Neoplasms

Digestive System Diseases

All Conditions

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Irinotecan

Leucovorin

Fluorouracil

Oxaliplatin

All patients will receive induction chemotherapy consisting of 4-6 cycles of FOLFOXIRI. Restaging will be performed after 4 cycles with a pelvic MRI and a thoraco-abdominal CT-scan. In case of stable or responsive disease, the remaining 2 cycles of FOLFOXIRI will be provided. In case of progressive, but still resectable disease, chemoradiation will be provided immediately, without the remaining 2 cycles of FOLFOXIRI. Restaging will be performed after chemoradiation. In case of resectable disease, surgery is performed.

FOLFOXIRI consists of oxaliplatin, irinotecan, leucovorin and 5-fluorouracil and is administered every 2 weeks:

Dosing:

* Day 1: irinotecan 165 mg/m2 body-surface area (BSA) intravenously (IV), followed by oxaliplatin 85mg/m2 BSA IV in combination with leucovorin 400mg/m2 BSA, followed by:
* Day 1-2: 3200 mg/m2 BSA of continuous 5-fluorouracil IV
* Day 3-14: rest days.

Both regimen are initially administered for four cycles. In case of responsive or stable disease, a 5th and 6th cycle of FOLFOXIRI will be administered.

In case of unacceptable toxicity, the aforementioned dosages can be reduced or one or more chemotherapeutical agents can be omitted at discretion of the medical oncologist and will be noted in the patient's medical file. At discretion of the medical oncologist, a start dosage of 75% of the advised dosage could be considered in patients above 70 years of age.

FOLFOXIRI Protocol

Kim van den Berg, MD

Pim Burger, MD/PhD

Pim J.W.A. Burger, MD. PhD.

Despite developments in the multidisciplinary treatment of patients with locally advanced rectal cancer (LARC), such as the introduction of total mesorectal excision (TME) by Heald et al. and the shift from adjuvant to neoadjuvant (chemo)radiotherapy ((C)RT), local and distant recurrence rates remain between 5-10% and 25-40% respectively. Several studies established tumour characteristics with particularly bad prognosis; it was demonstrated that the occurrence of mesorectal fascia involvement (MRF+), grade 4 extramural venous invasion (EMVI), tumour deposits (TD) and enlarged lateral lymph nodes (LLN) lead to high local and distant recurrence rates and decreased survival when compared with LARC without these particularly negative prognostic factors. This type of LARC is described as high risk LARC (hr-LARC). Achieving a resection with clear resection margins (R0) is an important prognostic factor for local (LR) and distant recurrence (DM) as well as survival. With the aim to further reduce the risk of recurrent rectal cancer, to diminish distant metastasis and to improve overall survival for patients with LARC, induction chemotherapy (ICT) became a growing area of research. The addition of ICT has the ability to induce more local tumour downstaging, possibly leading to resectability of previously unresectable tumours, more R0 resections and less extensive surgery. In the case of a complete clinical response, surgery may even be omitted. ICT may also have the potential to eradicate micrometastases. Hence, increased local downstaging and reducing distant metastatic spread may reduce LR and DM rates and improve survival and quality of life. In recent years, the use of ICT was investigated and showed promising results, but little is known about the addition of ICT in patients with high risk LARC. Since these patients have a particularly bad prognosis, both with regard to locoregional and distant failure, a more intensified neoadjuvant treatment with FOLFOXIRI is anticipated to improve short- and long term results.

This is a multicentre, single-arm, prospective phase 2 study.

Induction Chemotherapy for Locally Advanced Rectal Cancer

Neo-adjuvant FOLFOXIRI and Chemoradiotherapy for High Risk ("Ugly") Locally Advanced Rectal Cancer

The pCR is evaluated by an experienced pathologist. A pCR is defined as the absence of residual tumour cells in the complete resected specimen including all resected regional lymph nodes (ypT0N0). A cCR is defined as the absence of viable tumour tissue based on MRI, evaluated by an experienced radiologist. There is a cCR in case of a sustained clinical response at 1 year after chemoradiotherapy.

ocal recurrence is confirmed by either radiological or histopathological examination. A recurrence is registered by the treating physician in the patient's medical file.

