| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with peritoneal carcinomatosis from colorectal cancer are treated with a combination chemotherapy (FOLFOXIRI+ Bevacizumab) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with peritoneal carcinomatosis from colorectal cancer are treated with a combination chemotherapy (FOLFOXIRI+ Bevacizumab) |
| Dick- und Mastdarmkrebspatienten mit Peritonealmetastasen welche eine Kombinationstherapie (FOLFOXIRI+ Bevacizumab) erhalten |
|
| 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 | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| 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 | LLT |
| E.1.2 | Classification code | 10034672 |
| E.1.2 | Term | Peritoneal metastases |
| E.1.2 | System Organ Class | 100000016861 |
|
| 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 prospectively assess the histopathological response to neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab in peritoneal tumor deposits of 30 patients with pcCRC by determining the % of viable tumor cells (vtc) in the resected specimen after neoadjuvant chemotherapy using standard pathology. In case of multiple specimens, the median % of viable cells will be calculated and used for analysis. The timepoint of the assessment of the primary objective will be during re-exploratory surgery/surgical cytoreduction between days 78 and 106 of the treatment phase of the study. We hypothesize that there will be >30% responders after neoadjuvant FOLFOXIRI + bevacizumab treatment.
Responders will be defined as patients with pCR (0% vtc) and major response (1-49% vtc) after FOLFOXIRI + bevacizumab chemotherapy.
Non-responders will be defined as patients with minor/no response (≥50% vtc) after FOLFOXIRI + bevacizumab chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
•%of viable tumor cells in peritoneal tumor deposits(ptd)before vs after neoadjuvant chemotherapy(NAC)
•Peritoneal Cancer Index before/after FOLFOXIRI+bevacizumab(BV)treatment
•resectability at initial surgical exploration vs surgical re-exploration after FOLFOXIRI+BV treatment
•(FDG-PET) CT/MRI at baseline(BL)vs after NAC and before surgical re-exploration
•Immuno-infiltrate(II)of ptd before vs after chemotherapy,II of primary tumors vs II in ptd at BL
•PD-1/PD-L1 expression on immune/tumor cells within the microenvironment of ptd before/after FOLFOXIRI+BV treatment,comparison of PD-1/PD-L1 expression in primary tumors and ptd at BL
•cancer stem cell distribution within ptd and association with hypoxia before/after neoadjuvant anti-angiogenic therapy
•measurements of response parameters(i.a.methylated septin-9 at BL)during FOLFOXIRI+BV treatment,before/during/after surgical re-exploration
•Quality of life
•toxicity/safety
•Survival: progression-free/recurrence-free/overall |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
For molecular biological analyses (Secondary Objectives) tissues of 20 patients without peritoneal carcinosis (pT>=2) will be included. They will be selected from all consecutive included patients from which we will get untreated tumor tissues from the pathology and which will not present with synchronous peritoneal carcinosis or metacronous peritoneal carcinosis up to the time of the analysis (best two years).
Objective:
To compare all secondary objectives with tissues (if available) and data from colorectal cancer patients without peritoneal deposits |
|
| E.3 | Principal inclusion criteria |
General inclusion criteria:
1. Histologically confirmed carcinoma of the colon or rectum with synchronous or metachronous peritoneal metastasis.
2. Male and female patients, aged ≥ 18 years.
3. ECOG performance score of ≤ 2.
4. Life expectancy ≥ 26 weeks.
5. Neutrophils (absolute count) ≥ 1.5 g/l.
6. Platelet count ≥ 100 g/l.
7. Hemoglobin > 9 g/dL.
8. Total bilirubin ≤ 1.8 mg/dl.
9. AST and ALT ≤ 88 U/l (≤ 175 U/l if liver metastases present).
10. Alkaline phosphatase ≤ 325 U/l (≤ 650 U/l if liver metastases present).
11. Calculated creatinine clearance > 50 mL/min OR serum creatinine ≤ 1.5 mg/dl.
12. Proteinuria < 2+ by dipstick or urine protein <1 g by 24-hr urine collection.
13. Not pregnant or nursing.
14. Negative pregnancy test (for females of childbearing potential)
15. Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment.
