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
Primary Purpose
Gastrointestinal Cancer, Biliary Tract Cancer
Status
Terminated
Phase
Phase 1
Locations
Taiwan
Study Type
Interventional
Intervention
D07001-softgel capsules
Sponsored by
About this trial
This is an interventional treatment trial for Gastrointestinal Cancer
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
Sites / Locations
- China Medical University Hospital
- National Cheng-Kung University Hospital
- National Taiwan University Hospital
- Taipei Veterans General Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Part 1:Dose-Escalation Phase
Part 2: Dose-Expansion Phase (Phase 2)
Arm Description
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
higher dose-expansion of D07001-softgel capsules lower dose-expansion of D07001-softgel capsules
Outcomes
Primary Outcome Measures
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.
Part 1 and Part 2: 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
Part 2: Incidence of dose modifications, including dose reduction, interruption, or discontinuation of study drug
Secondary Outcome Measures
Part 1: Pharmacokinetics (PK)- maximum plasma concentration (Cmax) of gemcitabine (dFdC) and difluorodeoxyuridine (dFdU)
Part 1: PK- Area Under Curve (AUC) of dFdC and dFdU
Part 2: PK- Cmax of dFdC and dFdU
Part 2: PK- AUC of dFdC and dFdU
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03531320
Brief Title
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
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
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Terminated
Why Stopped
The Sponsor is considering revising the protocol design of the Part II study, so it has decided not to continue the Part II of the study at this stage.
Study Start Date
August 6, 2018 (Actual)
Primary Completion Date
December 28, 2020 (Actual)
Study Completion Date
December 29, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
InnoPharmax Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastrointestinal Cancer, Biliary Tract Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
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)
Allocation
Non-Randomized
Enrollment
19 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part 1:Dose-Escalation Phase
Arm Type
Experimental
Arm Description
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
Arm Title
Part 2: Dose-Expansion Phase (Phase 2)
Arm Type
Experimental
Arm Description
higher dose-expansion of D07001-softgel capsules lower dose-expansion of D07001-softgel capsules
Intervention Type
Drug
Intervention Name(s)
D07001-softgel capsules
Intervention Description
Active Ingredient:Gemcitabine hydrochloride
Primary Outcome Measure Information:
Title
Part 1: Establish the maximum tolerated dose (MTD)
Description
MTD will be defined based on the number of dose limiting toxicities (DLT) in subjects at each dose level.
Time Frame
During Cycle 1 of treatment (each cycle is 21 days) for each subject
Title
Part 1 and Part 2: Incidence of adverse events (AEs)/ serious adverse event (SAEs)
Description
AEs will be assessed via the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame
From date of informed consent to 30-day follow-up visit for each subject, an average of 10 months
Title
Part 2: Incidence of dose modifications, including dose reduction, interruption, or discontinuation of study drug
Time Frame
First dose through last dose for each subject, an average of 8 months
Secondary Outcome Measure Information:
Title
Part 1: Pharmacokinetics (PK)- maximum plasma concentration (Cmax) of gemcitabine (dFdC) and difluorodeoxyuridine (dFdU)
Time Frame
Cycle 1 Days 1, 8, and 15
Title
Part 1: PK- Area Under Curve (AUC) of dFdC and dFdU
Time Frame
Cycle 1 Days 1, 8, and 15
Title
Part 2: PK- Cmax of dFdC and dFdU
Time Frame
Cycle 1 Days 1, 8, and 15; Cycle 1 Day 15 and Cycle 2 Day 1 for food-effect cohort only
Title
Part 2: PK- AUC of dFdC and dFdU
Time Frame
Cycle 1 Days 1, 8, and 15; Cycle 1 Day 15 and Cycle 2 Day 1 for food-effect cohort only
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Li-Tzong Chen, Ph. D
Organizational Affiliation
National Cheng-Kung University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
China Medical University Hospital
City
Taichung
ZIP/Postal Code
404
Country
Taiwan
Facility Name
National Cheng-Kung University Hospital
City
Tainan
ZIP/Postal Code
704
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
100
Country
Taiwan
Facility Name
Taipei Veterans General Hospital
City
Taipei
ZIP/Postal Code
11217
Country
Taiwan
12. IPD Sharing Statement
Learn more about this trial
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
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