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Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer (CEDAR)

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ClinicalTrials.gov Identifier: NCT03916510
Recruitment Status : Recruiting
First Posted : April 16, 2019
Last Update Posted : March 6, 2020
Sponsor:
Collaborators:
PsiOxus Therapeutics Ltd
Cancer Research UK
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE April 9, 2019
First Posted Date  ICMJE April 16, 2019
Last Update Posted Date March 6, 2020
Actual Study Start Date  ICMJE July 1, 2019
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2019)
  • Dose limiting toxicities [ Time Frame: From Day 1 to Week 13 ]
    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.
  • MRI tumour regression grade [ Time Frame: Week 13 ]
    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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2019)
  • Ability to deliver enadenotucirev concurrently with chemoradiation [ Time Frame: Week 9 ]
    Treatment tolerance measured by proportion of patients completing at least 80% of the intended Capecitabine dose and at least 20 fractions of radiotherapy.
  • MRI tumour regression grade [ Time Frame: Week 13 ]
    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
  • Pathological complete response rate [ Time Frame: 4-6 weeks post surgery ]
    To measure local response rate to combined therapy compared to pre-treatment status
  • Neoadjuvant Rectal (NAR) score [ Time Frame: 4-6 weeks post surgery ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 3, 2020)
  • To identify the 'proof of concept' that enadenotucirev replicates in the tumour. [ Time Frame: Archival, Week 4 biopsy and Resection sample ]
    Patients archival, week 4 biopsy and resection sample will be processed and stained for the presence of a hexon protein coat. 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.
  • Progression free survival [ Time Frame: 12 and 24 month follow up visits (standard of care) ]
    Progression free survival rates measured in patients treated with combined therapy
  • Loco-regional failure [ Time Frame: 12 and 24 month follow up visits (standard of care) ]
    Loco-regional recurrence rates measured in patients treated with combined therapy
  • To analyse changes in circulating tumour DNA in response to chemoradiation and Enadenotucirev [ Time Frame: Baseline (Pre 1st loading dose), week 4, week 13 and 4 to 6 week post surgery visit ]
    ctDNA analysis will explore the clearance of ctDNA and any/or emerging changes in persisting ctDNA
  • To analyse gene expression changes in rectal cancer in response to Enadenotucirev [ Time Frame: Baseline (i.e. Archival), Week 4 biopsy and Resection sample ]
    Patients archival, week 4 biopsy and resection sample will be processed using RNA sequencing to analyse whole genome RNA expression
Original Other Pre-specified Outcome Measures
 (submitted: April 11, 2019)
  • To identify the 'proof of concept' that enadenotucirev replicates in the tumour. [ Time Frame: Baseline, Week 4 biopsy and Resection sample ]
    Patients baseline, week 4 biopsy and resection sample will be processed and stained for the presence of a hexon protein coat. 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.
  • Progression free survival [ Time Frame: 12 and 24 month follow up visits (standard of care) ]
    Progression free survival rates measured in patients treated with combined therapy
  • Loco-regional failure [ Time Frame: 12 and 24 month follow up visits (standard of care) ]
    Loco-regional recurrence rates measured in patients treated with combined therapy
 
Descriptive Information
Brief Title  ICMJE Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer
Official Title  ICMJE 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
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 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.

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:
CEDAR is a dual escalation phase 1 trial using continual reassessment method .
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Locally Advanced Rectal Cancer
Intervention  ICMJE
  • Biological: Enadenotucirev
    Enadenotucirev is a live replicating oncolytic adenovirus; it is considered a BioSafety Level 1 (BSL-1) infectious substance.
  • Drug: Capecitabine
    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.
  • Radiation: Radiotherapy
    50 Gy/25#
Study Arms  ICMJE Experimental: Dosing schedules 1 to 6

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

Dosing Group 4:

- Loading dose pre CRT - 3x10^12vp

Dosing Group 5:

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

Dosing Group 6:

  • 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
Interventions:
  • Biological: Enadenotucirev
  • Drug: Capecitabine
  • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 11, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2024
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Steven Davis +44 (0)1865 617087 octo-cedar@oncology.ox.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03916510
Other Study ID Numbers  ICMJE OCTO_081
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • PsiOxus Therapeutics Ltd
  • Cancer Research UK
Investigators  ICMJE
Principal Investigator: Maria Hawkins, MD FRCR MRCP University of Oxford
PRS Account University of Oxford
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP