A Study of PEP503(Radio-enhancer) With Radiotherapy and Chemotherapy for Patients With Rectal Cancer

Study Overview
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Brief Summary
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This phase Ib/II study is a prospective, open-label, single arm, nonrandomized study of PEP503(radio-enhancer). There are 2 portions in this study. Escalation phase (Part Ib): A 3 + 3 dose escalation study design will be adopted in this phase to identify the recommended injection volume of PEP503 for intratumor injection. Expansion phase (Part II): Following the confirmation of the recommended volume of intratumor injection, 18 additional patients will be enrolled at the recommended volume level to evaluate for efficacy.

Detailed Description
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The target population is composed by patients who have confirmed adenocarcinoma of the rectum which is T3-4, N any, or locally unresectable, with tumor distal margin within 10 cm of the anal verge, with no evidence of distant metastatic disease, ECOG performance 0-1, and adequate bone marrow, renal and hepatic function.

Official Title
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A Phase Ib/II Study of PEP503 (Radioenhancer) With Radiotherapy, in Combination With Concurrent Chemotherapy for Patients With Locally Advanced or Unresectable Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: PEP503
* Drug: 5-fluorouracil
* Drug: capecitabine
* Procedure: surgical resection
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically proven adenocarcinoma of the rectum which is T3-4, N any, or locally unresectable disease , without evidence of distant metastases (M0) Distant border of the tumor must be located ≤ 10 cm from the anal verge Staging with MRI, transrectal ultrasound or CT-scan to confirm stage and resectability ECOG performance 0 - 1 Age: 20 - 80 years old Adequate bone marrow, renal, and hepatic function as: absolute neutrophil count (ANC) ≥ 1,500/mm3 platelet count ≥ 100,000/mm3 total bilirubin ≤ 1.5x the upper limit of normal (ULN) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x ULN alkaline phosphatase (ALP) ≤ 2.5 x ULN calculated creatinine clearance ≥ 50 mL/min, or creatinine within normal range All female patients of childbearing potential must have negative urine pregnancy test within the 7 days prior study treatment with PEP503. Patients must agree to use effective contraception during the study Exclusion Criteria: Prior history of pelvic radiation therapy Hypersensitivity to fluoropyrimidine Uncontrolled serious medical or psychiatric illness Myocardial infarction or uncontrolled angor pectoris (angina) within the prior 6 months No more than 4 weeks since prior participation in any investigational drug study Major surgery within 28 days Other malignancy within the past 3 years except effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum Cardiovascular disease that would preclude study treatment or follow-up Informed consent not duly signed and dated to participate in the study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PEP503+5-FU/capecitabine+Radiotherapy<br>Patients will receive PEP503 given as intratumor injection on Day 1, followed by preoperative radiation therapy. | Drug: PEP503<br>* The volume of PEP503 to be administered is based on the baseline tumor volume of each patient. There will be 4 dose levels in Phase Ib.<br>* Other names: NBTXR3;Drug: 5-fluorouracil<br>* 225 mg/m2 a day, 5 days/week for 5 weeks during radiotherapy period<br>* Other names: 5-FU;Drug: capecitabine<br>* 825 mg/m2 BID 5 days/week for 5 weeks during the radiotherapy period<br>* Other names: Xeloda;Procedure: surgical resection<br>* Approximately 8 weeks after the completion of chemoradiotherapy, surgical resection of the tumor (total mesorectal excision, TME) will be performed once the tumor become resectable.<br>Radiation: Radiotherapy<br>* Intensity-modulated radiation therapy (IMRT) or intensity modulated arc therapy (IMAT) of 5,000 cGy in 25 fractions (200 cGy/fraction, 5 times/week) to gross tumor and involved nodes and 4,500 cGy in 25 fractions (180 cGy/fraction, 5 times/week) to pelvis, starting at 24 hours after PEP503 injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety profile /the Dose Limiting Toxicity (DLT) | Safety as assess the safety profile and determine the Dose Limiting Toxicity (DLT) of PEP503 given as intratumor injection and activated by external beam radiation, with concurrent chemotherapy in patients with unresectable rectal cancer | up to 36 months | 
| the recommended volume (dose) | recommended volume (dose) of PEP503 examined by given as intratumor injection and activated by external beam radiation. with concurrent chemotherapy in patients with unresectable rectal cancer | up to 36 months | 
| anti-tumor activity | Anti-tumor activity as assessed by response rate (RR, as per RECIST 1.1) of PEP503 at the recommended volume given as intratumor injection and activated by external beam radiation, with concurrent chemotherapy in patients with unresectable rectal cancer | up to 36 months |