Clinical trial NCT04252456: Folfiri/aflIbercept in Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status
Official title: seconD-line Folfiri/aflIbercept in proSpecTIvely Stratified, Anti-EGFR resistaNt, Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Advanced Colorectal Cancer
Lead sponsor: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
Sponsor class: OTHER
First posted: 2020-02-05
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Biologically enriched phase II clinical trial. All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.
Primary purpose: TREATMENT

Brief summary: The study will a be a biologically enriched, prospectively stratified phase II trial in RAS wild type metastatic colorectal cancer patients progressing after first-line treatment with oxaliplatin, fluoropyrimidines and an anti-EGFR monoclonal antibody.

All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.

Detailed description: The study will a be a biologically enriched, prospectively stratified phase II trial in RAS wild type metastatic colorectal cancer patients progressing after first-line treatment with oxaliplatin, fluoropyrimidines and an anti-EGFR monoclonal antibody. Eligible patients will be prospectively allocated to either of two groups according to VEGFR2 levels (ELISA-based technique, pg/ml) at study entry.

Others angiogenetic factors levels concentration before and during treatment. VEGF, PlGF, HGF, VEGFR1, IL8, IL1a, T-cad, VEGFR3, SAP, VDBP, neuropilin1, CRP, endoglin plasma concentrations will be evaluated before each cycle according to an ELISA-based technique All patients will undergo a blood test for retrieving circulating tumor DNA (Liquid Biopsy) at selected time-points before and during treatment for determining whether the status of selected tumor biomarkers evolve during tumor progression by comparing different ctDNA samples.

All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.

Eligibility criteria: Inclusion Criteria:

* • Histological confirmation of colorectal cancer

  * Confirmed RAS wild type patient treated with an oxaliplatin-anti EGFR treatment in 1st line
  * At least one lesion measurable with CT or MRI scan
  * Radiologically documented progression while on or after discontinuation of treatment with FOLFOX in combination with an anti-EGFR monoclonal antibody (either cetuximab or panitumumab)
  * Radiologically documented progressing disease after FOLFOX in combination with an anti-EGFR monoclonal antibody (either cetuximab or panitumumab)
  * Life expectancy plus 3 months
  * Netrophils count ³ 1.5 x 109/L
  * Platelets count ³ 100 x 109/L
  * Hemoglobin ³ 9 g/dL
  * Creatinine £ 1.5 mg/dL, Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour.Bilirubin £ 1.5 x ULN
  * AST and ALT £ 2.5 x ULN (\< 5 ULN in case of liver metastases)
  * Informed written consent
  * ECOG Performance Status \< 2
  * Age plus18 yrs
  * Regular follow-up feasible.
  * For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment,
  * Female patients must commit to using reliable and appropriate methods of contraception until at least six months after the end of study treatment

Exclusion Criteria:

* • Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),

  * Treatment with any other investigational medicinal product within 28 days prior to First Study treatment.
  * Other serious and uncontrolled non-malignant disease,
  * History or evidence upon physical examination of CNS metastasis unless adequately treated
  * Gilbert's syndrome
  * Intolerance to atropine sulfate or loperamide
  * Known dihydropyrimidine dehydrogenase deficiency
  * Treatment with CYP3A4 inducers unless discontinued \> 7 days prior to First Study treatment.
  * Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis.
  * Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for \>5 years,
  * Major surgery or traumatic injury within the last 28 days or until the surgical wound is fully healed whichever came later
  * Pregnant or breastfeeding women,
  * Patients with known allergy to any excipient to study drugs,
  * Bowel obstruction.
  * Uncontrolled infections
  * Known drugs or alcohol abuse
  * History of severe cardiovascular disease within 6 months prior to First Study treatment Uncontrollable hypertension, when treated with three or more drugs.

Primary outcomes:
measure: Overall survival (OS) according to VEGFR2 levels, evaluating the difference in terms of median OS among patients with high VEGFR2 activity and patients with low VEGFR2 activity
timeFrame: From date of randomization until the date of death from any cause, whichever came first, assessed up to 3 years
Secondary outcomes:
measure: Progression free survival (PFS) defined as the interval between the start of Aflibercept-FOLFIRI therapy to tumor progression or death or last follow up visit if not progressed
timeFrame: time from the start of treatment untill the date of first documented progression or death from any cause, whichever came first, assessed up to 3 years
measure: Response rate (RR) defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), v. 1.1
timeFrame: Response of treatment is evaluated according to the RECIST criteria at the end of chemotherapyassessed up to 24 weeks
measure: Toxicity Profile defined according to the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03
timeFrame: every 4 cycles of chemotherapy (each cycle is 15 days), up to 16 weeks
measure: Angiogenetic factors levels concentration before and during treatment.
timeFrame: evaluated before treatment and before each cycle (each cycle is 15 days) according to an ELISA-based technique, through completion, an overage of 1 year
Other outcomes:
Locations:
city: Treviglio
country: Italy
facility: A.O. Treviglio-Caravaggio, P.le Ospedale n1
state: Bergamo
city: Bergamo
country: Italy
facility: A.O. Humanitas Gavazzeni
state: BG
city: Monserrato
country: Italy
facility: Policlinico Universitario D.Casula
state: Cagliari
city: Lecce
country: Italy
facility: A.O. Polo Oncologico Vito Fazzi
state: LE
city: Rho
country: Italy
facility: ASST-Rhodense
state: Milano
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Piacenza
country: Italy
facility: AUSL di Piacenza
state: PC
city: Aviano
country: Italy
facility: Centro Riferimento
state: PN
city: Potenza
country: Italy
facility: Azienda Ospedaliera San Carlo
state: PZ
city: Bergamo
country: Italy
facility: Ospedale Papa Giovanni XXIII
city: Brescia
country: Italy
facility: Fondazione Poliambulanza, Via Bissolati 57
city: Milano
country: Italy
facility: IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: IRCCS Istituto Europeo di Oncologia
city: Modena
country: Italy
facility: A.O.U. Policlinico di Modena
city: Roma
country: Italy
facility: A.O. S.Giovanni Calabita Fatebenefratelli
city: Vicenza
country: Italy
facility: Ospedale San Bortolo
Study officials:
References: