Infections

All Conditions

Neoplasms

Digestive System Diseases

Virus Diseases

Adenoviridae Infections

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Fluorouracil

Antimetabolites

Dosing Group 1:

- Loading dose pre chemoradiation (CRT) - 1x10\^12 viral particles (vp)

Dosing Group 2:

* Loading dose pre CRT - 1x10\^12 vp
* Maintenance dose post CRT - 1x10\^12vp

Dosing Group 3:

* Loading doses pre CRT - 3x10\^12vp
* Maintenance dose post CRT - 3x10\^12vp

Dosing Group 4:

* Loading dose pre CRT - 3x10\^12vp
* Concurrent doses on Week 1, Day 1 and Day 5 of CRT - 3x10\^12vp
* Maintenance post CRT - 3x10\^12vp

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

Enadenotucirev

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.

Radiotherapy

Maria Hawkins, MD FRCR MRCP

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 6, 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.

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 4 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 6, 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.

CEDAR is a dual escalation phase 1 trial using continual reassessment method .

Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer

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

Patients archival, week 4 biopsy and resection sample will be processed and stained for the presence of a hexon protein coat, viral gDNA. This will identify the virus and allow confirmatory analysis (yes/no) to be completed to determine if the virus is only present within the tumour cells or not.

ctDNA analysis will explore the clearance of ctDNA and any/or emerging changes in persisting ctDNA

Patients archival, week 4 biopsy and resection sample will be processed using RNA sequencing to analyse whole genome RNA expression and nanostring gene expression

Extraction of DNA and 16S sequencing and meta-transcriptomics from faecal samples

Multiplex Immunohistochemistry of immune cell markers

Used to determine the optimal dose and frequency of enadenotucirev that can be administered with chemoradiation. Highest treatment schedule resulting in less than 30% dose limiting toxicity rate.

Used to determine 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 will be classified as responders and scores of 3, 4 or 5 will be classified as non-responders:

1. - No/minimal fibrosis visible (tiny linear scar) and no tumour signal
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

Treatment tolerance measured by proportion of patients completing at least 80% of the intended Capecitabine dose and at least 20 fractions of radiotherapy.

To measure local response rate to combined therapy compared to pre-treatment status

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 will be classified as responders and scores of 3, 4 or 5 will be classified as non-responders:

1. - No/minimal fibrosis visible (tiny linear scar) and no tumour signal
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

To measure local response rate to combined therapy compared to pre-treatment status

To measure local response rate to combined therapy compared to pre-treatment status

The Neoadjuvant Rectal (NAR) score ranges from 0-100 where a higher score equates to a worse prognosis.

Akamis Bio

Cancer Research UK

University of Oxford

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Urinary Bladder Neoplasms

Colonic Diseases

Acute Graft Versus Host Disease

This is a multicentre, open-label, Phase I/II study of enadenotucirev in patients with either solid tumour of epithelial origin not responding to standard therapy or for whom no standard treatment exists (Phase I dose escalation stage Single cycle), mCRC not responding to standard therapy (Phase I dose escalation Repeat cycle cohort expansion stage ), mCRC not responding to standard therapy or advanced or metastatic bladder cancer not candidate for chemotherapy (Phase Ib) or mCRC in stable disease or partial response after 3-4 months of first line standard of care chemotherapy (Phase II).

Phase I / II Study of Enadenotucirev by Sub-acute Fractionated IV Dosing in Cancer Patients

A Clinical Study Of Enadenotucirev Administered by Sub-Acute Fractionated Intravenous Injection: Dose Escalation in Metastatic Epithelial Solid Tumours and Randomised Controlled Trial in Metastatic Colorectal Cancer

- Maximum tolerated dose (MTD) / maximum feasible dose (MFD) of enadenotucirev when administered by sub-acute fractionated IV injection (phase I Dose Escalation) and recommended dose for phase II.

Open label assessment of 2 repeat cycle schedules, with expansion cohort at the MTD or MFD with best repeat cycle schedule in advanced/metastatic UBC patients.

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Head and Neck Neoplasms

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

enadenotucirev

nivolumab

Tom Lillie, MD

This is a Phase I multicenter, open label, nonrandomized study of enadenotucirev administered in combination with nivolumab in subjects with metastatic or advanced epithelial tumors (with focus on CRC, SCCHN, escalation phase), not responding to standard therapy.

To characterise the safety and tolerability of enadenotucirev administered in combination with nivolumab in subjects with metastatic or advanced epithelial tumours.

A dose escalation phase is conducted in subjects with solid tumors of epithelial origin not responding to standard therapy to establish the MTD/MFD and optimum dosing schedule of the enadenotucirev and nivolumab combination treatment.

A dose expansion phase will further outline the dose level and schedule of enadenotucirev and nivolumab combination treatment and investigate signals of efficacy in three cohorts of subjects with specific epithelial tumour types.

Phase I Study of Enadenotucirev and PD-1 Inhibitor in Subjects With Metastatic or Advanced Epithelial Tumors

A Phase I Multicenter, Open Label Study of Enadenotucirev Combined With PD-1 Inhibitor in Subjects With Metastatic or Advanced Epithelial Tumors

Review of adverse events including serious adverse events (SAEs), adverse events meeting protocol defined DLT criteria, adverse events leading to study treatment or study discontinuation, and adverse events resulting in death

Maximum tolerated dose (MTD) / maximum feasible dose (MFD) of enadenotucirev administered IV in combination with nivolumab.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer	NCT03916510	Locally Advance...	Enadenotucirev Capecitabine Radiotherapy	18 Years -	University of Oxford
Phase I / II Study of Enadenotucirev by Sub-acute Fractionated IV Dosing in Cancer Patients	NCT02028442	Solid Tumours o... Metastatic Colo... Metastatic Blad...	Enadenotucirev	18 Years -	Akamis Bio
Phase I / II Study of Enadenotucirev by Sub-acute Fractionated IV Dosing in Cancer Patients	NCT02028442	Solid Tumours o... Metastatic Colo... Metastatic Blad...	Enadenotucirev	18 Years -	Akamis Bio
Phase I Study of Enadenotucirev and PD-1 Inhibitor in Subjects With Metastatic or Advanced Epithelial Tumors	NCT02636036	Colorectal Canc... Squamous Cell C... Epithelial Tumo...	enadenotucirev nivolumab	18 Years -	Akamis Bio
Phase I Study of Enadenotucirev and PD-1 Inhibitor in Subjects With Metastatic or Advanced Epithelial Tumors	NCT02636036	Colorectal Canc... Squamous Cell C... Epithelial Tumo...	enadenotucirev nivolumab	18 Years -	Akamis Bio

Spots Global Cancer Trial Database for enadenotucirev