FOLFOXIRI With or Without Panitumumab in Metastatic Colorectal Cancer (VOLFI)

Sponsor

AIO-Studien-gGmbH (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01328171

Collaborator

Amgen (Industry), ClinAssess GmbH (Industry)

Enrollment

Locations

Arms

129.1

Anticipated Duration (Months)

4.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the trial is to optimize response rates and rates of secondary resections of metastases in patients with initially non-resectable metastatic colorectal cancer of RAS wildtype. The patients will be treated in two therapy groups:

Experimental arm A: Chemotherapy with FOLFOXIRI + panitumumab Standard arm B: Chemotherapy with FOLFOXIRI

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: FOLFOXIRI + Panitumumab Drug: FOLFOXIRI	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

93 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label 2:1 Randomized Phase II Study of Panitumumab Plus FOLFOXIRI or FOLFOXIRI Alone as First-line Treatment of Patients With Non-resectable Metastatic Colorectal Cancer and RAS Wild Type

Actual Study Start Date :

Apr 1, 2011

Actual Primary Completion Date :

Jun 1, 2017

Anticipated Study Completion Date :

Jan 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A (FOLFOXIRI + Panitumumab) FOLFOXIRI + Panitumumab	Drug: FOLFOXIRI + Panitumumab irinotecan 150 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 3000 mg/m² cont. inf. + panitumumab, iv, 6 mg/kg BW all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles Other Names: Vectibix (Panitumumab) folic acid 5-FU oxaliplatin irinotecan
Active Comparator: B (FOLFOXIRI) FOLFOXIRI	Drug: FOLFOXIRI irinotecan 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 3200 mg/m² cont. inf. all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles Other Names: folic acid 5-FU oxaliplatin irinotecan

Arm

Intervention/Treatment

Experimental: A (FOLFOXIRI + Panitumumab)

FOLFOXIRI + Panitumumab

Drug: FOLFOXIRI + Panitumumab

irinotecan 150 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 3000 mg/m² cont. inf. + panitumumab, iv, 6 mg/kg BW all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles

Other Names:

Vectibix (Panitumumab)

folic acid

5-FU

oxaliplatin

irinotecan

Active Comparator: B (FOLFOXIRI)

FOLFOXIRI

Drug: FOLFOXIRI

irinotecan 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 3200 mg/m² cont. inf. all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles

Other Names:

folic acid

5-FU

oxaliplatin

irinotecan

Outcome Measures

Primary Outcome Measures

overall response rate [up to about 6 month]
RECIST

Secondary Outcome Measures

overall response rate in each cohort [up to about 6 month]
RECIST
secondary resection rate with curative intent for patients cohort I [up to about 6 month]
pathological response in liver surgery specimen [up to about 6 month]
metrics: Pathological complete response (pCR): no residual cancer cells;major response (pPR): 1% to 49% residual cancer cells remaining; minor response (pMR): 50% to 99% residual cancer cells remaining; no response (pNR): 100% residual cancer cells remaining
disease control rate [up to about 6 month]
CR + PR + SD rate according to RECIST
progression free survival [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years]
duration of response [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years]
analyzed for responders only
time to response [up to about 6 month]
overall survival [From date of randomization until the date of death from any cause assessed up to 4 years]
time to recurrence (cohort II in case of secondary resection) [up to 4 years]
toxicity and feasibility [up to about 6 month]
number of patients with adverse events and severity according to NCI CTC 3.0
liver toxicity for resected patients (central histological review); biopsies should be obtained for all patients pre-treatment [up to 1 year]
histological findings according to CASH/SOS scores
QL (QLQ C30) [Pre-treatment, before start of every 3rd cycle and at the end of treatment]
scores according to EORTC QLQ-C30 scoring manual (Quality of life)
translational research (EGFR genetics and proteomics): prognostic and predictive impact on efficacy outcomes [up to 4 years]
Determination of EGFR mutations (exons 18, 19, 20, 21) in tumor tissue; determination of PIK3CA mutations (exon 9, 20) in tumor tissue; determination of EGFR, ERCC1, TS, MTHFR, OPRT, DHFR and CDKN polymorphism from normal and tumor tissue; determination of ERCC1, PTEN and TS protein expression in tumor tissue; epigenetic candidates; further exploratory studies such as miRNA analysis as approved by the AIO review board

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Cohort I: Histologically confirmed and definitively inoperable or irresectable metastatic colorectal cancer. Focus on patients with large tumor load at metastatic sites and/or symptomatic metastatic disease
Cohort II: Chance of secondary resection with curative intent defined and reviewed by expert panel
Adult patients (≥ 18 years of age)
RAS wild-type tested in
KRAS exon 2 (codons 12/13)
KRAS exon 3 (codons 59/61)
KRAS exon 4 (codons 117/146)
NRAS exon 2 (codons 12/13)
NRAS exon 3 (codons 59/61)
NRAS exon 4 (codons 117/146) assessed by an institution participating in and certified by the specific working group of the Deutsche Gesellschaft für Pathologie)
At least one measurable lesion according to RECIST measured within 3 weeks prior to registration
No previous chemotherapy for metastatic disease (adjuvant chemotherapy for non-metastatic disease is allowed if terminated more than 6 months ago)
Performance status ECOG 0-1
Male and female subjects > 18 years of age
Adequate haematological, hepatic, renal and metabolic function parameters:

