Vectibix for the Treatment of Anal Cancer (VITAL)

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

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

Study Overview

• Status: Completed
• Conditions: Anal Squamous Cell Carcinoma
• Intervention / Treatment: Drug: panitumumab, mytomicin C, 5-FU, radiation

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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • A Coruña, Spain, 15009
    • Centro Oncológico de Galicia
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 08036
    • Hospital Clinic I Provincial
  • Barcelona, Spain, 08041
    • Hospital Santa Creu i Sant Pau
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall Hebron
  • León, Spain, 24071
    • Hospital Virgen Blanca
  • Madrid, Spain, 28040
    • Fundación Jiménez Díaz
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28009
    • Hospital Universitario Gregorio Marañón
  • Málaga, Spain, 29010
    • Hospital Virgen de la Victoria
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Valencia, Spain, 46009
    • Instituto Valenciano de Oncología
  • Valencia, Spain, 46014
    • Hospital General de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitario Germans Trias i Pujol. Institut Català Oncologia
    • Sabadell, Barcelona, Spain, 08208
      • Corporacio Sanitaria Parc Tauli
  • Madrid
    • San Sebastian de los Reyes, Madrid, Spain, 28702
      • Hospital Infanta Sofia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Panitumumab, mytomicin C, 5-FU, radiation

Drug: panitumumab, mytomicin C, 5-FU, radiation; Radiation therapy will be administered concurrent with chemotherapy and Panitumumab treatment. It will start the day 1 of the systemic treatment. That is, the first day of radiation therapy will be the day of the administration of the first dose of Panitumumab and Mitomycin C, as well as the first day of the first 96-hours course of 5-FU continuous infusion. On day 1, drugs and radiation will be administered in the following order: First, Panitumumab. Panitumumab will be administered by IV infusion on day 1, and every 2 weeks during 8 weeks; Then Mitomycin C, 10mg/m2 on days 1 and 29; Then start the 5-FU continuous infusion, 1000mg/m2 on days 1-4 and 29-32; Finally, no less than 2 hours after the start of the 5-FU infusion, first dose of radiation therapy.; Other Names: Vectibix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Three-year disease-free survival rate	To estimate the three-year disease-free survival rate in patients treated with 5-FU, mytomicin C and Panitumumab concurrently with radiation therapy as treatment for anal squamous cell carcinoma	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival rate	To assess disease free survival in patients treated with 5-FU, Mytomicin C and Panitumumab concurrently with radiation therapy as treatment for anal squamous cell carcinoma.	3 years
Three-year free local-regional failure rate	To assess three-year free local-regional failure rate in patients treated with 5-FU, Mytomicin C and Panitumumab concurrently with radiation therapy as treatment for anal squamous cell carcinoma.	3 years
Overall survival	To assess overall survival in patients treated with 5-FU, Mytomicin C and Panitumumab concurrently with radiation therapy as treatment for anal squamous cell carcinoma.	3 years
Colostomy-free survival rate	To assess two-year colostomy-free survival rate in patients treated with 5-FU, Mytomicin C and Panitumumab concurrently with radiation therapy as treatment for anal squamous cell carcinoma.	2 years
Complete response rate	To assess complete response rate in patients treated with 5-FU, Mytomicin C and Panitumumab concurrently with radiation therapy as treatment for anal squamous cell carcinoma.	3 years
Safety profile	Incidence of adverse events (including all serious, grade 3, grade 4, and treatment related events); Changes in laboratory values.	3 years
Predictive potential of different biomarkers	To investigate the predictive potential of different biomarkers involved in different pathways on efficacy and/or safety endpoints:EGFR pathwayDNA reparation mechanisms and apoptosis controlOxidative stress control mechanismResistance mechanisms to alkylants (mitomycin C) and antimetabolits (5-FU); To describe the presence of HPV infection, isotype study and impact of the status on efficacy and/or safety.; To evaluate the role of magnetic resonance imaging (MRI) in the determination of therapeutic efficacy and follow-up of these patients.	3 years

Collaborators and Investigators

• Sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
• Collaborators: Amgen; Trial Form Support S.L.
• Investigators: Study Director: Jaime Feliu, MD, Hospital Universitario La Paz; Principal Investigator: Vicente Alonso, MD, Hospital Miguel Servet; Principal Investigator: Jaume Capdevila, MD, Hospital Universitario Vall Hebron; Principal Investigator: Miriam Lopez, MD, Hospital Infanta Sofia; Principal Investigator: Carmen Castañon, MD, Hospital Virgen Blanca (León); Principal Investigator: Carlos Fernández-Martos, MD, Instituto Valenciano de Oncología; Principal Investigator: Carlos García Girón, MD, Hospital General Yagüe (Burgos); Principal Investigator: Ana León, MD, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Principal Investigator: Juan Carlos Méndez, MD, Centro Oncológico de Galicia; Principal Investigator: Rocío García Carbonero, MD, Hospital Universitario Virgen del Rocío (Sevilla); Principal Investigator: Jordi Remon, MD, Hospital de Mataró; Principal Investigator: Fernando Rivera, MD, Hospital Universitario Marqués de Valdecilla (Santander); Principal Investigator: Laura Cerezo, MD, Hospital Universitario La Princesa (Madrid); Principal Investigator: Pilar García-Alfonso, MD, Hospital Universitario Gregorio Marañón (Madrid); Principal Investigator: Emilio Fonseca, MD, University of Salamanca; Principal Investigator: Aleydis Pisa, MD, Corporació Sanitaria Parc Taulí (Sabadell, Barcelona); Principal Investigator: Mónica Caro, MD, Institut Català d´Oncologia. Hospital Germans Trias i Pujol (Badalona); Principal Investigator: José María Vicent, MD, Hospital de Manises, Valencia; Principal Investigator: Isabel Sevilla, MD, Hospital Universitario Virgen de la Victoria (Málaga); Principal Investigator: I Guasch, MD, Hospital Sant Joan de Déu; Principal Investigator: Jesus Garcia-Foncillas, MD, Clinica Universidad de Navarra; Principal Investigator: Antonio Arrivi, MD, Hospital Son Llatzer

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2010
• Primary Completion (ACTUAL): March 24, 2017
• Study Completion (ACTUAL): March 24, 2017

Study Registration Dates

• First Submitted: January 20, 2011
• First Submitted That Met QC Criteria: January 27, 2011
• First Posted (ESTIMATE): January 28, 2011

Study Record Updates

• Last Update Posted (ACTUAL): May 16, 2018
• Last Update Submitted That Met QC Criteria: May 11, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: chemoradiation; panitumumab; anal cancer; Anal squamous cell carcinoma; GEMCAD-09-02
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms, Squamous Cell; Rectal Neoplasms; Anus Diseases; Carcinoma; Carcinoma, Squamous Cell; Anus Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Panitumumab
• Other Study ID Numbers: GEMCAD-0902