorption of an oral agent
6. Known brain or leptomeningeal metastases
7. Surgery or radiation therapy within the past 28 days
8. 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
9. Any active disease or condition that would not permit compliance with the protocol
10. Residual toxicity from prior chemotherapy or CCRT that is Grade ≥2 (residual Grade 2 neuropathy and alopecia are permitted)
11. 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
12. Patient has a history of drug or alcohol abuse within last year
13. Patient has documented cerebrovascular disease
14. Patient has a seizure disorder not controlled on medication (based on decision of Investigator)
15. Patient received an investigational agent within 28 days of enrollment
16. Patients with uncontrolled active viral, bacterial, or systemic fungal infection
17. Patient has known human immunodeficiency virus (HIV) infection
18. 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
19. Patient has received yellow fever vaccine or other live attenuated vaccine(s) within the 4 weeks prior to screening
20. 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