Neoplasms

All Conditions

Digestive System Diseases

Adenocarcinoma

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Oxaliplatin

Fluorouracil

Capecitabine

Immunomodulating Agents

Durvalumab

Antimetabolites

Antineoplastic Agents, Immunological

* Durvalumab 1500mg IV over 60 minutes, starting in the week prior to day 1 of radiotherapy, and continuing every 4 weeks until completion of FOLFOX chemotherapy
* Short course radiotherapy (25Gy delivered in 5 fractions) starting on day 1
* FOLFOX chemotherapy will be given every 2 weeks, starting approximately 1-2 weeks after radiotherapy and continuing for 6 cycles in total
* Assessment of response will be at approximately 16-18 weeks after day 1 of RT. If the patient is proceeding to surgery, this will be performed at approximately 18-20 weeks after day 1 of RT where possible.

* Durvalumab 1500mg IV over 60 minutes, starting in the week prior to day 1 of radiotherapy, and continuing every 4 weeks until completion of FOLFOX chemotherapy
* Long course chemoradiotherapy (50Gy to boost volume, 45Gy to elective volume delivered in 25 fractions) starting on day 1
* FOLFOX chemotherapy will be given every 2 weeks, starting approximately 1-2 weeks after radiotherapy for 4 cycles
* Assessment of response at approximately 16-18 weeks after day 1 of RT. If the patient is proceeding to surgery, this will be performed at approximately 18-20 weeks after day 1 of RT where possible.

Flat dose of 1500mg delivered intravenously over 30 minutes every 4 weeks.

Oxaliplatin 85mg/m2 delivered intravenously as per institutional standard on Day 1 of mFOLFOX6 treatment every 2 weeks.

5-fluorouracil bolus 400mg/m2 delivered intravenously as per institutional standard on D1 of mFOLFOX6 treatment every 2 weeks.

5-fluorouracil infusion 2400mg/m2 delivered intravenously over 46 hours continuously as per institutional standard following bolus 5-fluorouracil.

FOLFOX

25 Gray of photon radiation treatment delivered over 5 fractions.

Short Course Radiotherapy (Arm A)

50 Gray of photon radiation treatment delivered over 25 fractions.

Long course chemoradiation (Arm B)

Capecitabine is a non-cytotoxic pre-cursor of cytotoxic 5-fluorouracil and delivered in oral form. It is given concomitantly with long course radiation treatment on days of radiotherapy only. The dose is 825mg/m2 and this is delivered twice daily.

Liz-Anne Lewsley

PRIME-RT is an open label, multi-centre phase II randomised trial with 1:1 allocation between arm A and arm B. The principal research question is whether the addition of durvalumab to FOLFOX chemotherapy and radiation treatment (either SCRT or LCRT) in the neoadjuvant setting for patients with locally advanced rectal cancer (LARC) improves rates of complete response. The working hypothesis is that the use of radiation and cytotoxic chemotherapy may prime the tumour immune microenvironment for treatment with immune checkpoint blockade. The main trial will commence after completion of a safety run-in which will enrol at least three patients per arm to test the safety and tolerability of the treatment combinations in each.

In rectal cancer, strategies to enhance local treatment responses by expanding neoadjuvant regimens are sought to enable organ preservation in more patients. The addition of systemic FOLFOX post long course chemoradiotherapy (LCRT) and post short course radiotherapy (SCRT) has been reported with encouraging results demonstrating higher rates of complete response than with radiotherapy based treatment alone. Immunotherapy using PD-1/ PD-L1 inhibition is recognised to be effective in mismatch repair deficient colorectal cancer (dMMR). Generally, dMMR tumours are characterised by a higher mutational burden, a higher neoantigen load with high density T cell infiltrates and increased expression of PD-1/ PD-L1 in the tumour microenvironment (TME). Mismatch repair proficient (pMMR) colorectal cancer is not thought to be responsive to immunotherapies partly due to the fact they exhibit low levels of tumour infiltrating lymphocytes (TILs) and PD-1/PD-L1 within the TME. Attempts to expand the role of anti-PD-L1 treatment to pMMR CRC is likely to rely on provision of conventional DNA damaging treatments to increase tumour immunogenicity/ T cell infiltration. At baseline few rectal tumours (10-20%) demonstrate moderate-high grade CD3+ responses within the TME, but there is evidence that radiotherapy (e.g. SCRT or LCRT) and systemic chemotherapy (FOLFOX) induce favourable immune responses. In this phase II trial, the investigators plan to evaluate the potential treatment efficacy of anti-PD-L1 systemic anticancer treatment, durvalumab, alongside either SCRT or LCRT with FOLFOX in the gap up to post treatment assessment. This trial will evaluate rates of complete response in each arm as its primary endpoint in addition to safety and toxicity as secondary endpoints. It is a translationally rich trial which involves the collection of biospecimens prior to, during and following treatment in order to understand the molecular and immunological factors underpinning treatment response.

