Advanced Biliary Tract Cancer (BTC)

Part 1: Dose-Escalation Phase (Phase 1b) Primary Objective  To assess the safety and tolerability of increasing doses of D07001-softgel in patients with unresectable locally advanced or metastatic gastrointestinal (GI) cancer Secondary Objectives  To evaluate the PK profile of D07001-softgel Exploratory Objectives  To evaluate the preliminary data on the efficacy of increasing doses of D07001-softgel  To investigate the effect of increasing doses of D07001-softgel on additional parameters such as tumor markers  To investigate the relationship between the efficacy, safety, and PK of D07001-softgel and pharmacogenomic, pharmacoproteomic, and cellular markers, including the levels of immune cells, circulating endothelial progenitor cells and circulating tumor cells Part 2: Dose-Expansion Phase (Phase 2) Primary Objectives  To assess the safety and tolerability of D07001-softgel in patients who have achieved stable disease or better following first-line chemotherapy or CCRT for unresectable metastatic or locally advanced BTC Secondary Objectives  To assess the PK profile of D07001-softgel, including the effect of food Exploratory Objectives  To evaluate the efficacy of D07001-softgel, as assessed by PFS, OS, time-to-progression (TTP), and objective response rate (ORR; in patients with measurable disease at baseline only), in patients who have achieved stable disease or better following first-line chemotherapy or CCRT for unresectable metastatic or locally advanced BTC  To investigate the effect of D07001-softgel on tumor markers  To investigate the relationship between the efficacy, safety, and PK of D07001-softgel and pharmacogenomic, pharmacoproteomic, and cellular markers, including the levels of immune cells, circulating endothelial progenitor cells and circulating tumor cells

D07001-Softgel Capsules

Gemcitabine Hydrochloride

Softgel Capsules
Softgel Capsules

20
40

Part 1: Dose-Escalation Phase (Phase 1b)
Primary Endpoint:
 The safety endpoints are:
o DLTs
o MTD
o Hematology, serum chemistry, coagulation parameters, and urinalysis laboratory data
changes
o AE/SAE incidence
o Incidence of patients experiencing toxicity Grade ≥3 according to Common
Terminology Criteria for Adverse Events (CTCAE) v4.03
o Physical examination result changes
o Vital signs changes
o ECG results (including PR, QRS, QT, QTc, and RR intervals)
Secondary Endpoints:
 PK parameters: maximum plasma concentration (Cmax), time to maximum plasma
concentration (Tmax), area under the curve (AUC), elimination half-life (t1/2 el), apparent
clearance (Cl/F), and apparent volume of distribution (Vz/F)
Exploratory Endpoints:
 The efficacy endpoints are:
o PFS
o OS
o TTP
o ORR (in patients with measurable disease at baseline only)
 Tumor marker (cancer antigen [CA]-19-9, carcinoembryonic antigen [CEA]) levels at the
times specified in the event schedule
 Pharmacogenomic, pharmacoproteomic, and cellular analysis

Part 2: Dose-Expansion Phase (Phase 2)
Primary Endpoints:
 The safety endpoints are:
o Dose interruptions/modifications
o Hematology, serum chemistry, coagulation parameters, and urinalysis laboratory data
changes
o AE/SAE incidence
o Incidence of patients experiencing toxicity Grade ≥3 according to CTCAE v4.03
o Physical examination result changes
o Vital signs changes
o ECG results (including PR, QRS, QT, QTc, and RR intervals)
o
Secondary Endpoints:
 PK parameters: Cmax, Tmax, AUC, t1/2 el, Cl/F, and Vz/F
Exploratory Endpoints:
 The efficacy endpoints are:
o PFS
o OS
o TTP
o ORR (in patients with measurable disease at baseline only)
 Tumor marker (CA-19-9, CEA) levels at the times specified in the event schedule
 Pharmacogenomic, pharmacoproteomic, and cellular analysis

Inclusion Criteria
Patients will be entered into this study only if they meet all of the following 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:
a. 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
b. 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:
a. Absolute neutrophil count (ANC) ≥1,500 cell/mm3
b. Platelet count ≥100,000 cells/mm3
c. Hemoglobin ≥9 g/dL
11. Adequate liver function, demonstrated by:
a. AST and ALT ≤2.5 x upper limit of normal (ULN), or ≤5.0 x ULN in the case of
liver metastases
b. Total bilirubin ≤1.5 x ULN
c. Albumin ≥3.0 g/dL
d. International normalized ratio (INR) <1.5
12. Adequate renal function, demonstrated by:
a. Serum creatinine ≤1.5 x ULN
b. Creatinine clearance ≥ 60mL/min calculated by Cockcroft-Gault formula or
directly measured with 24hr 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
Patients will not be entered into this study if they meet any of the following 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 HBV and/or 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