Clinical trial NCT01285778: Vectibix for the Treatment of Anal Cancer
Official title: Phase 2 Trial to Assess the Efficacy and Safety of Chemoradiation With 5-fluorouracil, Mytomicin C and Panitumumab as a Treatment for Anal Squamous Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anal Squamous Cell Carcinoma
Keywords: Anal squamous cell carcinoma
panitumumab
chemoradiation
anal cancer
GEMCAD-09-02
Lead sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
Sponsor class: OTHER
Collaborators: name: Amgen
name: Trial Form Support S.L.
First posted: 2011-01-28
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Chemoradiation with 5-FU and Mitomycin C is the standard treatment in anal canal SCC. Panitumumab has shown efficacy in other tumors and anti-EGFR treatment has shown clinical activity in a single report of a refractory anal canal SCC patient. Based on this background, we propose to conduct a phase II study to investigate the efficacy and toxicity of radiotherapy with the association:

* 5-FU 1000mg/m2 on days 1-4 and 29-32
* Mitomycin C 10mg/m2 on days 1 and 29
* Panitumumab 6 mg/kg on day 1, then every 2 weeks for 8 weeks

Detailed description: In the 1980s, the treatment of choice for anal cancer was abdominal-perineal amputation, which included the removal of the anus, rectum and lymphatic drainage areas and a permanent colostomy. With this treatment, 5-year survival rates were 40-70%. In the following years, however, it was shown that anal cancer was a tumor that was sensitive to chemotherapy and radiation, so surgery was not the first choice and was only reserved for resistant cases or relapses. Concomitant chemo and radiotherapy based on the Mitomycin C - 5-FU regimen is currently the standard treatment for localized (except T1N0) and locally advanced cases. This statement is supported by two randomized studies that showed that the administration of chemoradiation with Mitomycin C - 5FU was better than radiation in monotherapy. The trial conducted by the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) randomized 585 patients to receive radiotherapy (45 Gy in 4-5 weeks) or the same radiotherapy regimen coupled with 5-FU (1000 mg/m2 x 4 days or 750 mg/m2 x 5 days), for the first and last week of radiotherapy and Mitomycin C 12 mg/m2 on day 1. The 3-year local failure rate was 39% in the combined arm versus 61% with radiotherapy alone. There were no differences in the 3-year overall survival rate. On the other hand, in the study conducted by EORTC, 110 patients were distributed to receive radiotherapy (45 Gy in 5 weeks, with an overimpression of 15 Gy in the patients with CR and 20 Gy if PR) or radiotherapy plus 5-FU (750 mg/m2 days 1-5 and 29-33) associated to Mitomycin C (15 mg/m2 on day 1). The CR rate was significantly greater in the group treated with chemoradiation (80% vs. 54%). After 5 years of follow-up, there was still an 18% increase in the local control rate in favor of the group treated with chemoradiation.

More recently, the results of a phase II CALGB trial, suggests that the administration of induction treatment with two cycles of cisplatin-5FU (cisplatin 100 mg/m2 on days 1 and 29 and 5FU 1000 mg/m2 days 1-4 and 29-32) followed by chemoradiotherapy with 5-FU and Mitomycin C was very promising, especially in patients with a poor prognosis, with 50% of patients remaining colostomy and disease-free at 48 months. However, in a randomized study by the RTOG group, which included 682 patients, this strategy was compared with the classic concomitant chemoradiation with 5-FU (1000 mg/m2 days 1-4 and 29-32) and Mitomycin C (10 mg/m2 days 1 and 29). No differences in survival were found, but it was also detected that the colostomy rate was greater in the patients treated with the regimen containing Cisplatin (HR, 1.68; 95% CI, 1.07-2.65; P=.02). The authors concluded that induction with cisplatin was not superior to the traditional administration of 5FU-Mitomycin C with RT.

Epidermoid anal cancer is a tumor that often expresses the EGFR receptor. In an initial study with 21 cases, it was reported that there was EGFR expression in all the biopsies. In another study with 38 cases, it was found that 55% of the tumors expressed EGFR. No study has been published, however, which has investigated the efficacy of Panitumumab in this tumor. There is only one report of a refractory case in which cetuximab was administered together with CPT-11 with an excellent response.

