Background
Rationale for the trial
Enadenotucirev
Aims of the trial
Design/methods
Objectives
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Dose limiting toxicity
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MRI tumour regression grade
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Ability to deliver enadenotucirev concurrently with chemoradiation
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Assessment of treatment tolerance as measured by the proportion of patients completing at least 80% of the intended Capecitabine dose and at least 20 fractions of radiotherapy by the end of week 9
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To measure local response rate to combined therapy compared to pre-treatment status
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Pathological complete response rate
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Neoadjuvant rectal (NAR) score [35]
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To identify ‘proof of concept’ that enadenotucirev replicates in the tumour during chemoradiotherapy
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IHC staining of hexon protein coat in tumour cells from ‘on-treat’ biopsy performed on week 2 of radiotherapy
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Study population
Inclusion criteria
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Histologically confirmed invasive adenocarcinoma of the rectum.
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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
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Patients with oligometastatic disease suitable for radical treatment are permitted provided that the site specific MDT deems them suitable for chemoradiation
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Male or female, Age ≥ 18 years.
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ECOG performance score of 0–1
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The patient is willing and able to comply with the protocol scheduled biopsy, follow-up visits and examinations for the duration of the trial.
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Written (signed and dated) informed consent.
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Adequate renal function demonstrated by:
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Creatinine ≤1.5 mg/dL and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (or measured creatinine clearance ≥60 mL/min)
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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:
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≤3 mg/mmol or
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> 3 mg- < 70 mg/mmol with a 24 h urinary protein < 0.2 g/24 h and
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Serum complement components C3 and C4 within the normal range
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Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used.
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Past medical history:
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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)
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Splenectomy
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Prior allogeneic or autologous bone marrow or organ transplantation
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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
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History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or evidence of active pneumonia or pneumonitis on computed tomography scan
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Active viral disease or known positive serology for HIV, hepatitis B or hepatitis C
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Active infections requiring antibiotics, physician monitoring, or recurrent fevers > 38.0 °C associated with a clinical diagnosis of active infection
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Prior pelvic radiotherapy
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Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions.
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Uncontrolled cardiorespiratory comorbidity (e.g. inadequately controlled angina or myocardial infarction in the last 6 months)
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Major disturbance in bowel function (e.g. severe incontinence, Crohn’s disease, > 6 loperamide/day)
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Use of the following antiviral agents: ribavirin, adefovir, lamivudine or cidofovir within 7 days prior to the first dose of trial treatment; or pegylated interferon in the 14 days before the first dose of trial treatment
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Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment. Observational studies are allowed
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Warfarin that cannot be discontinued at least 7 days prior to starting treatment
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Known dihydropyrimidine dehydrogenase (DPYD) deficiency
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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
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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 trial results.
Statistical design
Approvals
Interventions
Chemoradiotherapy
Enadenotucirev
Dose schedule | Loading (Pre CRT) (3 doses given on 3 non-consecutive days over a 7 day period) | Concurrent | Maintenance (post CRT)(3 doses given on 3 non-consecutive days over a 7 day period) | |
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Week 1 Day 1 CRT (week 3 day 1) | Week 1 Day 5 CRT (week 3 day 5) | |||
1 (start level) | 1 × 1012vp | |||
2 | 1 × 1012vp | 1 × 1012vp | ||
3 | 1 × 1012vp | 1 × 1012vp | 1 × 1012vp | 1 × 1012vp |
4 | 3 × 1012vp | |||
5 | 3 × 1012vp | 3 × 1012vp | ||
6 | 3 × 1012vp | 3 × 1012vp | 3 × 1012vp | 3 × 1012vp |