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

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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