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Aflibercept +/- LV5FU2 in First Line of Non-resectalbe Metastatic Colorectal Cancers

Information source: Federation Francophone de Cancerologie Digestive
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Colorectal Neoplasms

Intervention: aflibercept (Drug); LV5FU2 (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Federation Francophone de Cancerologie Digestive

Official(s) and/or principal investigator(s):
Jean Louis LEGOUX, MD, Principal Investigator, Affiliation: ORLEANS - Centre Hospitalier La Source

Summary

This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for

strategic studies evaluating the usefulness of including targeted therapeutics from the first line with aflibercept +/- LV5FU2.

Clinical Details

Official title: Phase II Randomized Trial Evaluting Aflibercept Associated With LV5FU2 Regimen as First Line Treatment of Non-resectalbe Metastatic Colorectal Cancers

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Radiological progression-free survival according to the investigator

Secondary outcome:

Aflibercept tolerance withe LV5FU2

Quality of life

Overall survival

Radiological progression-free survival accordint to central reading

Clinical and radiological progression-free survival according to the investigator

Best response

Curative resectability

Detailed description: The aflibercept-5-FU combination has never been evaluated as yet. Aflibercept, at a dose of 4 mg/kg, has already been used in combination with 5-FU at the doses used in the simplified LV5FU2 regimen (folinic acid 400 mg/m2 IV in 90 min, then 5-FU 400 mg/m2 IV bolus on D1, followed by continuous perfusion of 5-FU 2,400 mg/m2 in 46h) (23) as part of the above-mentioned VELOUR trial, evaluating its combination with FOLFIRI (= simplified LV5FU2 + irinotecan). This trial was preceded by a phase I trial validating the doses used (24). It is therefore not necessary to perform a phase I trial if you use the same doses of 5-FU without irinotecan, within the context of a strategy for reducing toxicity in patients to be treated over a long period, and not search for the maximum tolerated dose of the combination. The aflibercept-LV5FU2 combination can be useful for patients who will never be resectable or operable, and for whom 5-FU monotherapy can be suggested to delay the toxicities of combined chemotherapies. Within this context, it is possible for aflibercept to provide a survival benefit. The previous VELOUR trial (18) did not indicate that toxicity would have a major effect on quality of life and increase the hope of prolonged progression-free survival in the arm with aflibercept.

This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for

strategic studies evaluating the usefulness of including targeted therapeutics from the first line. This trial will evaluate the efficacy of the combination and its tolerance by studying toxicities and quality of life. Quality of life will be studied via the EORTC questionnaire QLQ-C30. The thymidylate synthase polymorphism type 2R2R-2R3R versus 3R3R seems to predict greater efficacy of 5-FU monotherapy. Stratification in this criterion will confirm or negate the prognostic or predictive nature of 5-FU efficacy linked to these polymorphisms. The draft version of this trial has been studied and evaluated by the scientific council of the Fédération Francophone de Cancérologie Digestive (FFCD) then the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) within the framework of their Partnership for Research in Digestive Oncology (PRODIGE cooperation).

Eligibility

Minimum age: 65 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age ≥ 65 years

- General condition WHO ≤ 2

- Metastatic rectal or colonic adenocarcinoma, histologically proved on the primary

tumour or a metastasis

- Metastases non-resectable and/or patient inoperable

- patients where a single agent chemotherapy combined with an anti-angiogenic agent is

an appropriate approach

- At least one measurable target according to RECIST v1. 1 criteria, no previously

irradiated

- No previous treatment of the metastatic disease. Previous chemotherapy in an adjuvant

situation completed 6 months or more before diagnosis of the metastasis is authorized.

- Adequate biological examination: Hb > or = 9 g/dl, polynuclear neutrophils > or =

1,500/mm3, platelets > or =100,000/mm3, total bilirubin < or = 1. 5 x UNL, creatinine clearance, calculated according to Cockroft-Gault formula, > 50 ml/min creatininemia < 1. 5 x UNL, ALP < 5 x UNL, transaminases < 5 x ULN, GGT< 5 x UNL

- Proteinuria (strip) < 2+; if > or = 2+, test proteinuria over 24 hours which must be

≤ 1 g.

- Central genotyping of thymidylate synthase (TS) in blood DNA

- Patients treated with anticoagulants (coumadin, warfarin) can be included if the INR

can be closely monitored. A change in anticoagulant treatment for low molecular weight heparin is preferable in order to respect indications

- Signed written informed consent obtained prior to inclusion

Exclusion Criteria:

- Patients with a primary tumour in place and presenting clinical symptoms (occlusion,

haemorrhage)

- History of brain metastases, uncontrolled spinal cord compression, or carcinomatous

meningitis or new evidence of brain or leptomeningeal disease.

- Uncontrolled hypercalcemia

- Uncontrolled hypertension (SBP > 150 mmHg and DBP > 100 mmHg) or history of

hypertensive attacks or hypertensive encephalopathy

- Any progressive pathology not balanced over the past 6 months: hepatic insufficiency,

renal insufficiency, respiratory insufficiency,

- Any of the following within 6 months prior to inclusion: myocardial infarction,

severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack.

- Any of the following within 3 months prior to inclusion: Grade 3-4 gastrointestinal

bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event, wound or fractured bone

- Major surgery during the 28 days preceding the start of treatment

- Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV

disease requiring antiretroviral treatment.

- Treatment with concomitant anticonvulsivant agents that are CYP3A4 inducers

(phenytoin, phenobarbital, carbamazepine), unless discontinued >7 days.

- Anti-tumoral treatments other than the trial treatments (chemotherapy, targeted

therapy, immunotherapy)

- Macronodular peritoneal carcinosis (risk of perforation)

- Known DPD deficit

- Prior history of malignant haemopathy or cancer except those treated more than 5

years ago and considered to be cured, in situ cervical carcinomas and treated skin cancers (excluding melanoma)

- Patients on new oral anticoagulant therapy (rivaroxaban XARELTOR, apixaban ELIQUIS,

dagigatran PRADAXA except if relay by vitamine K antagonist therapy)

- Any contraindication to the treatments used in the trial

- Impossibility of undergoing medical monitoring during the trial for geographic,

social or psychological reasons

Locations and Contacts

CH de la Côte Basque, Bayonne 64109, France

La Source, Orleans 45067, France

Additional Information

Starting date: February 2015
Last updated: March 4, 2015

Page last updated: August 23, 2015

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