Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer

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 (TiTE CRM). 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 which uses number of Dose Limiting Toxicities (DLT) experienced in different dosing schedules, 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 4 different dose groups they are assigned to. The individual doses given will be either 1x10^12 viral particles (vp) or 3x10^12 vp.

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 4-6 weeks after surgery.

Dose Limiting Toxicities (DLTs)

DLTs are defined as any of the following occurring between the start of trial treatment until the Week 13 visit and assessed as possibly, probably or definitely related to enadenotucirev or the interaction between enadenotucirev and radiotherapy and/or capecitabine.

Renal:

• Development of proteinuria, 2+ as measured by urinalysis and confirmed with an albumin/creatinine ratio of >3g/mmol with a 24-hour urinary protein ≥1g/24h or if there is a decline in estimated glomerular filtration rate (eGFR) (where a decline in eGFR is defined as eGFR <60ml/min/1.73m2 or a drop in eGFR by 20% from screening, baseline of previous visit), following administration of enadenotucirev, shall be classified as a DLT. No further doses of enadenotucirev will be administered to that patient.

Acute hematologic toxicity:

• Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (absolute neutrophil count (ANC) <1.0 x 10^9/L)
• Neutropenia grade 4 (ANC < 0.5 x 10^9/L) lasting for ≥7 days
• Febrile neutropenia grade 4 (fever of unknown origin without clinically or microbiologically documented infection) (ANC <1000/mm3 with a single temperature of >38.3 degrees Celsius or a sustained temperature of >=38 degrees Celsius for more than one hour)
• Thrombocytopenia grade 3 (Platelet count < 50 x 10^9/L) in the presence of bleeding or requiring platelet transfusion
• Thrombocytopenia grade ≥ 4 (Platelet count < 25 x 10^9/L)
• Anemia grade 3 in the presence of blood transfusion dependency as judged by the Principal Investigator
• Anemia grade ≥ 4
• Clinically significant bleeding attributed to grade 3 thrombocytopenia or requiring platelet transfusion or other grade ≥3 clotting disorder or occurring concurrently with Grade 2 or 3 activated partial thromboplastin time (aPTT) prolongation, unless there is a clear explanation for the event, such as tumour-related bleeding in the presence of Lupus Anticoagulant.
• Any other grade ≥3 non-hematological toxicity with the exception of: aPTT prolongation
• Clotting event (i.e. deep vein thrombosis, pulmonary embolism) occurring concurrently with Grade 2 or 3 aPTT prolongation

Acute non-hematologic toxicity:

• Any documented ≥ grade 4 non-hematologic toxicity in the presence of maximal support/active management
• Grade ≥3 cystitis or radiation dermatitis onset within 2 weeks of starting radiotherapy or lasting more than 2 weeks after the end of radiotherapy
• Grade ≥3 proctitis or diarrhea onset within 2 weeks of starting radiotherapy
• Grade ≥3 nausea or vomiting not controlled by optimal outpatient anti-emetic treatment
• Grade ≥3 diarrhea despite optimal outpatient anti-diarrheal medication use
• Grade ≥3 hematuria or neuropathic pain
• Other grade 3 ≥ effects thought to be due to the combination of enadenotucirev with radiotherapy
• Missing 2 consecutive doses of enadenotucirev due to enadenotucirev toxicity
• An elevation of alanine transaminase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of normal lasting 8 days or more
• A concurrent elevation of ALT or AST >3 × upper limit of normal and total bilirubin >2 × upper limit of normal in whom there is no evidence of biliary obstruction or other causes that can reasonably explain the concurrent elevation
• Death due to drug related complications
• Grade ≥3 cytokine release syndrome

General:

• Discontinuation of the active treatment due to toxicity definitely attributable to enadenotucirev, irrespective of the grade of toxicity
• Missing 3 consecutive fractions of radiotherapy, related to enadenotucirev, as judged by the Principal Investigator
• Any toxicity causing a delay of radiotherapy completion by greater than one week