Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer

NCT03916510 | Completed Phase 1 Results DMC

• 1 other identifier: OCTO_081
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 4

Brief Summary

The use of chemoradiotherapy (CRT), in combination with surgery is the standard of care in the treatment of locally advanced rectal cancer. However some patients don't respond well to radiation. More advanced radiotherapy techniques, that result in fewer toxicities, means that we are now able to combine new anti-cancer agents into standard treatment. Targeting the tumour early in this way has the potential to improve response rates. Enadenotucirev is a specific type of anti-cancer virus that only targets cancer cells. It acts in the same way as any virus and can only survive by replicating inside cancer cells and not normal, non-cancerous cells. This means that it can selectively target and destroy tumours, without directly affecting normal cells. It also has the ability to attract cells from the body's immune system to help fight the cancer. The addition of enadenotucirev to standard chemoradiotherapy treatment may have a combined effect on the cancer cells with potentially few, additional side effects. This trial aims to determine the optimal dose and frequency of the virus to give by gradually increasing the number of doses each successive patient receives, and then increasing the dose of the virus itself. Each patient will receive a minimum of 3 doses, up to a maximum of 8, spread over the course of their 5 week standard chemoradiotherapy treatment. Patients will be closely monitored at all times to ensure that with each dosing group, there aren't excessive side effects. Patients will then undergo surgery as part of their standard of care and be followed up for up to 4-6 weeks post-surgery. This trial aims to determine the optimal dose and frequency that can then be used in future studies with the possibility of exploring the addition of Enadenotucirev to other chemoradiotherapy treatments.

Conditions

Locally Advanced Rectal Cancer

Keywords

locally advanced; rectal cancer; Enadenotucirev; oncolytic virus; adenovirus; dose escalation; Time To Event Continual Reassessment Method; chemoradiotherapy; phase 1

Outcome Measures

Primary Outcomes (2)

• Number of Participants Who Had a Dose Limiting Toxicity (DLT) Following Treatment With Enadenotucirev and Chemoradiotherapy (Capecitabine and Radiation) at 1 of 4 Different Dosing Schedules.

  Dose escalation for this trial was informed by a Time To Event Continual Reassessment Method (TiTE CRM). This statistical model was also able to determine the optimal dose schedule of enadenotucirev that can be administered with chemoradiation (highest treatment schedule resulting in less than 30% dose limiting toxicity rate). The definition of a DLT for this trial can be found in the study description section of this record.

  From Day 1 of treatment to Week 13 (13 weeks +/- 3 days)

• Magnetic Resonance Imaging (MRI) Tumour Regression Grade on a Scale of 1-5 for Patients Treated With Enadenotucirev Delivered in Conjunction With Chemoradiotherapy (Capecitabine and Radiation) at 1 of 4 Different Dosing Schedules.

  To inform the optimal dose and frequency of enadenotucirev that can be administered with chemoradiation. The MRI tumour regression grade uses the following scale and for the purposes of the trial analysis and dose escalation, scores of 1 or 2 were classified as responders and scores of 3, 4 or 5 were classified as non-responders: 1. \- No/minimal fibrosis visible (tiny linear scar) and no tumour signal (best outcome) 2. \- Dense fibrotic scar (low signal intensity) but no macroscopic tumour signal (indicates no or microscopic tumour) 3. \- Fibrosis predominates but obvious measurable areas of tumour signal visible 4. \- Tumour signal predominates with little/minimal fibrosis 5. \- Tumour signal only: no fibrosis, includes progression of tumour (worst outcome)

  13 weeks after starting treatment (+/- 3 days)

Secondary Outcomes (3)

• Number of Patients Completing at Least 80% of the Intended Capecitabine Dose and at Least 20 Fractions of Radiotherapy.

  From start of treatment to end of treatment (9 weeks)

• Number of Participants With Pathological Complete Response (pCR) of Tumour Following Resection (Staged According to Royal College of Pathologists Guidelines).

  At 4-6 weeks post surgery (minimum 18 weeks after start of treatment)

• Neoadjuvant Rectal (NAR) Score on a Scale of 0-100 Following Resection.

  At 4-6 weeks post surgery (minimum 18 weeks after start of treatment)

Study Arms (4)

Dosing Group 1

EXPERIMENTAL

* Chemotherapy: 900 mg/m2 capecitabine twice daily, Mon-Fri (on radiotherapy days) for 5 weeks, except on days patients received enadenotucirev. * Radiotherapy: 50 Gy in 25 fractions. * Enadenotucirev: 3 x loading doses pre-chemoradiation (low-low-low\*). * Low = 1x10\^12 viral particles High = 3x10\^12 viral particles

Biological: Enadenotucirev; Drug: Capecitabine; Radiation: Radiotherapy

Dosing Group 2

EXPERIMENTAL

* Chemotherapy: 900 mg/m2 capecitabine twice daily, Mon-Fri (on radiotherapy days) for 5 weeks, except on days patients received enadenotucirev. * Radiotherapy: 50 Gy in 25 fractions. * Enadenotucirev: 3 x loading doses pre-chemoradiation (low-low-low\*). 3 x maintenance doses post-chemoradiation (low-low-low\*). * Low = 1x10\^12 viral particles High = 3x10\^12 viral particles

Biological: Enadenotucirev; Drug: Capecitabine; Radiation: Radiotherapy

Dosing Group 3

EXPERIMENTAL

* Chemotherapy: 900 mg/m2 capecitabine twice daily, Mon-Fri (on radiotherapy days) for 5 weeks, except on days patients received enadenotucirev. * Radiotherapy: 50 Gy in 25 fractions. * Enadenotucirev: 3 x loading doses pre-chemoradiation (low-low-low\*). 3 x maintenance doses post-chemoradiation (low-high-high\*). * Low = 1x10\^12 viral particles High = 3x10\^12 viral particles