16. Written informed consent.
Resectability:
17. General condition considered feasible for major abdominal surgery after systemic chemotherapy.
18. ≤3 liver metastases amenable to curative resection using a minor liver resection.
Inclusion criteria for control group:
- Histologically confirmed carcinoma of the colon or rectum without synchronous or metachronous (up to two years) peritoneal metastasis.
- Male and female patients, aged ≥ 18 years
- pT stage 2 or 3 (or 4)
|
|
| E.4 | Principal exclusion criteria |
General exclusion criteria:
1. Major surgical procedure or significant traumatic injury within 28 days prior to study enrolment (surgical exploration with diagnostic biopsy/sampling of peritoneal tumor deposits but without bowel resection or comparable surgical procedure is allowed).
2. History of previous cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy.
3. Pregnancy or lactation.
4. Inability or unwillingness to comply with the protocol.
Resectability:
5. Evidence of current extraabdominal metastatic disease. Prior extraabdominal metastatic disease is allowed, provided that it has been curatively resected ≥6 months before study entry and that current staging shows no evidence of disease recurrence.
6. >3 liver metastases or any liver metastases not amenable to upfront curative resection using a minor liver resection.
Prior treatment:
7. Prior systemic chemotherapy completed ≤3 months before study inclusion.
8. Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study.
Other disease or conditions:
9. History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) unless adequately treated with standard medical therapy (e.g. uncontrolled seizures)
10. Untreated brain metastases, spinal cord compression or primary brain tumors.
11. Past or current history (within the last 2 years prior to treatment start) of other malignancies except colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
12. Clinically significant cardiovascular disease, for example CVA, myocardial infarction (£ 12 months before treatment start), unstable angina, New York Heart Association (NYHA) > Class II congestive heart failure (CHF), arrhythmia requiring medication, or uncontrolled hypertension.
13. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
14. Any previous venous thromboembolism > NCI CTCAE Grade 3.
15. Prior history of hypertensive crisis or hypertensive encephalopathy.
16. Evidence of bleeding diathesis or significant coagulopathy.
17. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.
18. Known hypersensitivity to any of the study drugs.
19. Serious, non-healing wound, ulcer or bone fracture.
20. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that puts the patient at high risk for treatment-related complications.
21. Symptomatic peripheral neuropathy ≥ grade 1 according to the NCI Common Toxicity Criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Histopathological response to chemotherapy with FOLFOXIRI + bevacizumab as determined by 0-49% or ≥50% of viable tumor cells within the resected peritoneal tumor specimens will be tested against the reference value of 30% responders by a one-sided significance level of 10%.
Null and alternative hypotheses:
H0: ≤30% responders
H1: >30% responders
Sample size calculation
It is desirable to achieve a response rate (patients with a pCR or major response as defined above) of at least 30%. Then a test of the null hypothesis of ≤30% responders versus the alternative hypothesis of >30% responder will have 80% power to detect a response probability of 49% with a one-sided significance level of 10% if 30 evaluable patients are included in the study. Estimation of sample size was calculated by East (Version 6). Correspondingly, a one-sided test would become significant at the one-sided 10 % significance level if 13 or more responses out of 30 patients are observed. In analogy, the one-sided confidence interval of 90 % would not cover 30 % (null-hypothesis value) if 13 or more responses are observed in 30 patients.
No interim analyses are planned.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• During Re-exploratory/surgical cytoreduction (3 to 5 weeks after completion of chemotherapy (days 78 to 106))
|
|
| E.5.2 | Secondary end point(s) |
- To determine the change in the percentage of viable cells in peritoneal tumor deposits by comparing the percentage of viable tumor cells in the specimens before and after neoadjuvant chemotherapy. In case of multiple specimens, the median percentages before and after chemotherapy will be compared.
