Brief Title
Study of TH-302 Monotherapy as Second-line Treatment in Advanced Biliary Tract Cancer
Brief Summary
Biliary tract cancer is relatively rare cancer, with generally poor prognosis. In
metastatic/recurrent biliary tract cancer, the most commonly used 1st-line chemotherapy is
gemcitabine+cisplatin combination. However, there is no standard 2nd-line chemotherapy and
there is no validated targeted therapeutic agent, even though this tumor harbors diverse
genetic characteristics.
TH-302 (1-methyl-2-nitro-1H-imidazole-5-yl)methyl N,N'-bis(2-bromoethyl) diamidophos-phate is
a nitroimidazole-linked prodrug of a brominated version of isophosphoramide mustard (Br-IPM).
When exposed to hypoxic conditions, TH-302 is reduced at the nitroimadazole site of the
prodrug by intracellular reductases leading to the release of Br-IPM. Br-IPM can then act as
a DNA crosslinking agent. In areas of normoxia, TH-302 remains intact as a prodrug and
toxicity is minimized. In addition, preclinical data suggest that after activation, the
active moiety may diffuse to areas outside the hypoxic region, demonstrating a "bystander"
effect and possibly exhibiting additional anti-tumor activity.
It is well known that biliary tract cancer is hypovascular tumor, so it contains large
hypoxic area in the tumor. Therefore it would be worthy to test TH-302 in biliary tract
cancer.
This study is a phase II study of TH-302 monotherapy as second-line treatment in advanced
biliary tract cancer, to investigate efficacy and safety of TH-302 monotherapy.
Detailed Description
Biliary tract cancer is relatively rare disease worldwide among all kinds of solid tumors.
However the incidence of biliary tract cancer is relatively higher in Korea compared to the
western countries. The prognosis of all biliary tract cancer is poor, that is, the 5-year
overall survival rate is 26.7%. The main reasons of poor prognosis are: 1) there is no
screening method to detect in early stage, 2) the relapse rate after curative surgery is
high, 3) in metastatic/recurrent biliary tract cancer, the chemo-sensitivity is relatively
low. And another important reason of poor prognosis is low interest of investigators. So the
researches with new agents have been limited compared with other types of cancer such as lung
cancer, breast cancer and colon cancer etc. In metastatic/recurrent biliary tract cancer, the
available cytotoxic chemotherapies are composed of gemcitabine, cisplatin, 5-FU, etc. The
most commonly used 1st-line chemotherapy is gemcitabine+cisplatin combination. (N Engl J Med
2010; 362 (14): 1273-81) There is no standard 2nd-line chemotherapy so far.
The overall survival with these cytotoxic chemotherapies is about 8-10 months. So far, there
is no validated targeted therapeutic agent in biliary tract cancer, even though this tumor
harbors diverse genetic characteristics.
Therefore, there is a huge unmet medical need in biliary tract cancer.
TH-302 (1-methyl-2-nitro-1H-imidazole-5-yl)methyl N,N'-bis(2-bromoethyl) diamidophos-phate is
a nitroimidazole-linked prodrug of a brominated version of isophosphoramide mustard (Br-IPM).
When exposed to hypoxic conditions, TH-302 is reduced at the nitroimadazole site of the
prodrug by intracellular reductases leading to the release of Br-IPM. Br-IPM can then act as
a DNA crosslinking agent. Tumors often consist of large areas of highly hypoxic regions that
are known to be resistant to chemotherapy and radiation treatment. In areas of normoxia,
TH-302 remains intact as a prodrug and toxicity is minimized. Thus, TH-302 has been designed
to target these highly hypoxic tumor regions and this makes it an attractive candidate for
clinical development. In addition, preclinical data suggest that after activation, the active
moiety may diffuse to areas outside the hypoxic region, demonstrating a "bystander" effect
and possibly exhibiting additional anti-tumor activity.
It is well known that biliary tract cancer is hypovascular tumor, so it contains large
hypoxic area in the tumor. Therefore it would be worthy to test TH-302 in biliary tract
cancer.
This study is a phase II study of TH-302 monotherapy as second-line treatment in advanced
biliary tract cancer.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
progression-free survival at 4-months (PFS4mo)
Secondary Outcome
Objective Response Rate (ORR)
Condition
Biliary Tract Cancer
Intervention
TH-302 monotherapy
Study Arms / Comparison Groups
treatment
Description: single arm study: TH-302 monotherapy is given
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
24
Start Date
April 2015
Completion Date
October 2017
Primary Completion Date
October 2017
Eligibility Criteria
Inclusion Criteria:
1. Histologically / cytologically verified, non-resectable, recurrent, or metastatic
biliary tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic
cholangiocarcinoma and gallbladder carcinoma.
2. Patients who were previously treated with one palliative chemotherapy (patients who
recurred within 6 months after completion or during adjuvant chemotherapy are allowed)
3. Patients must have measurable or evaluable disease by RECIST 1.1
4. ECOG PS: 0, 1
5. Age ≥ 20 years
6. Adequate bone marrow function defined as: Hb ≥ 8 g/dl, ANC ≥ 1500/mcL, Platelets ≥
100K/mcL
7. Adequate renal function defined as serum creatinine < 1.6 mg/dl and/or measured
creatinine clearance from 24-hour urine collection of ≥ 60 ml/min
8. Adequate hepatic function defined as total bilirubin ≤ 2 mg/dl, ALT/AST ≤ 5 x ULN.
9. Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
1. Evidence of another active cancer that may influence patient outcome, except for
nonmelanoma skin carcinoma, melanoma in-situ, in-situ carcinoma of the cervix
curatively treated, treated superficial bladder cancer, and adenocarcinoma of the
prostate that has been surgically treated with a post-treatment PSA that is
non-detectable.
2. Known brain metastases or primary central nervous system tumors with seizures that are
not well controlled with standard medical therapy.
3. Uncontrolled intercurrent illness including, but not limited to psychiatric
illness/social situations that would limit compliance with study requirements.
4. Known HIV positive patient
5. Significant cardiovascular disease including congestive heart failure (New York Heart
Association Class II or higher) or active angina pectoris.
6. History of a myocardial infarction within 6 months.
7. History of a stroke or transient ischemic attack within 6 months.
8. Clinically significant peripheral vascular disease.
9. Major surgical procedure within 4 weeks.
10. Uncontrolled infection.
11. Pregnant (positive pregnancy test)
12. Breast-feeding should be discontinued if a nursing mother is to be treated on clinical
trial.
13. History of any organ or bone marrow transplant.
14. Subjects who are taking medications that prolong QT interval and have a risk of
Torsades de Pointes.
15. Subjects taking a medication that is a moderate or strong inhibitor or inducer of
CYP3A4.
Gender
All
Ages
20 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Do-Youn Oh, MD, PhD, ,
Location Countries
Korea, Republic of
Location Countries
Korea, Republic of
Administrative Informations
NCT ID
NCT02433639
Organization ID
H-1412-023-631
Responsible Party
Principal Investigator
Study Sponsor
Seoul National University Hospital
Collaborators
Threshold Pharmaceuticals
Study Sponsor
Do-Youn Oh, MD, PhD, Principal Investigator, Seoul National University Hospital
Verification Date
September 2018