Distant metastases may be confirmed by either radiological or histopathological examination. Data on distant metastases are registered by the treating physician in the patient's medical file.

Progression is defined as progression of the primary tumour, local recurrence, distant metastases confirmed by radiological or histopathological examination or death. Data regarding disease progression are registered by the treating physician in the patient's medical file.

Disease free survival is defined as no confirmed recurrence, distant metastases or death. Disease recurrence is registered by the treating physician in the patient's medical file.

Mortality is registered in the patient's medical file which is linked to the municipal personal records database.

Assessment and reporting of all MRI scans is performed according to a standard operating procedure and is registered in the patient file by the radiologist.

The pathologic response is graded according to the Mandard grading system. The Mandard grading is registered by the pathologist in the pathology report in the patient's medical file.

Systemic related toxicity is graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity caused by induction therapy will be scored from day one of the first cycle of induction therapy until one month after the last administration of the induction therapy and is registered in the patient's medical file by the treating medical oncologist. Only all non-hematologic NCI-CTCAE grade 3-4 and all NCI-CTCAE ≥4 are registered.

Information on completion of induction therapy is registered by the treating medical oncologist. In all patients in whom a dose reduction is required the reason for dose reduction will be recorded in the patient's medical file.

Chemoradiotherapy related toxicity is graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity caused by chemoradiotherapy will be scored from start of radiotherapy until 3 months after the last administration of the radiotherapy and is registered in the patient's medical file by the treating radiation oncologist. Only all non-hematologic NCI-CTCAE grade 3-4 and all NCI-CTCAE ≥4 are registered.

Information on completion of chemoradiotherapy is registered by the treating radiation oncologist and registered in the patient's medical file. In all patients in whom a dose reduction is required the reason for dose reduction will be recorded in the patient's medical file.

This is calculated as a percentage from the total number of patients that were included.

Directly after surgery, information with respect to procedure related characteristics is registered in the surgical report in the patient's medical file by the operating surgeon. Data on intra-operative radiotherapy, if administered, are registered in the patient's medical file by the treating radiation oncologist.

Surgical complications are graded according to the Clavien-Dindo grading system. Complications will be scored up to 3 months after surgery and are registered in the patient file by the treating physician.

Generic and cancer-specific quality of life assessments are assessed with QLQ-C30, a 4 point scale. Higher scores correspond with a higher response level.

Generic and cancer-specific quality of life assessments are assessed with QLQ-CR29, a 4 point scale. Higher scores represent better functioning on functional scales and a higher level of symptoms on the symptom scale.

Generic and cancer-specific quality of life assessments are assessed with EQ-5D-5L, a 5 point scale. Higher scores corresponds with a higher level of symptoms on the symptom scale.

For the purpose of economic evaluation, the EQ-5D-5L questionnaire is used at inclusion and at 3 and 12 months post-operatively. The questionnaires will be sent either by mail or digitally, according to the patient's preference.

Catharina Ziekenhuis Eindhoven

Principal investigator

Rare Diseases

Carcinoma

Carcinoma, Neuroendocrine

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Adenocarcinoma

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

Etoposide

Carboplatin

Cisplatin

Etoposide phosphate

Folfirinox

Enzyme Inhibitors

mFOLFIRINOX will be administered once every 14 days for up to 12 cycles. One cycle consists of 14 days (2 weeks) with injection on D1 of each cycle (D1=D15). Patients are eligible for repeated treatment cycles in the absence of disease progression and undue adverse events.

Platinum-Etoposide regimen will be administered once every 21 days. Treatment will be continued for 6 to 8 cycles or 24 weeks maximum. One cycle consists of 21 days (3 weeks) with injection on D1 of each cycle (D1=D22). Patients are eligible for repeated treatment cycles in the absence of disease progression and undue adverse events.