- To determine the clinical response to combination chemotherapy with FOLFOXIRI + bevacizumab within the peritoneum by assessing the Peritoneal Cancer Index (PCI) before and after combination chemotherapy with FOLFOXIRI + bevacizumab.
- To compare resectability at the time of initial surgical exploration with resectability at surgical re-exploration after administration of combination chemotherapy with FOLFOXIRI + bevacizumab.
- To asses the radiologic response to combination chemotherapy with FOLFOXIRI + bevacizumab by comparing the (FDG-PET) CT/MRI at baseline with the (FDG-PET) CT/MRI after completion of neoadjuvant chemotherapy/before surgical re-exploration.
- To compare the immuno-infiltrate of peritoneal tumor deposits before and after combination chemotherapy with FOLFOXIRI + bevacizumab as well as to compare the immuno-infiltrate of primary tumors with that of peritoneal tumor deposits at baseline.
- To assess the expression of PD-1/PD-L1 on immune and tumor cells within the microenvironment of peritoneal tumor deposits before and after combination chemotherapy with FOLFOXIRI + bevacizumab as well as to compare the expression of PD-1/PD-L1 in primary tumors with that of peritoneal tumor deposits at baseline.
- To assess cancer stem cell distribution within peritoneal tumor deposits and its association with hypoxia before and after neoadjuvant anti-angiogenic therapy with FOLFOXIRI + bevacizumab.
- To perform serial measurements of surrogate parameters for response, including but not limited to methylated septin-9, at baseline, during the course of combination chemotherapy with FOLFOXIRI + bevacizumab as well as before, during and after surgical re-exploration/cytoreductive surgery.
- To assess the status of the type of peritoneal tumor spread, either many small millet sized implants (miliary) or few bigger implants (non-miliary).
- To determine the genome-wide gene expression, the mutational status, and the DNA-methylation status (epigenetics) of the tumor cells from the peritoneal tumor deposits before therapy, different for both tumor spread types.1
- To determine selected cyto- and chemokines and metabolites from ascites (if present) and blood before therapy.
- To build a discriminative biomarker signature from genome-wide data, to diagnose the tumor spread status.
- To validate this biomarker signature with different methods and with publicly available data from The Cancer Genome Atlas (TCGA).1
- To compare all secondary objectives with tissues (if available) and data from colorectal cancer patients without peritoneal deposits
- To serially assess patients’ quality of life using the EORTC-QLQ-C30 and C29 questionnaires (and additional defined questions) throughout the study.
- To assess toxicity and safety
- To assess relapse-free survival (RFS)
- To assess progression-free survival (PFS)
- To assess overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor tissue viability,PCI,Immune-infiltrate,PD-1/PD-L1,Cancer stem cell distribution,Resectability
•Exploratory surgery(ES)d1•Re-expl.surgery(RES)d78-106
(FDG-PET) CT/(FDG-PET) MRI
•Baseline(BL)d-28-0•Before surgery(BS)(d71-106)•FollowupVisit3(FU)3mth(+/-2w)post re-expl.surgery(pRES),FU4 6mth(+/-1mth)pRES,FU5 9mth(+/-1mth)pRES,EOS Vist(EOSV)12mth(+/-1mth)pRES
Blood samples(septin-9)
•BL•Preoperative chemotherapy(PreOpCh):d1 of each chemocycle(1.cycle:14-28d after ES)add:before administration of chemotherapy,d2+8 of chemocycle1•BS,immediately preop•RES,intraop•FU1 1w(+/-2d)pRES,FU2 1mth(+/-2w)pRES,FU3,FU4,FU5,EOSV
QLQ
•BL,BS,FU1,FU2,FU3,FU4,FU5,EOSV
Safety
SAEs:BL,ES,PreOpCh,BS,FU1,FU2,FU3,FU4,FU5,EOSV,AEs:BL,ES,PreOpCh,BS,FU1,FU2
Survival
•ES,PreOpCh,BS,FU1,FU2,FU3,FU4,FU5,EOSV |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