Eligibility criteria: Inclusion Criteria:

* Man or woman ≥ 18 years
* Competent to comprehend, sign, and date an IEC-approved informed consent form
* Histologically or cytologically-confirmed anal canal SCC
* T status 2-4 and any N status (pelvic or inguinal) radiologically defined by MRI
* De novo diagnosis of anal canal SCC not previously treated
* ECOG performance status of 0, 1 or 2
* If a subject has prior history of cancer other than anal canal SCC, non-melanoma skin carcinoma, or in situ cervical carcinoma, then the subject should neither have received any treatment nor have shown any signs of active disease within the previous 5 years
* Adequate bone marrow function: neutrophils≥1.5 x109/ L; platelets≥100 x109/ L; hemoglobin≥ 9 g/ dL
* Hepatic function as follows: total bilirubin count ≤ 1.5 x ULN; ALT and AST ≤ 2.5 x ULN
* Calculated creatinine clearance or 24 hour creatinine clearance ≥ 50 mL/ min
* Magnesium≥ lower limit of normal

Exclusion Criteria:

* Metastatic anal canal SCC
* HIV infection (except patients with an undetectable viral load and CD4 cells count \>400/mL which are eligible for the study)
* Known hypersensitivity to any of the study drugs
* Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
* Patients they have received prior systemic therapy or radiotherapy for the treatment of SCC anal carcinoma.
* Prior malignant tumor in the last 5 years, except a history of non-melanoma skin carcinoma, or in situ cervical carcinoma.
* Clinically significant cardiovascular disease, for example myocardial infarction (\< 6 months before treatment start), unstable angina, congestive heart failure, arrhythmia requiring medication, or uncontrolled hypertension
* Known positive test for, hepatitis C virus, chronic active hepatitis B infection
* Any kind of disorder that compromises the ability of the subject to give written informed consent and/or comply with the study procedures
* Any investigational agent within 30 days before enrolment
* Subject who is pregnant or breast feeding
* Surgery (excluding diagnostic biopsy or central venous catheter placement) and/or radiotherapy within 28 days prior to inclusion in the study.
* Woman or man of childbearing potential not consenting to use adequate contraceptive precautions i.e. double barrier contraceptive methods (eg diaphragm plus condom), or abstinence during the course of the study and for 6 months after the last study drug administration for women, and 3 month for men
* Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Primary outcomes:
measure: Three-year disease-free survival rate
timeFrame: 3 years
Secondary outcomes:
measure: Disease free survival rate
timeFrame: 3 years
measure: Three-year free local-regional failure rate
timeFrame: 3 years
measure: Overall survival
timeFrame: 3 years
measure: Colostomy-free survival rate
timeFrame: 2 years
measure: Complete response rate
timeFrame: 3 years
measure: Safety profile
timeFrame: 3 years
measure: Predictive potential of different biomarkers
timeFrame: 3 years
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol. Institut Català Oncologia
state: Barcelona
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
state: Barcelona
city: San Sebastian de los Reyes
country: Spain
facility: Hospital Infanta Sofía
state: Madrid
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: León
country: Spain
facility: Hospital Virgen Blanca
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital General de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Universitario La Paz
name: Jaime Feliu, MD
role: STUDY_DIRECTOR
affiliation: Hospital Miguel Servet
name: Vicente Alonso, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Vall Hebron
name: Jaume Capdevila, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Navarra
name: Ruth Vera, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Infanta Sofia
name: Miriam Lopez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Virgen Blanca (León)
name: Carmen Castañon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Valenciano de Oncología
name: Carlos Fernández-Martos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital del Mar
name: Clara Montagut, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Yagüe (Burgos)
name: Carlos García Girón, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
name: Ana León, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de la Santa Creu i Sant Pau de Barcelona
name: Marta Martín, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro Oncológico de Galicia
name: Juan Carlos Méndez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Virgen del Rocío (Sevilla)
name: Rocío García Carbonero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Mataró
name: Jordi Remon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Marqués de Valdecilla (Santander)
name: Fernando Rivera, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Princesa (Madrid)
name: Laura Cerezo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Gregorio Marañón (Madrid)
name: Pilar García-Alfonso, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Salamanca
name: Emilio Fonseca, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Corporació Sanitaria Parc Taulí (Sabadell, Barcelona)
name: Aleydis Pisa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Català d´Oncologia. Hospital Germans Trias i Pujol (Badalona)
name: Mónica Caro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Manises, Valencia
name: José María Vicent, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Virgen de la Victoria (Málaga)
name: Isabel Sevilla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clinic of Barcelona
name: Joan Maurel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Sant Joan de Deu
name: I Guasch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinica Universidad de Navarra
name: Jesus Garcia-Foncillas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Son Llatzer
name: Antonio Arrivi, MD
role: PRINCIPAL_INVESTIGATOR
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