Clinical trial NCT01328171: FOLFOXIRI With or Without Panitumumab in Metastatic Colorectal Cancer (VOLFI)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Lead sponsor: AIO-Studien-gGmbH
Sponsor class: OTHER
Collaborators: name: Amgen
name: ClinAssess GmbH
First posted: 2011-04-04
Enrollment: 93
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: overall response rate
timeFrame: up to about 6 month
Secondary outcomes:
measure: overall response rate in each cohort
timeFrame: up to about 6 month
measure: secondary resection rate with curative intent for patients cohort I
timeFrame: up to about 6 month
measure: pathological response in liver surgery specimen
timeFrame: up to about 6 month
measure: disease control rate
timeFrame: up to about 6 month
measure: progression free survival
timeFrame: 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
measure: duration of response
timeFrame: 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
measure: time to response
timeFrame: up to about 6 month
measure: overall survival
timeFrame: From date of randomization until the date of death from any cause assessed up to 4 years
measure: time to recurrence (cohort II in case of secondary resection)
timeFrame: up to 4 years
measure: toxicity and feasibility
timeFrame: up to about 6 month
measure: liver toxicity for resected patients (central histological review); biopsies should be obtained for all patients pre-treatment
timeFrame: up to 1 year
measure: QL (QLQ C30)
timeFrame: Pre-treatment, before start of every 3rd cycle and at the end of treatment
measure: translational research (EGFR genetics and proteomics): prognostic and predictive impact on efficacy outcomes
timeFrame: up to 4 years
Other outcomes:
Locations:
city: Esslingen
country: Germany
facility: Klinikum Esslingen
state: Baden-Württemberg
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH
state: Baden-Württemberg
city: Lahr
country: Germany
facility: Ortenau Klinikum
state: Baden-Württemberg
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
state: Baden-Württemberg
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim
state: Baden-Württemberg
city: Mutlangen
country: Germany
facility: Klinikum Schwäbisch Gmünd
state: Baden-Württemberg
city: Nürtingen
country: Germany
facility: Kreiskliniken Esslingen gGmbH Klinik Nürtingen
state: Baden-Württemberg
city: Stuttgart
country: Germany
facility: Schwerpunktpraxis und Tagesklinik Onkologie Hämatologie Gastroenterologie Palliativmedizin Drs. Höring, Respondek, Schwinger, Thunert
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Zentrum für Innere Medizin
state: Baden-Württemberg
city: Augsburg
country: Germany
facility: Klinikum Augsburg
state: Bayern
city: Schweinfurt
country: Germany
facility: Leopoldina-Krankenhaus der Stadt Schweinfurth gGmbH
state: Bayern
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe-Universität Frankfurt
state: Hessen
city: Marburg
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH
state: Hessen
city: Georgsmarienhütte
country: Germany
facility: Franziskus Hospital Niels-Stensen-Kliniken Klinik für Internistische Onkologie und Hämatologie
state: Niedersachsen
city: Osnabrück
country: Germany
facility: Marienhospital Osnabrück Niels-Stensen-Kliniken Klinik für Innere Medizin
state: Niedersachsen
city: Paderborn
country: Germany
facility: St. Vincenz-Krankenhaus
state: Nordrhein-Westfalen
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH
state: Rheinland-Pfalz
city: Halle
country: Germany
facility: Universitätsklinikum Halle
state: Sachsen-Anhalt
city: Jena
country: Germany
facility: Universitätsklinikum Jena
state: Thüringen
Study officials:
affiliation: Department of Oncology and Gastroenterology, Academic Teaching Hospital Esslingen
name: Michael Geißler, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschutz A, Wessendorf S, Ettrich T, Kanzler S, Norenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. doi: 10.1200/JCO.19.01340. Epub 2019 Oct 14.