Study of TH-302 Monotherapy as Second-line Treatment in Advanced Biliary Tract Cancer

September 6, 2018 updated by: Do-Youn Oh, Seoul National University Hospital

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.

Study Overview

Status

Completed

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Seoul, Korea, Republic of, 110-744
        • Seoul National University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: treatment
single arm study: TH-302 monotherapy is given
TH-302 (480 ) mg/m2 D1, D8, D15 Q 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
progression-free survival at 4-months (PFS4mo)
Time Frame: 4 months
PFS is defined as the interval from the date of enrollment to the date of disease progression or death due to any cause, whichever occurs first. PFS4m is defined as the proportion of patients alive and progression-free at 4 months relative to all enrolled patients.
4 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate (ORR)
Time Frame: 6 months
6 months
Disease Control Rate (DCR)
Time Frame: 6 months
6 months
Duration of Response (DR)
Time Frame: 2 years
2 years
Progression-Free Survival (PFS)
Time Frame: 2 years
2 years
Time to Progression (TTP)
Time Frame: 10 months
10 months
Overall Survival (OS)
Time Frame: 2 years
2 years
safety and tolerability as measured by number and grade of toxicity events
Time Frame: 15 months
Overall Safety Profile, as characterized by type, frequency, severity as graded by NCI Common Toxicity Criteria for Adverse Events version 4.0 (NCI CTCAEv4.0), timing and relationship to treatment, and laboratory abnormalities observed.
15 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
protein/genomic biomarkers of efficacy from serum, plasma or tumor
Time Frame: 2 years
To explore the association of potential predictive biomarkers and of hypoxia biomarkers from serum, plasma, and tumor with efficacy endpoints
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2015

Primary Completion (Actual)

October 1, 2017

Study Completion (Actual)

October 1, 2017

Study Registration Dates

First Submitted

April 26, 2015

First Submitted That Met QC Criteria

April 29, 2015

First Posted (Estimate)

May 5, 2015

Study Record Updates

Last Update Posted (Actual)

September 10, 2018

Last Update Submitted That Met QC Criteria

September 6, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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