Cisplatin 100 mg/m2, IV infusion over 3 hours or Carboplatin AUC 5, IV infusion over 30 minutes on day 1 \[the dose of carboplatin will be determined for each cycle using the Calvert's formula (carboplatin dose (mg) = target AUC 5 x estimated glomerular filtration rate (eGFR, mL/min) + 25)\];

• Etoposide 100 mg/m² IV infusion over 1 hour on day 1,2 and 3

Cisplatin injection

Karine BOUHIER LEPORRIER, Dr

Côme LEPAGE, Pr

Geneviève BOILLEAU-JOLIMOY, Dr

Frédéric THUILLIER, Dr

Romain Desgrippes, Dr

William MINA, Dr

there is a need for improving chemotherapy regimen for metastatic G3 NEC of GEP and Unknown origin and this goal may be achieved through more "personalized" chemotherapy regimen.the hypothesis is that mFOLFIRINOX regimen could be a good candidate for challenging the platinum-etoposide regimen in patients with metastatic G3 NEC of GEP or unknown origin. Furthermore, in order to get insights in the putative predictive biomarkers of efficacy of these two regimens, an effort toward a precise molecular characterization of these tumors is required in order to be able to define which subgroup of G3 NEC needs to be treated by which chemotherapy regimen. The FOLFIRINEC trial is set up in order to try to answer these questions

Grade 3 poorly differentiated neuroendocrine carcinomas (G3 NEC) are rare diseases. The diagnosis is often done at the metastatic stage and the prognosis is poor. The standard first-line treatment is the platinum-etoposide chemotherapy regimen, mostly based on retrospective studies .With this regimen, response rate (RR) is 40 to 70% but the median progression-free survival is between 4 and 9 months. Disease progression almost always occurs during or just after treatment and median overall survival (OS) is only about 12-15 months for gastro-entero-pancreatic (GEP) NEC with similar efficacy of either cisplatin or carboplatin in the NORDIC study and of 8 to 10 months for pulmonary NEC. After progression, only 40 to 45% of patients will receive a second line chemotherapy which will include 5-fluoro-uracil (5FU) and irinotecan (FOLFIRI or oxaliplatin (XELOX, FOLFOX).This second line treatment can provide around 30% of responses and a median progression-free survival of 4 months. Taken together, these data indicate a major medical need for improving G3 NEC treatments.

Few trials have tried to challenge the standard platinum-etoposide first-line treatment. Clinical trials challenging the platinum-etoposide combination in the first-line setting feasibility has already been demonstrated with paclitaxel-carboplatin-etoposide combination and the cisplatin-irinotecan phase III trials. However, these trials have shown equivalent activities between experimental group and platinum-etoposide regimen. Furthermore, the lack of randomization precluded any definitive conclusion. Therefore, prospective randomized studies aiming at improving first-line chemotherapy remains challenging and clinically meaningful. Currently, the only randomized trial in progress in first line treatment of metastatic G3 GEP NEC compares platinum-etoposide to temozolomide-capecitabine. Other mono-arm phase II studies evaluate carboplatin - nab-paclitaxel and everolimus - temozolomide combinations. FOLFIRINOX is also planned to be evaluated in a mono-arm first or subsequent line setting at Lee. H Moffit Cancer Institute.

Although the second-line treatment studies of metastatic G3 NEC of GEP or unknown origin were retrospective, they have suggested that both irinotecan and oxaliplatin, in conjunction with 5FU can have anti-tumor effect in G3 NEC. In recent years, the intensified chemotherapy regimen FOLFIRINOX, which associates 5FU, oxaliplatin and irinotecan, has shown great efficacy in several digestive cancer such as pancreas or colorectal adenocarcinoma. Tolerance of this regimen has improved over the years with better management and dose adaptations that has led to the development of the mFOLFIRINOX regimen . mFOLFIRINOX could be a good first-line treatment candidate in metastatic GEP NEC because: (i) Oxaliplatin, irinotecan and 5FU have anti tumor effect in metastatic GEP NEC; (ii) trichemotherapy with a potential high RR could be efficient in these chemosensitive cancers; (iii) the degradation of performance status following tumor progression after first-line treatment makes access to a second line uncertain which argue for the use of an aggressive first-line treatment; (iiii) administration on a one-day outpatient basis (day hospital) as well as acceptable and manageable side effects, could have an impact on quality of life in these patients with a poor prognosis. the hypothesis is that the intensive trichemotherapy mFOLFIRINOX, improves the prognosis of patients with metastatic G3 NEC from GEP or unknown primary.