An initial 6 patient safety run-in (3 patients in each arm) will be performed treating patients with metastatic disease with a locally advanced rectal cancer in situ or patients with locally advanced rectal cancer who will never undergo radical surgery due to patient choice, in order to establish safety and lack of significant local toxicity due to the combination (for example colo-proctitis). Depending on the toxicity observed in the first 3 evaluable patients in each of the arm, an additional 3 patients may be add to that arm for the safety run-in cohort. Following an independent safety review and approval by an Independent Data Monitoring Committee (IDMC), the main trial will commence.

Following the safety run-in, 42 patients with non-metastatic, biopsy confirmed rectal adenocarcinoma (cT3b+, N+, EMVI+ based on MRI staging or low rectal tumours requiring abdominoperineal resection) will be recruited to the main trial and randomised to one of two treatment arms. These patients must have adequate physical fitness and no previous pelvic radiotherapy or immunotherapy.

Recruitment to the Safety Run-in period is expected to take 6 months (based on 6 patients in this cohort) with the main trial taking a further 12 months. Recruitment should therefore take place over a total period of 18 months. If the safety run-in requires more than 6 patients, these timelines will be revised. Patients will be followed up for 36 months from date of randomisation.

A Trial of Durvalumab (MEDI 4736) in Combination With Extended Neoadjuvant Regimens in Rectal Cancer

Priming the Tumour MicroEnvironment for Effective Treatment With Immunotherapy in Locally Advanced Rectal Cancer A Phase II Trial of Durvalumab (MEDI 4736) in Combination With Extended Neoadjuvant Regimens in Rectal Cancer

Pathological or clinical complete response

Occurrence of Grade 3-5 treatment-emergent adverse events and treatment-related adverse events.

Presence of a moderate-high grade CD3+ T cell infiltrate on rectal tumour biopsy during treatment.

In patients who do not achieve a clinical complete respose (cCR), the proportion of patients with a Neodjuvant Rectal (NAR) score \<8. The NAR score is a pseudo-continuous scale with 24 possible discrete scores ranging from 0-100. A low score was defined as \<8, intermediate as 8-16 and high as \>16 with corresponding 5 year OS in this patient cohort of 92%, 89% and 68% respectively, showing that higher scores are associated with poorer prognosis.

Proportion of patients achieving MRI-confirmed near or complete tumour regression

Proportion of patients achieving MRI-confirmed down-staging in T stage

Proportion of patients with local regrowth after a cCR.

Proportion of patients who have a permanent colostomy.

Proportion of patients who proceed to surgery (or who have a complete clinical response and go onto the deferred surgery pathway).

Proportion of patients receiving at least 4 fractions of short course RT or 20 fractions of long course RT.

Proportion of patients with Grade 3-5 complications

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social) (higher score = better functioning), global health status (higher score=better functioning), symptom scales (fatigue, pain, nausea/vomiting) (higher score= worse symptoms), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties) (higher scores=worse difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale.

All scales and single-item measurements range from 0 to 100. A higher score for a symptom scale / item indicates a higher symptomatology and problem level.

Quality of life questionnaire that measures quality of life in 5 dimensions on a 3 part scale (1=no problems, 3=extreme problems). Min score: 11111 Max score: 33333

Spots Global Cancer Trial Database for long course chemoradiation (arm b)