Leukocytes > 3000/mm³, ANC ≥ 1500/mm3, platelets ≥ 100,000/mm3, Hb > 9g/dl (may be transfused or treated with erythropoietin to maintain or exceed this level)Creatinine clearance ≥ 50 ml/min or serum creatinine ≤ 1.5 x upper limit of normal Bilirubin ≤ 1.5 x upper limit of normal, GOT-GPT ≤ 2.5 x upper limit of normal in absence of liver metastases, or ≤ 5 x upper limit of normal in presence of liver metastases, AP ≤ 5 x upper limit of normal Magnesium ≥ lower limit of normal; calcium ≥ lower limit of normal (may be substituted to maintain or exceed this level)

Negative pregnancy test and willingness to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
Before subject registration, written informed consent must be given according to ICH-GCP, and national/local regulations.

Exclusion Criteria:

Past or current history of malignancies except for the indication under this study and curatively treated:
Basal and squamous cell carcinoma of the skin
In-situ carcinoma of the cervix
Other malignant disease without recurrence after at least 5 years of follow-up
Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
Clinically relevant interstitial lung disease, e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan.
History of evidence upon physical examination of CNS disease unless adequately treated (e.g. primary brain tumour, seizure not controlled with standard medical therapy, brain metastases or history of stroke).
Pre-existing neuropathy > grade 1 (NCI CTCAE), except for loss of tendon reflex
Allogeneic transplantation requiring immunosuppressive therapy.
Severe non-healing wounds, ulcers or bone fractions.
Evidence of bleeding diathesis or coagulopathy.
Patients not receiving therapeutic anticoagulation must have an INR < 1,5 ULN and aPTT < 1,5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of randomisation.
Concomitant therapy with certain anti-viral medicines (sorivudine and brivudine or analogue compounds).
Major surgical procedure, open biopsy, nor significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study except for surgery for colorectal cancer with curative intent and central venous line placement for chemotherapy administration.
Pregnancy or breastfeeding women.
Subjects with known allergy to the study drugs or to any of its excipients.
Known DPD deficiency.
Current or recent (within the 28 days prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
Known grade III/IV allergic reaction against monoclonal antibodies.
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Klinikum Esslingen	Esslingen	Baden-Württemberg	Germany	73730
2	SLK-Kliniken Heilbronn GmbH	Heilbronn	Baden-Württemberg	Germany	74078
3	Ortenau Klinikum	Lahr	Baden-Württemberg	Germany	77933
4	Klinikum Ludwigsburg	Ludwigsburg	Baden-Württemberg	Germany	71640
5	Universitätsklinikum Mannheim	Mannheim	Baden-Württemberg	Germany	68135
6	Klinikum Schwäbisch Gmünd	Mutlangen	Baden-Württemberg	Germany	73557
7	Kreiskliniken Esslingen gGmbH Klinik Nürtingen	Nürtingen	Baden-Württemberg	Germany	72622
8	Schwerpunktpraxis und Tagesklinik Onkologie Hämatologie Gastroenterologie Palliativmedizin Drs. Höring, Respondek, Schwinger, Thunert	Stuttgart	Baden-Württemberg	Germany	70190
9	Universitätsklinikum Ulm Zentrum für Innere Medizin	Ulm	Baden-Württemberg	Germany	89081
10	Klinikum Augsburg	Augsburg	Bayern	Germany	86156
11	Leopoldina-Krankenhaus der Stadt Schweinfurth gGmbH	Schweinfurt	Bayern	Germany	97422
12	Klinikum der J.W. Goethe-Universität Frankfurt	Frankfurt	Hessen	Germany	60590
13	Universitätsklinikum Gießen und Marburg GmbH	Marburg	Hessen	Germany	35043
14	Franziskus Hospital Niels-Stensen-Kliniken Klinik für Internistische Onkologie und Hämatologie	Georgsmarienhütte	Niedersachsen	Germany	49124
15	Marienhospital Osnabrück Niels-Stensen-Kliniken Klinik für Innere Medizin	Osnabrück	Niedersachsen	Germany	49074
16	St. Vincenz-Krankenhaus	Paderborn	Nordrhein-Westfalen	Germany	33098
17	Klinikum Mutterhaus der Borromäerinnen gGmbH	Trier	Rheinland-Pfalz	Germany	54290
18	Universitätsklinikum Halle	Halle	Sachsen-Anhalt	Germany	6120
19	Universitätsklinikum Jena	Jena	Thüringen	Germany	7740