Biological: Enadenotucirev; Drug: Capecitabine; Radiation: Radiotherapy

Dosing Group 4

EXPERIMENTAL

* Chemotherapy: 900 mg/m2 capecitabine twice daily, Mon-Fri (on radiotherapy days) for 5 weeks, except on days patients received enadenotucirev. * Radiotherapy: 50 Gy in 25 fractions. * Enadenotucirev: 3 x loading doses pre-chemoradiation (low-high-high\*). 2 x concurrent doses on week 1, days 1 and 5 of chemoradiation (high-high\*). 3 x maintenance doses post-chemoradiation (low-high-high\*). * Low = 1x10\^12 viral particles High = 3x10\^12 viral particles

Biological: Enadenotucirev; Drug: Capecitabine; Radiation: Radiotherapy

Interventions

Enadenotucirev BIOLOGICAL

Enadenotucirev is a live replicating oncolytic adenovirus; it is considered a BioSafety Level 1 (BSL-1) infectious substance.

Dosing Group 1; Dosing Group 2; Dosing Group 3; Dosing Group 4

Capecitabine DRUG

Capecitabine is a chemotherapy drug licensed for use in rectal cancer, it is a non-cytotoxic pre-cursor of the cytotoxic 5-fluorouracil. Due to Capecitabine not being taken on Enadenotucirev dosing days it is considered an investigational medicinal product within this trial.

Dosing Group 1; Dosing Group 2; Dosing Group 3; Dosing Group 4

Radiotherapy RADIATION

50 Gy/25#

Dosing Group 1; Dosing Group 2; Dosing Group 3; Dosing Group 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed invasive adenocarcinoma of the rectum
• Patients with oligometastatic disease suitable for radical treatment are permitted provided that the site specific MDT deems them suitable for chemoradiation
• Male or female, Age ≥ 18 years
• ECOG performance score of 0 - 1
• The patient is willing and able to comply with the protocol scheduled biopsy, follow-up visits and examinations for the duration of the trial.
• Written (signed and dated) informed consent
• Adequate renal function demonstrated by:
• Adequate ≤1.5 ULN and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m (measured creatinine clearance ≥60 mL/min) and
• Urine dipstick for proteinuria at screening and baseline negative or trace. Patients may be included with results of 1+ if they have a spot urinary albumin creatinine ratio (ACR) of either:
• (i) ≤3 mg/mmol or (ii) \>3 mg/mmol with a 24 hour urinary protein \<1.0 g/24 hours and
• Serum complement C3 and C4 within the normal range
• Haematological and Biochemical indices within the ranges shown below:
• Haemoglobin: ≥90 g/L
• Absolute neutrophil count: ≥1.5x10\^9/L
• Platelet count: ≥100x10\^9/L

You may not qualify if:

• Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used.
• Pulmonary lymphangitis (if metastatic disease present)
• Past medical history:
• Known history or evidence of significant immunodeficiency due to underlying illness and/or medication (e.g. systemic corticosteroids, or other immunosuppressive medications including cyclosporine, azathioprine, interferons in the 4 weeks before the first dose of trial treatment)
• Splenectomy
• Prior allogeneic or autologous bone marrow or organ transplantation
• Patients with a history of, or active, known or suspected auto-immune disease or a syndrome that requires systemic or immunosuppressive agents; patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune disease only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
• History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or evidence of active pneumonia or pneumonitis on computed tomography scan
• Active viral disease or known positive serology for HIV, hepatitis B or hepatitis C
• Active infections requiring antibiotics, physician monitoring, or recurrent fevers \>38.0°C associated with a clinical diagnosis of active infection
• Prior pelvic radiotherapy
• Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions
• Uncontrolled cardiorespiratory comorbidity (e.g. severe pulmonary fibrosis, inadequately controlled angina or myocardial infarction in the last 6 months)
• Major disturbance in bowel function (e.g. severe incontinence, Crohn's disease, \>6 loperamide/day), risk of bowel obstruction due to tumour - exception defunctioning colostomy performed
• Treatment with any COVID-19 vaccine in the 28 days before the first dose of enadenotucirev, unless the vaccine is known to not be based on an adenoviral vector (e.g. mRNA vaccines)

Sponsors & Collaborators

• University of Oxford: lead
• Akamis Bio: collaborator
• Cancer Research UK: collaborator

Study Sites (4)

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

Location

Beatson West Of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

The Churchill Hospital, Oxford University Hospitals Trust

Oxford, OX3 7LE, United Kingdom

Location

Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• O'Cathail SM, Davis S, Holmes J, Brown R, Fisher K, Seymour L, Adams R, Good J, Sebag-Montefiore D, Maughan T, Hawkins MA. A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR). Radiat Oncol. 2020 Jun 12;15(1):151. doi: 10.1186/s13014-020-01593-5.

  PMID: 32532291 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms; Adenoviridae Infections

Interventions

enadenotucirev; Capecitabine; Radiotherapy

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; DNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics

Results Point of Contact

• Title: CEDAR Trial Manager, Oncology Clinical Trials Office (OCTO)
• Organization: University of Oxford

octo-CEDAR@oncology.ox.ac.uk

01865 617085

Study Officials

• Maria Hawkins, MD FRCR MRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: CEDAR is a dual escalation phase 1 trial using a TiTE CRM (Time To Event Continual Reassessment Method).

Study Record Dates

• First Submitted: April 9, 2019
• First Posted: April 16, 2019
• Study Start: July 29, 2019
• Primary Completion: February 24, 2023
• Study Completion: February 24, 2023
• Last Updated: February 6, 2025
• Results First Posted: February 6, 2025

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4)