Phase I Study of TBI-1401(HF10) Plus Chemotherapy in Patients With Unresectable Pancreatic Cancer.

Study Overview
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Brief Summary
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The purpose of this study is to determine the recommended dose of TBI-1401(HF10) treatment in combination with chemotherapy (Gemcitabine + Nab-paclitaxel or TS-1) in patients with stage III or IV unresectable pancreatic cancer.

Detailed Description
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A Phase I, open-label, multi-center study to determine the recommended dose of TBI-1401(HF10) treatment in combination with chemotherapy (Gemcitabine + Nab-paclitaxel or TS-1) in patients with stage III or IV unresectable pancreatic cancer. Patients with stage IV must failed a gemcitabine based first-line chemotherapy. Patients with stage III will receive the repeated intratumoral injection of TBI-1401(HF10) at recommended dose at 2-week intervals in combination with intravenous infusion of 1000 mg/m^2 Gemcitabine and 125 mg/m^2 Nab-paclitaxel at weekly for 3 weeks followed by 1 week rest. Patients with stage IV will receive the repeated intratumoral injection of TBI-1401(HF10) at recommended dose at 2-week intervals in combination with oral of 40 - 60 mg TS-1 at twice daily for 4 weeks followed by 2 weeks rest. Patients will receive the combination therapy of TBI-1401(HF10) + chemo for up to 1 year if eligible for treatment.

Official Title
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Phase I Study of Combination With TBI-1401(HF10), a Replication-competent HSV-1 Oncolytic Virus, and Chemotherapy in Patients With Stage III or IV Unresectable Pancreatic Cancer.

Conditions
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Pancreatic Cancer Stage III, Pancreatic Cancer Stage IV

Intervention / Treatment
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* Biological: TBI-1401(HF10)
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Drug: TS-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically or cytologically confirmed unresectable pancreatic cancer (stage III or IV) based on the General Rules for the Study of Pancreatic Cancer (The 7th edition), and never received anti-cancer therapy (radiation therapy, chemotherapy, immunotherapy, surgery, clinical trials). Patients with primary lesion will be intratumorally injectable for TBI-1401(HF10) by EUS (endoscopic ultrasound). Patients must be ≧20 years of age. Patients must have at least one measurable lesion evaluated by Computed Tomography (CT) scan on RECIST ver.1.1 at pre-treatment. Patients must have a life expectancy ≧12 weeks. Patients must have an ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 0-1. Patients demonstrated adequate organ function (≦7 days prior to treatment). Females of childbearing potential must have a negative urine or serum pregnancy test within 1 week prior to start of treatment. Patients must be able to understand the study and willing to sign a written informed consent document. Exclusion Criteria: Patients receiving anti-herpes medication within 1 week prior to TBI-1401(HF10) treatment (except local treatment such as ointment). Patients with a significant tumor bleeding or coagulation abnormality that could not treat intratumoral injection or biopsy in safe. Patients with clinically evident Hepatitis B surface antigen (HBs) positive, Hepatitis C virus (HCV) antibody positive and HSV-RNA positive, Human Immunodeficiency Virus (HIV) antibody positive. Patients with the active symptom of Epstein-Barr virus (EBV) infection. Patients with active CNS metastases. Patients with ascites, except acceptable mild ascites. Patients with multiple cancer. Patients need to treat anticoagulant or antiplatelet agent. Patients has a history of allergy for CT contrast agent, live vaccine, any drug excipients, Nab-paclitaxel, Gemcitabine, or any study drugs.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TBI-1401(HF10) + Gem/nab-PTX<br>1x10^6 or 1x10^7 TCID50/mL TBI-1401(HF10) administered to the tumor in a total volume up to 2.0 mL (injection volume will be adjusted based on the tumor size) by EUS-guided intratumoral injection and 1000 mg/m^2 Gemcitabine and 125 mg/m^2 Nab-paclitaxel injected by intravenous infusions. | Biological: TBI-1401(HF10)<br>* 1x10^6 or 1x10^7 TCID50/mL TBI-1401(HF10) administered by intratumoral injection at 2-week intervals. Patients may continue to receive the injections for up to 1 year if eligible for injection.<br>* Other names: canerpaturev;Drug: Gemcitabine<br>* 1000 mg/m^2 Gemcitabine administered by intravenous infusion at weekly for 3 weeks followed by a week of rest.<br>* Other names: Gemzar;Drug: Nab-paclitaxel<br>* 125 mg/m^2 Nab-paclitaxel administered by intravenous infusion at weekly for 3 weeks followed by a week of rest.<br>* Other names: Abraxane;|
| Experimental: TBI-1401(HF10) + TS-1 (primary)<br>1x10^6 or 1x10^7 TCID50/mL TBI-1401(HF10) administered to the primary tumor in a total volume up to 2.0 mL (injection volume will be adjusted based on the tumor size) by EUS-guided intratumoral injection and TS-1 administered by oral. | Biological: TBI-1401(HF10)<br>* 1x10^6 or 1x10^7 TCID50/mL TBI-1401(HF10) administered by intratumoral injection at 2-week intervals. Patients may continue to receive the injections for up to 1 year if eligible for injection.<br>* Other names: canerpaturev;Drug: TS-1<br>* TS-1 (40-60 mg per body surface area) administered by oral at twice daily for 4 weeks followed by 2 weeks of rest.<br>* Other names: Tegafur-gimeracil-oteracil potassium;|
| Experimental: TBI-1401(HF10) + TS-1 (primary and meta)<br>1x10^6 or 1x10^7 TCID50/mL TBI-1401(HF10) administered to the primary tumor in a total volume up to 2.0 mL (injection volume will be adjusted based on the tumor size) by EUS-guided intratumoral injection and hepatic metastasis in a total volume up to 2.0 mL (injection volume will be adjusted based on the tumor size) by EUS-guided intratumoral injection or percutaneous injection and TS-1 administered by oral. | Biological: TBI-1401(HF10)<br>* 1x10^6 or 1x10^7 TCID50/mL TBI-1401(HF10) administered by intratumoral injection at 2-week intervals. Patients may continue to receive the injections for up to 1 year if eligible for injection.<br>* Other names: canerpaturev;Drug: TS-1<br>* TS-1 (40-60 mg per body surface area) administered by oral at twice daily for 4 weeks followed by 2 weeks of rest.<br>* Other names: Tegafur-gimeracil-oteracil potassium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) | Determine the recommended dose of TBI-1401(HF10) in combination with Gemcitabine and Nab-paclitaxel. | Through 1st TBI-1401(HF10) injection to before 3rd injection (basically 4 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). | Through 1st TBI-1401(HF10) injection to study completion (up to 13 month). | 
| Objective response rate (ORR) by RECIST | Overall tumor response evaluated by RECIST version 1.1 | At 16 weeks and through study completion (up to 1 year). | 
| Objective response rate (ORR) by irRECIST | Overall tumor response evaluated by irRECIST. | At 16 weeks and through study completion (up to 1 year). | 
| Progression-free survival (PFS) by RECIST | Evaluation the time to progression during and after the treatment. | Through disease progression (up to 1 year). | 
| Progression-free survival (PFS) by irRECIST | Evaluation the time to progression during and after the treatment. | Through disease progression (up to 1 year). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unresectable pancreatic cancer, Metastatic pancreatic cancer, Pancreatic adenocarcinoma, TBI-1401(HF10), HF10, Oncolytic virus, Oncolytic viral immunotherapy, Gemcitabine, Nab-paclitaxel, Albumin-bound paclitaxel, Abraxane, Tegafur-gimeracil-oteracil potassium, TS-1, canerpaturev