Durvalumab (MEDI4736) Plus Total Neoadjuvant Therapy (TNT) in Locally Advanced Rectal Cancer

NCT04293419 | Unknown Phase 2

• 1 other identifier: ESR-17-13082
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 10

Brief Summary

The addition of durvalumab to total neoadjuvant therapy (TNT) in locally advanced rectal cancer may improve the pathological complete response rate. The induction platinum-based chemotherapy may increase the neoantigen formation together with the chemoradiotherapy period. Starting durvalumab during the first chemotherapy session and continuing during the 6-week period of chemoradiotherapy could change and create the needed environment to increase the efficacy of durvalumab in this setting. Additionally, the 8-12 week rest period from the end of the chemoradiotherapy and the radical surgery, treatment with durvalumab may continue improving the response and outcome of patients without jeopardizing the surgery (which needs this period out of chemotherapy and radiotherapy to avoid postoperative complications, but not for anti-PDL-1 therapy). Patients will be included following inclusion/exclusion criteria in a prospective, non-randomized, open label, single arm phase II study to receive 6 cycles of mFOLFOX6 (oxaliplatin, leucovorin and fluorouracil) followed by long course chemoradiotherapy (50.4 Gy together with capecitabine) followed by surgery. Patients will receive durvalumab 1500 mg every 4 weeks during induction chemotherapy, chemoradiotherapy and waiting period until surgery.

Conditions

Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• Pathological complete response (pCR) rate

  Immediately after the surgery

Secondary Outcomes (8)

• Tumor downstaging

  Will be assessed during the 3-year period of follow-up

• Tumor regression grade (TRG)

  Will be assessed during the 3-year period of follow-up

• R0 resection rate

  Immediately after the surgery

• Clear circumferential resection margin (CRM) rate

  Immediately after the surgery

• 3-year disease-free survival (DFS)

  3 years after the surgery

Interventions

Durvalumab (MEDI4736) DRUG

6 cycles of mFOLFOX6 (oxaliplatin, leucovorin and fluorouracil) followed by long course chemoradiotherapy (50.4 Gy together with capecitabine) followed by surgery. Patients will receive durvalumab 1500 mg every 4 weeks during induction chemotherapy, chemoradiotherapy and waiting period until surgery.

Eligibility Criteria

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

You may qualify if:

• \- 1) Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
• \) Age \> 18 years at time of study entry. 3) Must have a life expectancy of at least 12 weeks 4) Eastern Cooperative Oncology Group (ECOG)performance status of 0 or 1. 5) Body weight \>30kg. 6) 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.
• \) Mandatory tumour and blood samples for translational research. 8) High risk MRI-defined rectal cancer: Presence of at least 1 of the following on high resolution, thin-slice MRI (3 mm): Upper-Middle Third Tumours
• mrT3
• Extramural vascular invasion (EMVI) positive
• Extramural extension \> 5 mms into perirectal fat
• Mesorectal fascia (MRF) threatened or involved (tumour or lymph node \< 1mm from MRF) -mrT4 Distal Third Tumours (≤5 cm from anal verge) - mrT3 tumour at or below levators - T4 as above N2(≥4 lymph nodes at mesorectum radiologically suggestive of metastatic lymph nodes) 9) No contraindications to chemotherapy and radiotherapy 10) Adequate normal organ and marrow function as defined below:
• \- Haemoglobin ≥9.0 g/dL.
• \- Absolute neutrophil count (ANC) \>1500 per mm3.
• \- Platelet count ≥100,000 per mm3.
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal.
• Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
• Males:
• Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

You may not qualify if:

• \) Participation in another clinical study with an investigational product during the last 6 months.
• \) 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.
• \) 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.
• \) 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.
• \) Known DPD deficiency. 7) Persistent peripheral neural toxicity \> grade 2. 8) 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.
• \) Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab. 10) Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction.
• \) 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. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
• Steroids as premedication for hypersensitivity reactions (e.g.,CT scan premedication).
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
• \) 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.
• \) Previous radiotherapy in the pelvic region (e.g. prostate) or previous rectal surgery (e.g.TEM).
• \) History of allogenic organ transplantation. 16) 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 \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:

Sponsors & Collaborators

• Grupo Espanol Multidisciplinario del Cancer Digestivo: lead
• AstraZeneca: collaborator
• Vall d'Hebron Institute of Oncology (VHIO): collaborator

Study Sites (10)

Parc Taulí

Sabadell, Barcelona, Spain

RECRUITING

H. Moises Broggi

Sant Joan Despí, Barcelona, 08970, Spain

NOT YET RECRUITING

H. Navarra

Pamplona, Navarre, Spain

NOT YET RECRUITING

Complejo Hospitalario Universitario A Coruña (CHUAC)

A Coruña, 15006, Spain

NOT YET RECRUITING

Hospital Vall d'Hebron

Barcelona, 08035, Spain

RECRUITING

H. Clínic Barcelona

Barcelona, 08036, Spain

RECRUITING

H. de Elche

Elche, Spain

NOT YET RECRUITING

H. 12 de Octubre

Madrid, 28041, Spain

NOT YET RECRUITING

Instituto Valenciano de Oncología (IVO)

Valencia, 46009, Spain

NOT YET RECRUITING

H. Miguel Servet Zaragoza

Zaragoza, 50009, Spain

NOT YET RECRUITING

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

durvalumab

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

Central Study Contacts

Susana Muñoz

CONTACT

+34 625925779; smunoz@vhio.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be included following inclusion/exclusion criteria in a prospective, non-randomized, open label, single arm phase II study to receive 6 cycles of mFOLFOX6 (oxaliplatin, leucovorin and fluorouracil) followed by long course chemoradiotherapy (50.4 Gy together with capecitabine) followed by surgery. Patients will receive durvalumab 1500 mg every 4 weeks during induction chemotherapy, chemoradiotherapy and waiting period until surgery.

Study Record Dates

• First Submitted: February 13, 2020
• First Posted: March 3, 2020
• Study Start: December 18, 2019
• Primary Completion: December 18, 2024
• Study Completion: March 1, 2025
• Last Updated: June 21, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

ES (10)