Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer

• Status: Recruiting
• Trial end date: 2024-01-01
• Target enrollment: 0
• Participant gender: All

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 24 months to determine the long term effects of this treatment.

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Oxford
• Collaborators: Cancer Research UK; PsiOxus Therapeutics Ltd
• Treatments: Capecitabine

Criteria

Inclusion Criteria:

1. Histologically confirmed invasive adenocarcinoma of the rectum

2. Locally advance colorectal cancer as defined by pelvic MRI with a threatened circumferential resection margin (cT3mrf+ve), or inclusion of an adjacent organ, or low tumours at/below the level of the levators or enlarged pelvic side wall nodes or selected by the multidisciplinary team MDT for treatment with neoadjuvant (chemo)radiotherapy, regardless of TNM classification

3. Patients with oligometastatic disease suitable for radical treatment are permitted provided that the site specific MDT deems them suitable for chemoradiation

4. Male or female, Age ≥ 18 years

5. ECOG performance score of 0 - 1

6. The patient is willing and able to comply with the protocol scheduled biopsy, follow-up visits and examinations for the duration of the trial.

7. Written (signed and dated) informed consent

8. 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-<70 mg/mmol with a 24 hour urinary protein <0.2 g/24 hours and

• Serum complement C3 and C4 within the normal range

9. 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

• Bilirubin: < 1.5 upper limit of normal

• Aspartate transaminase and/or alanine transaminase: ≤3 x upper limit of normal

• INR: ≤1.5

• aPTT: within laboratory normal range

Exclusion Criteria:

1. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used.

2. Pulmonary lymphangitis (if metastatic disease present)

3. Past medical history:

1. 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)

2. Splenectomy

3. Prior allogeneic or autologous bone marrow or organ transplantation

4. 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.

5. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or evidence of active pneumonia or pneumonitis on computed tomography scan

6. Active viral disease or known positive serology for HIV, hepatitis B or hepatitis C

7. Active infections requiring antibiotics, physician monitoring, or recurrent fevers >38.0°C associated with a clinical diagnosis of active infection

8. Prior pelvic radiotherapy

9. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions

10. Uncontrolled cardiorespiratory comorbidity (e.g. severe pulmonary fibrosis, inadequately controlled angina or myocardial infarction in the last 6 months)

11. 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

4. Use of the following anti-viral agents: ribavirin, adefovir, lamivudine or cidofovir within 7 days prior to the first dose of trial treatment

5. Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment. In follow up for an interventional trials and observational studies are allowed

6. History of DVT or pulmonary embolus in the 12 months before the first dose of study of study treatment

7. History of significant bleeding requiring hospitalisation in the 12 months before the first dose of study treatment

8. Patients receiving therapeutic or prophylactic anticoagulation therapy

9. Known dihydropyrimidine dehydrogenase (DPYD) deficiency

10. Prior chemotherapy is allowed as long as >28 days since the last administration and any toxicity has resolved to NCI CTCAE grade 1 or less

11. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trials results