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

NCT04621370 | Unknown Phase 2 DMC

• 1 other identifier: PrimeRT-2018
• Study Type: interventional
• Target: 48
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Rectal Cancer; Rectal Adenocarcinoma; Rectal Neoplasms

Keywords

Radiotherapy; Chemotherapy; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Complete response

  Pathological or clinical complete response

  6 months

Secondary Outcomes (15)

• Adverse events

  During neo-adjuvant treatment and for up to at least 90 days after the last dose of Investigatinal Medicinal Product (IMP).

• CD3+ T cell infiltrate

  Week 2, week 6 and end of treatment (Week 15-18)

• Neoadjuvant Rectal (NAR) score

  Immediately after the surgery

• MRI defined tumour regression

  End of Treatment (Week 15-18)

• MRI defined down-staging

  End of Treatment (Week 15-18)

Study Arms (2)

Arm A

ACTIVE COMPARATOR

* 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.

Drug: Durvalumab; Drug: FOLFOX; Radiation: Short Course Radiotherapy (Arm A)

Arm B

ACTIVE COMPARATOR

* 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.

Drug: Durvalumab; Drug: FOLFOX; Radiation: Long course chemoradiation (Arm B); Drug: Capecitabine

Interventions

Durvalumab DRUG

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

Also known as: MEDI 4736

Arm A; Arm B

FOLFOX DRUG

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.

Also known as: mFOLFOX6

Arm A; Arm B

Short Course Radiotherapy (Arm A) RADIATION

25 Gray of photon radiation treatment delivered over 5 fractions.

Arm A

Long course chemoradiation (Arm B) RADIATION

50 Gray of photon radiation treatment delivered over 25 fractions.

Arm B

Capecitabine DRUG

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.

Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be willing and able to provide written informed consent for the trial.
• Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures including willingness to provide repeated biopsy samples of tumour via flexible sigmoidoscopy.
• Age 18 or over on the day of signing informed consent.
• Histologically confirmed non-metastatic, locally advanced rectal adenocarcinoma deemed appropriate for radical treatment.
• Non-metastatic disease confirmed with CT of chest/abdomen and pelvis.
• The rectal tumour must have at least one of the following high risk criteria on MRI scan:
• cT3b+ OR EMVI positive, OR Primary tumour or morphologically malignant lymph node at 2mm or less from the mesorectal fascia or beyond the mesorectal fascia OR Low rectal tumour and the consensus of the multi-disciplinary meeting is that abdomino-perineal excision would be required for sufficient surgical management.
• ECOG performance status 0-1
• No contra-indication to treatment with pelvic radiotherapy.
• Primary disease which can be encompassed within a radical radiotherapy treatment volume.
• Adequate haematological and biochemical function

You may not qualify if:

• Patients with Dihydroppyrimidine Dehydrogenase (DPD) deficiency (any degree).
• Unable to have MRI assessment.
• Patient weight less than or equal to 30kg.
• Previous pelvic radiotherapy
• Metastatic disease defined by CT (includes resectable metastases).
• Previous treatment with immunotherapy.
• Previous treatment with chemotherapy for the treatment of current malignancy or treatment with chemotherapy within the last 5 years for a separate malignancy (unless that malignancy was treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated/biochemically stable, organ confined prostate cancer).
• History of a separate malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated/biochemically stable, organ confined prostate cancer).
• Pregnant or lactating females or males unwilling to use a highly effective method of contraception. Women of childbearing potential, and men with female partners of childbearing potential, must agree to use adequate contraceptive measures (see section 9.1.12) for the duration of the study and for 6 months after the completion of study treatment.
• Major surgery within 28 days prior to trial entry
• Prolongation of corrected QT (QTc) interval to \>470 msec when electrolyte balance is normal.
• If a patient has had a recent occurrence (within 3-6 months) of a major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis, they must be stable on therapeutic anticoagulation. Subjects with a history of clinically non-significant thromboembolic events, not requiring anticoagulation, are allowed on study.
• Active inflammatory bowel disease affecting the colon and rectum based on previous endoscopy and defined as active by ongoing drug treatment.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisolone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial drug.

Sponsors & Collaborators

• Liz-Anne Lewsley: lead
• University of Glasgow: collaborator
• AstraZeneca: collaborator
• NHS Greater Glasgow and Clyde: collaborator

Related Publications (1)

• Hanna CR, O'Cathail SM, Graham JS, Saunders M, Samuel L, Harrison M, Devlin L, Edwards J, Gaya DR, Kelly CA, Lewsley LA, Maka N, Morrison P, Dinnett L, Dillon S, Gourlay J, Platt JJ, Thomson F, Adams RA, Roxburgh CSD. Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT). Radiat Oncol. 2021 Aug 26;16(1):163. doi: 10.1186/s13014-021-01888-1.

  PMID: 34446053 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

durvalumab; Folfox protocol; Capecitabine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Central Study Contacts

Liz-Anne Lewsley

CONTACT

01413017000; Liz-Anne.Lewsley@glasgow.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Project Manager

Study Record Dates

• First Submitted: October 19, 2020
• First Posted: November 9, 2020
• Study Start: December 7, 2020
• Primary Completion: June 30, 2025
• Study Completion: December 31, 2025
• Last Updated: November 9, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share