E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced rectal cancer |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038046 |
E.1.2 | Term | Rectal cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038050 |
E.1.2 | Term | Rectal cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to estimate the effect of radiochemotherapy followed by consolidation chemotherapy in locally advanced rectal cancer. As primary endpoint, the rate of patients with a clinical complete response (cCR) will be determined. This rate will then be the basis for patient number calculations in a consecutive trial with 3-year loco-regional control as endpoint. |
|
E.2.2 | Secondary objectives of the trial |
• Local regrowth rate • Safety of the treatment (toxicity assessment according to NCI CTCAE Version 4.0) • Fecal incontinence according to Wexner-Vaizey Score • Quality of life according to EORTC QOL-C30 and QOL-CR29 • Frequency of Low anterior resection syndrome (LARS-scale) • Surgical morbidity and complications in patients undergoing surgery • Pathological staging, tumor downstaging (assessed by ypTNM findings in relation to initial cTNM staging), tumor regression grading according to Dworak in patients undergoing surgery • R0 resection rate, rate of circumferential resection margin negativity (> 1mm) in patients undergoing surgery • Rate of sphincter-sparing surgery in patients undergoing surgery • Relapse-free survival (local / distant / overall) • Overall survival • Translational biomarker studies; cf. appendix for details
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• • Male and female patients with histologically confirmed diagnosis of rectal cancer localized 0 – 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum) • Any MRI staged cT3 tumor or any cT1 cN+ or cT2 cN+ with nodal staging according to “SOP MRI” • Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure. • Cross-sectional imaging of the abdomen and chest to exclude distant metastases. • Aged at least 18 years. No upper age limit. • WHO/ECOG Performance Status ≤ 1 • Adequate hematological, hepatic, renal and metabolic function parameters: o Leukocytes ≥ 3.000/mm^3 o ANC ≥ 2.000/mm^3 o Platelets ≥ 100.000/mm^3 o Hb > 9 g/dl o Serum creatinine ≤ 1.5 x upper limit of normal o Creatinin-Clearance ≥ 30 ml / min o Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal o Informed consent of the patient • Informed consent of the patient
|
|
E.4 | Principal exclusion criteria |
• • Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy • cT4 tumors • Positive lateral pelvic lymph nodes (s. SOP MRI) • Distant metastases (to be excluded by CT scan of the thorax and abdomen) • Preexisting fecal incontince for solid stool • Preexisting peripheral sensory neuropathy with functional impairment • Preexisting myelosuppression refleted by a neutrophil count < 2.000/mm^3 and/or platelets < 100.000/mm^3 • Severe impairment of kidney function with a Creatinin Clearance < 30 ml/min) • Prior antineoplastic therapy for rectal cancer • Prior radiotherapy of the pelvic region • Major surgery within the last 4 weeks prior to inclusion • Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment. • Subject (male or female) is not willing to use highly effective methods of contraception according to the “Clinical trial fertility group” recommendations (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) during treatment and for 6 months (male or female) after the end of treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasoing system, bilateral tubal occlusion, vasectomized partner1, sexual abstinence2). • On-treatment participation in an interventional clinical study in the period 30 days prior to inclusion • Previous or current drug abuse • Other concomitant antineoplastic therapy • Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder, severe liver function disorders • WHO/ECOG Performance Status > 1 • Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment. • Chronic diarrhea (> grade 1 according NCI CTCAE) • Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free • Known allergic reactions on study medication • Known dihydropyrimidine dehydrogenase deficiency • Medication inhibitors of the dihydropyrimidine dehydrogenase, such as Brivudin, Sorivudin and its analogues. • Pernicious anemia or other anemias caused by Vitamin B-12 deficiency. • Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial). • Additionally for hyperthermia cardiac pacemakers and metal implants in the proximity of the pelvis constitute a criterion for exclusion. 1 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success 2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
As primary endpoint, the rate of patients with a clinical complete response (cCR) will be determined |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Local regrowth rate • Safety of the treatment (toxicity assessment according to NCI CTCAE Version 4.0) • Fecal incontinence according to Wexner-Vaizey Score • Quality of life according to EORTC QOL-C30 and QOL-CR29 • Frequency of Low anterior resection syndrome (LARS-scale) • Surgical morbidity and complications in patients undergoing surgery • Pathological staging, tumor downstaging (assessed by ypTNM findings in relation to initial cTNM staging), tumor regression grading according to Dworak in patients undergoing surgery • R0 resection rate, rate of circumferential resection margin negativity (> 1mm) in patients undergoing surgery • Rate of sphincter-sparing surgery in patients undergoing surgery • Relapse-free survival (local / distant / overall) • Overall survival • Translational biomarker studies; cf. appendix for details
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |