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Folfiri/aflIbercept in Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status (DISTINCTIVE)

Primary Purpose

Advanced Colorectal Cancer

Status
Unknown status
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Aflibercept, 5fluorouracil, Folinic Acid andIrinotecan
Sponsored by
Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Colorectal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • A.O. Treviglio-Caravaggio, P.le Ospedale n1
  • A.O. Humanitas GavazzeniRecruiting
  • Policlinico Universitario D.CasulaRecruiting
  • A.O. Polo Oncologico Vito Fazzi
  • ASST-RhodenseRecruiting
  • Istituto Clinico HumanitasRecruiting
  • AUSL di PiacenzaRecruiting
  • Centro Riferimento
  • Azienda Ospedaliera San CarloRecruiting
  • Ospedale Papa Giovanni XXIIIRecruiting
  • Fondazione Poliambulanza, Via Bissolati 57Recruiting
  • IRCCS Cà Granda Ospedale Maggiore Policlinico
  • IRCCS Istituto Europeo di Oncologia
  • A.O.U. Policlinico di ModenaRecruiting
  • A.O. S.Giovanni Calabita Fatebenefratelli
  • Ospedale San BortoloRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

standard chemotherapy for advanced colorectal cancer

Arm Description

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

Outcomes

Primary Outcome Measures

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
Overall survival time is defined as the time from inclusion to the date of death. If subject has not died, survival will be censored on the last date the subject was known to be alive (last date of follow-up)

Secondary Outcome Measures

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
PFS time will defined as the time of inclusion until the date of first observed disease progression or death due to any cause, if death occurs before progression is documented
Response rate (RR) defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), v. 1.1
All patients must be considered in response analysis, including those who discontinue treatment or who die for any reason prior to respnse evaluation
Toxicity Profile defined according to the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03
Treatment-emergent adverse events, drug-related adverse events and safety laboratory parameters will be analysed by CTCAE grade
Angiogenetic factors levels concentration before and during treatment.
Angiogenetic factors levels concentration (VEGF, PlGF, HGF, VEGF-R, IL8, IL1a, T-cad, VEGFR3, SAP, VDBP, neuropilin1, CRP, endoglin plasma concentrations)

Full Information

First Posted
January 28, 2020
Last Updated
January 31, 2020
Sponsor
Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
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1. Study Identification

Unique Protocol Identification Number
NCT04252456
Brief Title
Folfiri/aflIbercept in Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status
Acronym
DISTINCTIVE
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

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Unknown status
Study Start Date
April 23, 2018 (Actual)
Primary Completion Date
April 2020 (Anticipated)
Study Completion Date
February 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Colorectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Biologically enriched phase II clinical trial. All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.
Masking
None (Open Label)
Masking Description
All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.
Allocation
N/A
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
standard chemotherapy for advanced colorectal cancer
Arm Type
Other
Arm Description
All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.
Intervention Type
Procedure
Intervention Name(s)
Aflibercept, 5fluorouracil, Folinic Acid andIrinotecan
Intervention Description
All patients will receive aflibercept in combination with FOLFIRI according to the Italian label
Primary Outcome Measure Information:
Title
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
Description
Overall survival time is defined as the time from inclusion to the date of death. If subject has not died, survival will be censored on the last date the subject was known to be alive (last date of follow-up)
Time Frame
From date of randomization until the date of death from any cause, whichever came first, assessed up to 3 years
Secondary Outcome Measure Information:
Title
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
Description
PFS time will defined as the time of inclusion until the date of first observed disease progression or death due to any cause, if death occurs before progression is documented
Time Frame
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
Title
Response rate (RR) defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), v. 1.1
Description
All patients must be considered in response analysis, including those who discontinue treatment or who die for any reason prior to respnse evaluation
Time Frame
Response of treatment is evaluated according to the RECIST criteria at the end of chemotherapyassessed up to 24 weeks
Title
Toxicity Profile defined according to the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03
Description
Treatment-emergent adverse events, drug-related adverse events and safety laboratory parameters will be analysed by CTCAE grade
Time Frame
every 4 cycles of chemotherapy (each cycle is 15 days), up to 16 weeks
Title
Angiogenetic factors levels concentration before and during treatment.
Description
Angiogenetic factors levels concentration (VEGF, PlGF, HGF, VEGF-R, IL8, IL1a, T-cad, VEGFR3, SAP, VDBP, neuropilin1, CRP, endoglin plasma concentrations)
Time Frame
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Silvia Rota, DM
Phone
+39 02 84968409
Email
centrotrialgiscad@yahoo.it
First Name & Middle Initial & Last Name or Official Title & Degree
Eleonora Lai, DM
Phone
+39 392 2886023
Email
sperimentazioniclinicheunica@gmail.com
Facility Information:
Facility Name
A.O. Treviglio-Caravaggio, P.le Ospedale n1
City
Treviglio
State/Province
Bergamo
ZIP/Postal Code
24047
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
A.O. Humanitas Gavazzeni
City
Bergamo
State/Province
BG
ZIP/Postal Code
24125
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giordano D Beretta, MD
Facility Name
Policlinico Universitario D.Casula
City
Monserrato
State/Province
Cagliari
ZIP/Postal Code
09121
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mario Scartozzi, PhD
First Name & Middle Initial & Last Name & Degree
Mario Scartozzi, PhD
Facility Name
A.O. Polo Oncologico Vito Fazzi
City
Lecce
State/Province
LE
ZIP/Postal Code
73100
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Silvana Leo, MD
Facility Name
ASST-Rhodense
City
Rho
State/Province
Milano
ZIP/Postal Code
20017
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sara DiBella, MD
First Name & Middle Initial & Last Name & Degree
Roberto Bollina, MD
Facility Name
Istituto Clinico Humanitas
City
Rozzano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lorenza Rimassa, MD
Facility Name
AUSL di Piacenza
City
Piacenza
State/Province
PC
ZIP/Postal Code
29100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Luigi Cavanna, MD
Phone
+39 0523 302697
Email
l.cavanna@ausl.pc.it
First Name & Middle Initial & Last Name & Degree
Luigi Cavanna, MD
Facility Name
Centro Riferimento
City
Aviano
State/Province
PN
ZIP/Postal Code
33081
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
Azienda Ospedaliera San Carlo
City
Potenza
State/Province
PZ
ZIP/Postal Code
85100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giuseppe Rosati, MD
First Name & Middle Initial & Last Name & Degree
Domenico Bilancia, MD
Facility Name
Ospedale Papa Giovanni XXIII
City
Bergamo
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stefania Mosconi, MD
First Name & Middle Initial & Last Name & Degree
Stefania Mosconi, MD
Facility Name
Fondazione Poliambulanza, Via Bissolati 57
City
Brescia
ZIP/Postal Code
25100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alberto Zaniboni, MD
Facility Name
IRCCS Cà Granda Ospedale Maggiore Policlinico
City
Milano
ZIP/Postal Code
20122
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
IRCCS Istituto Europeo di Oncologia
City
Milano
ZIP/Postal Code
20141
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
A.O.U. Policlinico di Modena
City
Modena
ZIP/Postal Code
41124
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gabriele Luppi, MD
Facility Name
A.O. S.Giovanni Calabita Fatebenefratelli
City
Roma
ZIP/Postal Code
00186
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
Ospedale San Bortolo
City
Vicenza
ZIP/Postal Code
36100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giuseppe Aprile, MD

12. IPD Sharing Statement

Learn more about this trial

Folfiri/aflIbercept in Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status

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