Biliary Tract CancerPhase 2NCT02433639
Study of TH-302 Monotherapy as Second-line Treatment in Advanced Biliary Tract Cancer
A Phase 2 study testing TH-302 monotherapy in people with Biliary Tract Cancer, run by Seoul National University Hospital at 1 site in South Korea.
Trial 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. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Biliary Tract Cancer
- What is being tested?
- TH-302 monotherapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteSouth Korea
- Study dates
- Apr 2015to Oct 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically / cytologically verified, non-resectable, recurrent, or metastatic biliary tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma.
- Patients who were previously treated with one palliative chemotherapy (patients who recurred within 6 months after completion or during adjuvant chemotherapy are allowed)
- Patients must have measurable or evaluable disease by RECIST 1.1
- ECOG PS: 0, 1
- Age ≥ 20 years
- Adequate bone marrow function defined as: Hb ≥ 8 g/dl, ANC ≥ 1500/mcL, Platelets ≥ 100K/mcL
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- 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
- Adequate hepatic function defined as total bilirubin ≤ 2 mg/dl, ALT/AST ≤ 5 x ULN.
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- 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.
- Known brain metastases or primary central nervous system tumors with seizures that are not well controlled with standard medical therapy.
- Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements.
- Known HIV positive patient
- Significant cardiovascular disease including congestive heart failure (New York Heart Association Class II or higher) or active angina pectoris.
- History of a myocardial infarction within 6 months.
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- History of a stroke or transient ischemic attack within 6 months.
- Clinically significant peripheral vascular disease.
- Major surgical procedure within 4 weeks.
- Uncontrolled infection.
- Pregnant (positive pregnancy test)
- Breast-feeding should be discontinued if a nursing mother is to be treated on clinical trial.
- History of any organ or bone marrow transplant.
- Subjects who are taking medications that prolong QT interval and have a risk of Torsades de Pointes.
- Subjects taking a medication that is a moderate or strong inhibitor or inducer of CYP3A4.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the 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.
- Conditions
- Biliary Tract Cancer
- Being tested
- TH-302 monotherapy
- Keywords
- advanced biliary tract cancer, TH-302
- Medical subject headings
- Biliary Tract Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TH-302 monotherapyDrug
TH-302 (480 ) mg/m2 D1, D8, D15 Q 4 weeks
| Study group | Role | What they receive |
|---|---|---|
| treatment | Experimental | single arm study: TH-302 monotherapy is given Receives: Drug: TH-302 monotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
progression-free survival at 4-months (PFS4mo)
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.
Measured: 4 months
Secondary outcomes (7)
Objective Response Rate (ORR)
Measured: 6 months
Disease Control Rate (DCR)
Measured: 6 months
Duration of Response (DR)
Measured: 2 years
Progression-Free Survival (PFS)
Measured: 2 years
Time to Progression (TTP)
Measured: 10 months
Overall Survival (OS)
Measured: 2 years
safety and tolerability as measured by number and grade of toxicity events
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.
Measured: 15 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 May 2015 (estimated)
- Study startApr 2015
- Primary completionOct 2017
- Study completionOct 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Biliary Tract CancerStudies of the same condition, open and under way.
- More trials run by Seoul National University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Seoul National University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Threshold Pharmaceuticals
- Responsible party
- Principal investigator, Do-Youn Oh, Seoul National University Hospital
- Investigators
- Do-Youn Oh, MD, PhD, Principal investigator, Seoul National University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02433639
- Sponsor's protocol ID
- H-1412-023-631
- Status last verified
- Sep 2018
- First submitted
- 26 Apr 2015
- Last updated
- 10 Sep 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study of TH-302 Monotherapy as Second-line Treatment in Advanced Biliary Tract Cancer
- ClinicalTrials.gov ID
- NCT02433639
- Acronym / sponsor ID
- H-1412-023-631
- Conditions
- Biliary Tract Cancer
- Keywords
- advanced biliary tract cancer, TH-302
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Seoul National University HospitalUniversity, hospital or other
- Collaborators
- Threshold Pharmaceuticals
- Study start
- Apr 2015
- Primary completion
- Oct 2017 (actual)
- Study completion
- Oct 2017 (actual)
- First posted
- 5 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| treatment | Experimental | Drug: TH-302 monotherapysingle arm study: TH-302 monotherapy is given |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Histologically / cytologically verified, non-resectable, recurrent, or metastatic biliary tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma.
- Patients who were previously treated with one palliative chemotherapy (patients who recurred within 6 months after completion or during adjuvant chemotherapy are allowed)
- Patients must have measurable or evaluable disease by RECIST 1.1
- ECOG PS: 0, 1
- Age ≥ 20 years
Key exclusion criteria (15 listed)
- 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.
- Known brain metastases or primary central nervous system tumors with seizures that are not well controlled with standard medical therapy.
- Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements.
- Known HIV positive patient
- Significant cardiovascular disease including congestive heart failure (New York Heart Association Class II or higher) or active angina pectoris.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TH-302 monotherapyTH-302 (480 ) mg/m2 D1, D8, D15 Q 4 weeks | Drug | treatment |
Primary outcome
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.
7 secondary outcomes
Objective Response Rate (ORR)
Time frame: 6 months
Disease Control Rate (DCR)
Time frame: 6 months
Duration of Response (DR)
Time frame: 2 years
Progression-Free Survival (PFS)
Time frame: 2 years
Time to Progression (TTP)
Time frame: 10 months
Overall Survival (OS)
Time frame: 2 years
safety and tolerability as measured by number and grade of toxicity events
Time frame: 15 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Sep 2018.
Related trials for Biliary Tract Cancer
Active, not recruitingPhase 2/3
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RecruitingPhase 2
At-Home Cancer Directed Therapy Versus in Clinic for the Treatment of Patients With Advanced Cancer
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Tissue Procurement and Natural History Study of Patients With Malignant Mesothelioma
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Durvalumab and Tremelimumab in Combination With Propranolol and Chemotherapy for Treatment of Advanced Hepatopancreabiliary Tumors (BLOCKED)
Pancreatic Cancer, Hepatocellular Cancer
Not yet recruitingPhase 3
Hepatic Arterial Infusion Chemotherapy Versus Capecitabine as Adjuvant Therapy for Resected Biliary Tract Cancer
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Do-Youn Oh, MD, PhD principal investigator
Seoul National University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing TH-302 monotherapy in people with Biliary Tract Cancer, run by Seoul National University Hospital at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
progression-free survival at 4-months (PFS4mo) (time frame: 4 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2018.