Little is known on the predictive factors of first-line chemotherapy in metastatic G3 NEC and few trials have tried to challenge the platinum-etoposide standard. Among G3 NEC, there are 2 histological subtypes; eg. small cell NEC (SCNEC) and large cell NEC (LCNEC). These two subtypes are treated with the same platinum-etoposide regimen, whatever the primary, although RR seem to differ between SCNEC and LCNEC. This difference has been reported for pulmonary G3 NEC: the RR to platinum-etoposide was 34% in the French phase II trial on LCNEC and 37% in a recent retrospective study, while the RR of SCNEC was 50 to 60% in different reports. Moreover, the difference in RR to platinum based chemotherapy has also been recently reported in a Japanese retrospective study of pancreatic NEC with RR of 68 and 44% for SCNEC and LCNEC respectively.

These results suggest that there could be some biological differences among G3 NEC, which could be responsible for the different responses to treatment and that G3 NEC could be a heterogeneous group of tumors. While pulmonary SCNEC are fairly homogeneous tumors and are characterized by a quasi-constant Rb loss of expression, LCNEC are more heterogeneous. A sequencing study of 45 pulmonary LCNEC samples has shown that 40% of the tumors had a mutational profile which looks like small cell lung cancer (SCLC) while 58% of the tumors had a mutation profile like those found in non-small cell lung cancer (NSCLC) (Rekhtman et al. 2016). According to their molecular profiles, LCNEC could be divided between "NSCLC-like" and "SCLC-like" tumors. "SCLC-like" tumors were characterized by p53 and Rb inactivating mutations while "NSCLC-like" tumors were characterized by p53 inactivating mutations but also KRAS and STK11 mutations like those found in lung adenocarcinomas. Therefore, when considering the pulmonary NEC model, it could be hypothesized that, among LCNEC, some tumors may be "adenocarcinoma-like" and some other may be really "SCNEC-like". This hypothesis is supported by some data from digestive tract G3 NEC. Rb loss of expression is found in 100% of SCNEC of the colon versus 31% of LCNEC of the colon; Rb loss is also found in 89% of SCNEC versus 60% of LCNEC of the pancreas . These data seem to parallel the pulmonary NEC data and suggest that G3 NEC, especially LCNEC, is a heterogeneous group of tumors with some of them being biologically very close to SCNEC with Rb loss and others being more biologically close to adenocarcinoma. G3 SCNEC are probably more homogeneous but some heterogeneity is also possible within this group because the pathological diagnosis of "large"versus "small cell" is challenging. This has led to the hypothesis that LCNEC could arise from different cell of origin, i.e; from neuroendocrine precursors and/or from trans-differentiation of adenocarcinoma cells as already described in prostate and lung cancer while SCNEC would represent the bona fide poorly differentiated NEC.

Taking together the putative biological heterogeneity of G3 NEC and the need, in clinical practice, for more effective chemotherapy regimen, it can be hypothesized that a more "tailored" chemotherapy regimen is needed for G3 NEC patients. This is supported by the retrospective analysis from the Dutch registry of pulmonary NEC which have suggested that "NSCLC-like" chemotherapy regimen without pemetrexed were more effective than "SCLC-like" chemotherapy regimen for the treatment of pulmonary LCNEC. Moreover, the same group has recently reported that the better efficacy of "NSCLC-like" chemotherapy was observed for pulmonary LCNEC without Rb mutation (the so-called "NSCLC-like" tumors in the Rekhtman et al study) while Rb mutated LCNEC did not have significantly different response to "SCLC-like" and "NSCLC like" chemotherapy regimens. This has also been shown in pancreatic LCNEC with a RR to first-line platinum-based chemotherapy of 80% in case of Rb loss of expression, and 38.4% in case of retained Rb expression.

