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

Phase 1

• Conditions: ocally advanced rectal cancer; MedDRA version: 20.0Level: PTClassification code 10038038Term: Rectal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-004835-56-ES
• Lead Sponsor: Grupo español mutidisciplinar en cáncer digestivo (GEMCAD)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-06-11
• Last Update Posted: 10 December 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

-Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
-Age = 18 years at time of study entry.
-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
-Body weight >30kg.
-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.
-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
a) Extramural vascular invasion (EMVI) positive
b) Extramural extension > 5 mms into perirectal fat
c) Mesorectal fascia (MRF) threatened or involved*
-mrT4
Distal Third Tumours (=5 cm from anal verge)
- mrT3 tumour at or below levatorani muscle
- T4 as above
N2**
* tumour or lymph node < 1mm from MRF.
** =4 lymph nodes at mesorectum radiologically suggestive of metastatic lymph nodes.
-No contraindications to chemotherapy and radiotherapy.
-Adequate normal organ and marrow function as defined below:
a)Haemoglobin =9.0 g/dL.
b)Absolute neutrophil count (ANC) > 1500 per mm3.
c)Platelet count =100,000 per mm3.
d)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.
e)AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal.
f)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)
Females:
Creatinine CL (mL/min)=Weight (kg) x (140 – Age) x 0.85
72 x serum creatinine (mg/dL)
-Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
oWomen <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
oWomen =50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
-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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects fo

Exclusion Criteria

-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.
-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.
-Persistent peripheral neural toxicity > grade 2.
-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.
-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.
-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
-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.
-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]).
-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.
-History of another primary malignancy. -History of active primary immunodeficiency.
-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 hepatiti

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Pathological complete response (pCR) rate.;Secondary Objective: 1)Tumor downstaging.<br>2)Tumor regression grade (TGR).<br>3)R0 resection rate.<br>4)Clear circumferential resection margin (CRM) rate. <br>5)3-year disease-free survival (DFS).<br>6)Toxicity profile (short and long-term).<br>7)Reduction of surgical complications.<br>8)Calculation of the neoadjuvant rectal (NAR) score;Primary end point(s): Pathological complete response (pCR) rate.;Timepoint(s) of evaluation of this end point: After the surgery

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Tumor downstaging.<br>2)Tumor regression grade (TGR).<br>3)R0 resection rate.<br>4)Clear circumferential resection margin (CRM) rate. <br>5)3-year disease-free survival (DFS).<br>6)Toxicity profile (short and long-term).<br>7)Reduction of surgical complications.<br>8)Calculation of the neoadjuvant rectal (NAR) score;Timepoint(s) of evaluation of this end point: Secondary endpoints will be assessed during the 3-year period of follow-up