Phase II study of Durvalumab (MEDI4736) plus Total Neoadjuvant Therapy (TNT) in locally advanced rectal cancer (The DUREC trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol Multidisciplinar En Cancer Digestivo

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-11-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Astra Zeneca

External identifiers

EU CT number

2024-515240-24-00

EudraCT number

2018-004835-56

ClinicalTrials.gov

NCT04293419

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Efficacy, Therapy

1) Pathological complete response (pCR) rate.

Secondary objectives 8

1. 1) Tumor downstaging.
2. 2) Tumor regression grade (TGR).
3. 3) R0 resection rate.
4. 4) Clear circumferential resection margin (CRM) rate.
5. 5) 3-year disease-free survival (DFS).
6. 6) Toxicity profile (short and long-term).
7. 7) Reduction of surgical complications.
8. 8) Calculation of the neoadjuvant rectal (NAR) score

Conditions and MedDRA coding

Locally advanced rectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. - Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
2. - Age ≥ 18 years at time of study entry.
3. - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. - Body weight >30kg.
5. - Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, with the lowest part of the tumour less than 12 cm from the anal verge using a rigid rectoscope or flexible endoscope.
6. - MSS (microsatellite stable) rectal cancer assessed by local practice (immunohistochemistry or PCR).
7. - Mandatory tumour and blood samples for translational research.
8. - High risk MRI-defined rectal cancer
9. - No contraindications to chemotherapy and radiotherapy.
10. - Adequate normal organ and marrow function
11. - Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients
12. - Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion criteria 26

1. - Participation in another clinical study with an investigational product during the last 6 months.
2. - Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
3. - Prior therapy for rectal cancer.
4. - Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn’s disease or active ulcerative Colitis.
5. - MSI (microsatellite inestable) rectal cancers assessed by local practice (immunohistochemistry or PCR).
6. - Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
7. - Known DPD deficiency
8. - Persistent peripheral neural toxicity > grade 2.
9. - Intestinal occlusion. Patients with intestinal occlusion due to the primary rectal tumour, that could participate in the study, may be included after a derivative intestinal surgery.
10. - Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
11. - Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s Correction.
12. - Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
13. - Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
14. - Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
15. - Previous radiotherapy in the pelvic region (e.g. prostate) or previous rectal surgery (e.g.TEM).
16. - History of allogenic organ transplantation.
17. - Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
18. - Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
19. - History of another primary malignancy
20. - History of active primary immunodeficiency.
21. - Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
22. - Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
23. - Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
24. - Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
25. - Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab monotherapy.
26. - Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1) Pathological complete response (pCR) rate.

Secondary endpoints 8

1. 1) Tumor downstaging.
2. 2) Tumor regression grade (TGR).
3. 3) R0 resection rate.
4. 4) Clear circumferential resection margin (CRM) rate.
5. 5) 3-year disease-free survival (DFS).
6. 6) Toxicity profile (short and long-term).
7. 7) Reduction of surgical complications.
8. 8) Calculation of the neoadjuvant rectal (NAR) score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol Multidisciplinar En Cancer Digestivo

Sponsor organisation

Grupo Espanol Multidisciplinar En Cancer Digestivo

Address

Calle Balmes No 243 Escalera A Planta 5 Puerta 1

City

Barcelona

Postcode

08006

Country

Spain

Scientific contact point

Organisation

Grupo Espanol Multidisciplinar En Cancer Digestivo

Contact name

Coordinator investigator

Public contact point

Organisation

Grupo Espanol Multidisciplinar En Cancer Digestivo

Contact name

SECRETARÍA TÉCNICA GEMCAD

Third parties 2

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications