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

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

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.

Study Overview

• Status: Terminated
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: PEP503; Drug: 5-fluorouracil; Drug: capecitabine; Procedure: surgical resection; Radiation: Radiotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung City, Taiwan
    • Kaohsiung Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PEP503+5-FU/capecitabine+Radiotherapy; Patients will receive PEP503 given as intratumor injection on Day 1, followed by preoperative radiation therapy.

Drug: PEP503; 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.; Other Names: NBTXR3; Drug: 5-fluorouracil; 225 mg/m2 a day, 5 days/week for 5 weeks during radiotherapy period; Other Names: 5-FU; Drug: capecitabine; 825 mg/m2 BID 5 days/week for 5 weeks during the radiotherapy period; Other Names: Xeloda; Procedure: surgical resection; 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.; Radiation: Radiotherapy; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: PharmaEngine
• Investigators: Principal Investigator: Jwa-Yuan Wang, phD, Kaohsiung Municipal United Hospital

Publications and helpful links

General Publications

• Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet. 1986 Jun 28;1(8496):1479-82. doi: 10.1016/s0140-6736(86)91510-2.
• Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001 Oct 20;358(9290):1291-304. doi: 10.1016/S0140-6736(01)06409-1.
• Lubowski DZ. Rectal cancer: the evolving role of adjuvant radiotherapy. ANZ J Surg. 2015 Mar;85(3):99-100. doi: 10.1111/ans.12916. No abstract available.
• Tural D, Selcukbiricik F, Yildiz O, Elcin O, Erdamar S, Guney S, Demireli F, Buyukunal E, Serdengecti S. Preoperative versus postoperative chemoradiotherapy in stage T3, N0 rectal cancer. Int J Clin Oncol. 2014 Oct;19(5):889-96. doi: 10.1007/s10147-013-0636-4. Epub 2013 Nov 12.
• Nel AE, Madler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater. 2009 Jul;8(7):543-57. doi: 10.1038/nmat2442. Epub 2009 Jun 14.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): July 28, 2021
• Study Completion (Actual): July 28, 2021

Study Registration Dates

• First Submitted: June 1, 2015
• First Submitted That Met QC Criteria: June 4, 2015
• First Posted (Estimate): June 8, 2015

Study Record Updates

• Last Update Posted (Actual): January 11, 2022
• Last Update Submitted That Met QC Criteria: December 17, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil; Capecitabine
• Other Study ID Numbers: PEP503-RC-1001