Endoscopic Assisted Electrochemotherapy in Addition to Neoadjuvant Treatment of Locally Advanced Rectal Cancer (nECT)

Endoscopic Assisted Electrochemotherapy in Addition to Neoadjuvant Treatment of Locally Advanced Rectal Cancer: a Randomized Clinical Phase II Trial

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant electrochemotherapy on locally advanced rectal cancer (UICC II-III) in an intended curative clinical setting, using an endoscopic electroporation device (EndoVE).

Study Overview

• Status: Unknown
• Conditions: Neoadjuvant Therapy; Locally Advanced Rectal Cancer; Electrochemotherapy; Down Staging
• Intervention / Treatment: Drug: Electrochemotherapy with bleomycin; Device: EndoVE

Detailed Description

Electroporation of cancer cells allows for a greater concentration of chemotherapy drugs to enter the tumor cells. The uptake of the chemotherapeutic drug is aided through the application of short electric pulses to the tumor mass (referred to as - Electrochemotherapy or ECT). The pulses make the tumor cells more porous which allows the drug easier access into the cancer cells, whereas other tissues and organs in the body remain relatively poor at absorbing the drug, thereby reducing the potential side effects on healthy tissues. Procedures with electrochemotherapy have previously been applied to human patients in other countries of the EU, the US and Japan.

The drug concentration used is significantly reduced due to the more targeted absorption by the tumor and this significantly reduces side effects normally associated with chemotherapy.

A large number of preclinical and clinical Phase I and I/II studies have demonstrated the efficiency and safety of ECT. These studies have included patients with melanoma, head and neck squamous cell carcinoma, merkel cell carcinomas, basal cell carcinoma and adenocarcinoma nodules.

An endoscopic system (EndoVE ) for delivering the electric pulses to gastrointestinal tumors has recently been developed. The treatment procedure is similar to standard endoscopic colorectal examination (therapeutic colonoscopy) with the added element of an intravenous injection of bleomycin followed by the delivery of electric pulses (each one less than 1msec in duration). The pulses are endoscopically delivered directly to the tumor mass. The entire procedure is minimally invasive and completely ambulatory. A successful treatment will cause the tumor to shrink in size in the weeks following the procedure.

The objective of this study is to investigate the efficacy and safety of this approach in downsizing locally advanced rectal tumors prior to intended curative surgery.

Time frame:

1. All patients will be treated with standard neoadjuvant chemoradiation therapy prior to enrollment in this trial.
2. Alle patients will have PET/MRI scans performed twice to evaluate treatment response (before and after ECT)
3. ECT treatment will be performed 4 weeks prior to surgery outlined by MDT.
4. Alle patients will be followed up for 3 months.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ismail Gögenur, MD, DMSc; Phone Number: +45 26336426; Email: igo@regionsjaelland.dk
• Study Contact Backup: Name: Rasmus P Vogelsang, MD; Phone Number: +45 27351103; Email: rvo@regionsjaelland.dk

Study Locations

• Denmark
  • Roskilde, Denmark, 4000
    • Recruiting
    • Department of Surgery
    • Contact: Ismail Gögenur, MD, DMSc; Phone Number: +45 26336426; Email: igo@regionsjaelland.dk
    • Contact: Rasmus P Vogelsang, MD; Phone Number: +45 27351103
  • Capitol Region
    • Herlev, Capitol Region, Denmark, 2730
      • Recruiting
      • Department of Oncology
      • Contact: Julie Gehl, MD, DMSc; Phone Number: +45 38683868; Email: karen.julie.gehl@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient must be mentally capable of understanding the information given.
2. Patients must give written informed consent.
3. Men or women aged at least 18 years.
4. Histologically verified rectal tumor (adenocarcinoma)
5. Case reviewed by MDT (surgery, radiology, oncology). Case considered curable with neoadjuvant therapy followed by surgical excision (UICC stadium II-III).
6. ASA class I-III (Classification of the American Society of Anesthesiology)

Exclusion Criteria:

1. Coagulation disorders
2. Highly inflamed gastrointestinal tissue which is ulcerated and bleeding
3. Patients with ICD or pacemaker units.
4. Patients with epilepsy.
5. Pregnancy or lactation/breastfeeding.
6. Patients with known Hepatitis B/C or HIV infection.
7. Patients who have undergone treatment with bevacizumab within 4 weeks prior to enrolment in this trial.
8. Patients with concomitant use of phenytoin.
9. Patients with concomitant use of clozapine.
10. Concurrent treatment with an investigational medicinal product.
11. Patients with any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the study recruitments.
12. Patients with contraindications for PET/MRI scan:
13. Advanced tumor stage, UICC stage IV.
14. Acute pulmonary infection.
15. Medical history of severe pulmonary disease.
16. Previous allergic reactions to bleomycin.
17. Previous cumulative dose of bleomycin exceeding 250.000 IU/m2.
18. Pre-existing renal dysfunction. Creatinine clearance < 40 ml/min.
19. Platelet count ≤50 mia/l.
20. Prothrombin time ≥ 40 sec
21. Patients registered in the Danish Tissue Register (Vaevsanvendelsesregistret)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: Standard care
EXPERIMENTAL: Electrochemotherapy with bleomycin; Systemic injection of bleomycin followed by electroporation of the primary tumor. Bleomycin administration: 15.000 IU/m2 BSA. BSA by Du Bois formula.	Drug: Electrochemotherapy with bleomycin; Systemic injection, once only treatment; Other Names: ATC code L01DC01; EV substance code SUB00844MIG; Device: EndoVE; Electroporation using an endoscopic electroporation device; Other Names: Endoscopic electroporation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histopathologic tumor regression following electrochemotherapy	Number of participants with histopathologic tumor regression following elctrochemotherapy as assesed by histopathological evaluation of Tumor Regression Grade (Mandard Classification, TRG 1-5)	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment safety of electrochemotherapy	Number of participants with treatment-related adverse events as assesed by CTCAE version 4.0	4 months
Treatment safety of surgery following electrochemotherapy	Number of participants with compromized surgery following electrochemotherapy assesed by R1 resection rate, CRM involvement, non-mesorectal resection plane, and post operative complications according to Clavien-Dindo Classification	4 weeks
Tumor regression according to Hybrid PET/MRI following electrochemotherapy	Tumor regression as assesed by tumor stage (T-stage)	4 weeks
Tumor Immunologic response following electrochemotherapy	Tumor immunologic infiltration as assesed by the Immunoscore through immunohistochemical analysis	4 weeks

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Collaborators: Rigshospitalet, Denmark; Herlev Hospital
• Investigators: Principal Investigator: Ismail Gögenur, Professor, Department of Surgery, Zealand University Hospital; Principal Investigator: Julie Gehl, MD, DMSc, Department of Oncology, Herlev Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2017
• Primary Completion (ANTICIPATED): June 1, 2019
• Study Completion (ANTICIPATED): September 1, 2019

Study Registration Dates

• First Submitted: January 25, 2017
• First Submitted That Met QC Criteria: January 30, 2017
• First Posted (ESTIMATE): February 2, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 25, 2019
• Last Update Submitted That Met QC Criteria: January 24, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Cancer; Neoplasms; Colorectal cancer; rectal cancer; Neoadjuvant therapy; Pathologic processes; Electrochemotherapy; Bleomycin; Electroporation; Neoplasms, primary; rectal cancer, locally advanced; Antineoplastic, antibodies; Neoplastic processes
• 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; Antineoplastic Agents; Antibiotics, Antineoplastic; Bleomycin
• Other Study ID Numbers: REG-32-2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Undecided