Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer

  • STATUS
    Recruiting
  • End date
    Jan 24, 2024
  • participants needed
    30
  • sponsor
    University of Oxford
Updated on 24 January 2021

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.

Description

At present identifying novel radiosensitising agents in colorectal cancer is an area of high need for patients considering sphincter preserving surgery or needing down staging to facilitate surgery.

Although the combination of Enadenotucirev with chemoradiation is novel, there is a wealth of evidence to support the rationale for combining this class of agent with radiation and chemotherapy.

Enadenotucirev is a group B oncolytic virus under development for the systemic treatment of metastatic or advanced epithelial tumours. Enadenotucirev is a chimeric adenovirus type 11p (Adp/adenovirus type 3 (Ad3) virus, discovered through a process of bio-selection from a library of chimeric viruses produced from a pool of adenoviruses from seven different serotypes utilizing human HT-29 colorectal cancer (CRC) cells.

Enadenotucirev shows selective and potent toxicity in humans carcinoma cells with only very limited or no toxicity to normal (non-cancerous) human cells. Other than humans, there is no known permissive species for Enadenotucirev. The principle advantage of oncolytic therapy is that the virus replicates only in diseased cells meaning that the concentration of drug is amplified at the site of pathology so that it is higher in the tumour than in healthy tissue. Virus particles spread from cell to cell within a tumour nodule until they reach non-permissive normal tissues, in principle destroying all viable tumour cells they encounter.

While the overall understanding of the mechanism of action of Enadenotucirev in humans is still under investigation, it is now well established from non-clinical and clinical studies that the mechanism of anti-cancer efficacy of oncolytic viruses not only involves direct infection and lysis of tumour cells, but that immune responses stimulated via an increased release of tumour-associated antigens and immune-inflammatory activation signals play a key role.

CEDAR is dual endpoint, dose escalation phase 1 trial using a time to event continual reassessment method (TiTECRM). Response and Toxicity endpoints will be combined in dose escalation models to identify the optimal dose schedule. Dose decisions are made using the statistical model instead of just using the data from that particular dose, as in the case of 3+3 model, meaning it uses all available data to make a dose decision.

This primary objective is to determine the optimal dose and frequency of the virus by firstly gradually increasing the number of doses each successive patient receives, and then increasing the dose of the virus itself. All participants will receive 3 loading doses in weeks 1-2, prior to initiation of standard chemoradiotherapy. Further doses of Enadenotucirev will either be given after or during and after standard chemoradiotherapy and this is dependent on which of the 6 different dose groups they are assigned to. The dose given will vary between either 1x1012 Viral Particles (VP) or 3x1012vp.

Each patient will receive a minimum of 3 doses, up to a maximum of 8, spread over the course of 9 weeks. 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.

Data on progression free survival and loco-regional failure will be requested from the routine clinical care team at 12 and 24 months.

Details
Condition Locally Advanced Rectal Cancer
Treatment Capecitabine, Radiotherapy, Enadenotucirev
Clinical Study IdentifierNCT03916510
SponsorUniversity of Oxford
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Histologically confirmed invasive adenocarcinoma of the rectum
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
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-<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

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 >38.0C 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
Use of the following anti-viral agents: ribavirin, adefovir, lamivudine or cidofovir within 7 days prior to the first dose of trial treatment
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
History of DVT or pulmonary embolus in the 12 months before the first dose of study of study treatment
History of significant bleeding requiring hospitalisation in the 12 months before the first dose of study treatment
Patients receiving therapeutic or prophylactic anticoagulation therapy
Known dihydropyrimidine dehydrogenase (DPYD) deficiency
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
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
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