mFOLFIRINOX (experimental arm) vs Platinum - Etoposide (standard arm)

Chemotherapy For Metastatic Grade 3 Poorly Differentiated NEuroendocrine Carcinoma Of GastroEnteroPancreatic And Unknown Primary

Folfirinox Versus Platinum - Etoposide as First Line Chemotherapy for Metastatic Grade 3 Poorly Differentiated Neuroendocrine Carcinoma of Gastro Entero Pancreatic and Unknown Primary Associated With Molecular Profiling for Therapeutic Targets & Predictive Biomarkers Identification

The primary endpoint is the median of progression-free survival. PFS is defined as the time interval between date of randomization and date of the first radiological progression (according to RECIST 1.1) or death due to any cause, whichever occurs first, according to investigator. Patient alive without progression will be censored at date of last follow-up visit.

time interval between date of randomization and date of the first radiological progression (according to RECIST 1.1) or death due to any cause, whichever occurs first, according to the centralized review.

OS is defined as the time interval between date of randomization and date of death (whatever the cause). Patients alive will be censored at date of last news.

The best objective response rate is defined as the proportion of patients with an objective response (Complete response (CR) + Partial response (PR)) at any evaluation during the treatment, according to RECIST 1.1.

Safety profile is defined as the percentage of patients who experienced toxicities and grading of these toxicities. Toxicities will be presented as the number of patients presenting at least an episode of toxicity by maximum grade. Toxicity grading will follow NCI-CTC V4 guidelines

National Cancer Institute, France

Centre Hospitalier Universitaire Dijon

5Fu + RT for five weeks --- 6-8 weeks of interval --- TME --- mFOLFOX \* 6-8

mFOLFOXIRI \* 4 --- TME --- mFOLFOXIRI \* 4

Fluorouracil 225 mg/m2/day continuous intravenous infusion on weekdays for five weeks; local irradiation 2GY/day on weekdays, totally 50GY.

Chemoradiation

Oxaliplatin 85 mg/m2 on day 1; irinotecan 150 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days; prophylactic G-CSF support is recommended.

Oxaliplatin 85 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days.

Folfox Protocol

Ping Lan, MD

Jian Xiao, MD

Preoperative radiation with single agent chemotherapy as sensitizer is the standard care of locally advanced rectal cancer.

Local irradiation significantly increases surgical complications and impairs quality of life.

Combination chemotherapy alone seems promising and provides similar benefit to chemoradiation as neoadjuvant therapy.

Early administration of systemic therapy is also proved beneficial for long-term survival.

The purpose of this study is to compare the efficacy of chemotherapy alone with short-term modified FOLFOXIRI or long-term mFOLFOX with standard chemoradiation as neoadjuvant therapy for locally advanced rectal cancer.

Patients with cT3-4 or cN+ and cM0 by pelvic MR and chest + abdominal CT scan will be randomized to the following three groups:

Group A: Traditional chemoradiation.

Fluorouracil 225 mg/m2/day continuous intravenous infusion on weekdays for five weeks; local irradiation 2GY/day on weekdays, totally 50GY.

At the end of chemoradiation, patients will receive an evaluation with MR and CT scan.

If the efficacy is defined as CR, PR or SD, the TME will be performed in 6-8 weeks since the last irradiation.

If the disease progress with the possibility of R0 resection, the operation will be given soon.

If the tumor progress to impossible for R0 resection, the salvage chemotherapy will be given accordingly.

Adjuvant chemotherapy of 6-8 cycles of mFOLFOX will be administered 3-4 weeks after R0 resection.

Group B: Short-term mFOLFOXIRI.

Oxaliplatin 85 mg/m2 on day 1; irinotecan 150 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days; prophylactic G-CSF support is recommended.

Patients are planned to receive 4 cycles of mFOLFOXIRI regimen preoperatively and postoperatively, respectively.

