locally advanced rectum cancer MedDRA version: 20.0 Level: LLT Classification code 10007464 Term: Carcinoma rectum System Organ Class: 100000004864
Conditions
Interventions
Product Code: E7046
Pharmaceutical Form: Capsule
INN or Proposed INN: Not available
CAS Number: 1369489-71-3
Current Sponsor code: E7046
Sponsors
Adlai Nortye USA Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Diagnosis of histologically confirmed invasive primary rectal carcinoma 2.Age =18 years at the time of informed consent 3.Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 4.Subjects must have locally advanced rectum cancer where primary resection without CRT is unlikely to achieve clear margins as defined by MRI, with no metastatic disease, as assessed by local review. 5.Disease which can be encompassed within a radical radiotherapy treatment volume 6.Subject must consent to repeated biopsy as detailed in Table 5 (Section 9.4.2.1) to allow the acquisition of fresh and/or formalin-fixed paraffin-embedded (FFPE) material. Available archived tumor material may be submitted as the pretreatment biopsy provided that minimum requirements are met by local pathology review as defined in the laboratory manual. If archived tumor material is not available or does not meet minimum requirements then a fresh tumor biopsy must be obtained in accordance with local institutional practice. 7.Adequate renal function defined as serum creatinine =65 years) yes F.1.3.1 Number of subjects for this age range 12
Exclusion criteria
Exclusion criteria: 1.Any contraindications to MRI. 2.Unfit to receive study treatment or subsequent surgical resection. 3.Active hydronephrosis. 4.Unequivocal evidence of metastatic disease defined by CT (includes resectable metastases). 5.Prolongation of corrected QT (QTc) interval to >480 msec when electrolyte balance is normal. 6.Recent occurrence (within 3-6 months) of a major thromboembolic event. 7.Subjects receiving oral warfarin are not eligible for this study. 8.Previous radiotherapy in the pelvic region. 9.Cardiac conditions. 10.Has a known additional malignancy that is progressing and/or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, previous ductal carcinoma in situ (DCIS), or breast cancer diagnosed more than 5 years ago, as long as adequately treated or in situ, or early (up to stage 1B1) cervical cancer, or vulval intraepithelial neoplasia (VIN), or vulval cancer adequately treated without pelvic RT 11.Refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatory bowel disease), or significant bowel resection that may impair adequate absorption and bioavailability of study drug. Major disturbance of bowel function (eg, gross fecal incontinence or requiring > 6 mg loperamide each day). 12.Subjects with prior Hepatitis B or C infection with inadequate liver function (adequate liver function as defined in inclusion Criterion # 9) 13.Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access and defunctioning stoma or any other surgical procedures not considered major by the investigator) which would prevent administration of study treatment. 14.Known dihydropyrimidine dehydrogenase (DPD) deficiency. 15.Subjects with progressive neurological dysfunction that would confound the evaluation of neurological and other toxicities; any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any subject with known active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection. 16.Subjects with interstitial pneumonia or extensive and symptomatic fibrosis of the lungs 17.Subjects with any active autoimmune disease or a documented history of autoimmune disease, poorly controlled asthma or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy. Subjects with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study. 18.Any other major illness that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in this study 19.Has received a live vaccine within 30 days of planned start of study therapy. 20.Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG). A separate baseline
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objectives: •To assess the safety and tolerability of E7046 in combination with preoperative radiotherapy and chemotherapy in the short course and long course radiotherapy settings •To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of E7046 in combination with preoperative radiotherapy and chemotherapy ; Secondary Objective: Secondary objectives: •To evaluate the effect of adding E7046 to standard radiotherapy and chemoradiotherapy on: –The rate of histopathologically confirmed complete response (pCR) –The rate of histopathologically confirmed circumferential margin negative (CRM-ve) resection –MRI-confirmed tumor regression grade (mrTRG) –MRI-confirmed downstaging in T stage –Histopathologically confirmed tumor regression grade (pTRG) –Disease-free survival (DFS) at 2 years –The pharmacokinetics of E7046 and its metabolite ER-888188 ; Primary end point(s): Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of E7046 in combination with preoperative radiotherapy and chemotherapy. Safety/tolerability profile of E7046 in combination with preoperative radiotherapy and chemotherapy. ;Timepoint(s) of evaluation of this end point: The maximum tolerated dose (MTD) is defined as 1 dose level below the dose level where =2 of 6 subjects experience a DLT. If =1/6 subjects in all dose cohorts experience a DLT, then an MTD will not have been reached. In this case, the RP2Dwill be selected based on integrated evaluation of safety, tolerability, clinical benefit, PK, and PD data, for all dose levels tested. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): A pathological complete response (pCR) will be defined as having no viable cancer cells in the resected specimen. The pCR rate will be calculated as the number of patients with a pCR, divided by those who undergo a surgical procedure to resect the primary tumour (even if this is not successful). A circumferential resection margin (CRM) negative resection will be defined as having a complete macroscopic resection with microscopic tumor >1 mm from the radial. The CRM negative rate will be calculated as the total number of CRM negative patients, divided by the total number of patients in the trial. The pathological tumor regression grade (pTRG) will be assessed by Mandard TRG system: The MRI-confirmed tumor regression grade (mrTRG) and MRI-confirmed down staging in T stage will be assessed. Disease-free survival (DFS) will be defined as the time for treatment start to the date of the first documented disease occurrence, or date of death, whichever occurs first. ;Timepoint(s) of evaluation of this end point: After the end of trial database lock. | — |
Countries
France, Poland, United Kingdom, United States
Contacts
Public ContactClinical Research & Operations
Adlai Nortye USA Inc
Outcome results
None listed