Before operation, efficacy evaluations will be performed every two cycles by CT and MR scan.

If the evaluation is defined as no progression without severe toxicity, the next 2 cycles will be given.

If the primary lesion progress without distant metastasis, patients will be assigned to group A.

If distant metastasis occurr during chemotherapy, patients will withdraw from the trial and be treated further at the discretion of attending physicians.

Postoperative chemotherapy will initiate 3-4 weeks after R0 resection.

Group C: Long-term mFOLFOX.

Oxaliplatin 85 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days.

Patients are planned to receive 8-9 cycles of mFOLFOX regimen preoperatively and 3-4 cycles postoperatively.

Efficacy evaluations will be performed every three cycles by CT and MR scan before TME.

If the evaluation is defined as no progression without severe toxicity, the next 3 cycles of mFOLFOX will be given with the maximum of 9 cyces.

If the primary lesion progress without distant metastasis, patients will be assigned to group A.

If distant metastasis occurr during chemotherapy, patients will withdraw from the trial and be treated further at the discretion of attending physicians.

Postoperative chemotherapy will initiate 3-4 weeks after R0 resection.

Triplet Combination or Doublet Regimen Versus Chemoradiation as Neoadjuvant Therapy for Locally Advanced Rectal Cancer

A Prospectively Randomized Phase III Trial Comparing Short-term mFOLFOXIRI, Long-term mFOLFOX6 and Traditional Chemoradiation as Preoperative Neoadjuvant Therapy for Locally Advanced Rectal Cancer

The interval from randomization to local recurrence, distant metastasis, death or the last follow-up.

The interval from randomization to local recurrence, death or the last follow-up.

The interval from randomization to distant metastasis, death or the last follow-up.

Surgical complication including anastomotic leakage, anastomotic stricture, intestinal obstruction, postoperative pelvic bleeding and poor wound healing.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Induction Chemotherapy for Locally Advanced Rectal Cancer	NCT04838496	Rectal Cancer	FOLFOXIRI Proto...	18 Years -	Catharina Ziekenhuis Eindhoven
Chemotherapy For Metastatic Grade 3 Poorly Differentiated NEuroendocrine Carcinoma Of GastroEnteroPancreatic And Unknown Primary	NCT04325425	Neuroendocrine ...	FOLFOXIRI Proto... Cisplatin injec...	18 Years -	Centre Hospitalier Universitaire Dijon
Triplet Combination or Doublet Regimen Versus Chemoradiation as Neoadjuvant Therapy for Locally Advanced Rectal Cancer	NCT03975049	Rectal Cancer Chemotherapy Ef...	Chemoradiation FOLFOXIRI Proto... Folfox Protocol	18 Years - 75 Years	Sixth Affiliated Hospital, Sun Yat-sen University
Induction Chemotherapy for Locally Advanced Rectal Cancer	NCT04838496	Rectal Cancer	FOLFOXIRI Proto...	18 Years -	Catharina Ziekenhuis Eindhoven
Chemotherapy For Metastatic Grade 3 Poorly Differentiated NEuroendocrine Carcinoma Of GastroEnteroPancreatic And Unknown Primary	NCT04325425	Neuroendocrine ...	FOLFOXIRI Proto... Cisplatin injec...	18 Years -	Centre Hospitalier Universitaire Dijon
Triplet Combination or Doublet Regimen Versus Chemoradiation as Neoadjuvant Therapy for Locally Advanced Rectal Cancer	NCT03975049	Rectal Cancer Chemotherapy Ef...	Chemoradiation FOLFOXIRI Proto... Folfox Protocol	18 Years - 75 Years	Sixth Affiliated Hospital, Sun Yat-sen University
Chemotherapy For Metastatic Grade 3 Poorly Differentiated NEuroendocrine Carcinoma Of GastroEnteroPancreatic And Unknown Primary	NCT04325425	Neuroendocrine ...	FOLFOXIRI Proto... Cisplatin injec...	18 Years -	Centre Hospitalier Universitaire Dijon

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