Phase II Study of Concomitant Intensity-modulated Radiotherapy Combined to Capecitabine, Mitomycin and Panitumumab in Patients With Stage II-IIIB Squamous-cell Carcinoma of the Anal Canal

There is increasing evidence of a role of EGFR, treatment with EGFR-inhibitors in anal cancer and synergies of EGFR-inhibitors with radiotherapy. Addition of the human anti-EGFR antibody Panitumumab to chemoradiotherapy seems therefore solidly justified. This trial investigates concurrent panitumumab/capecitabine/mitomycin concurrent to IMRT-radiotherapy. Treatment components used in this study have been selected on scientific rationale. The trial regimen should be feasible with acceptable toxicity and outcome similar to historic series.

OBJECTIVES:

Primary:

-To assess efficacy of treatment regimen composed of capecitabine, mitomycin, panitumumab, and radiotherapy in terms of locoregional control rate in patients with stage II-IIIB squamous-cell carcinoma of the anal canal.

Secondary:

* To further assess efficacy of this regimen based on complete response (CR) rate, colostomy-free survival, functional colostomy-free survival, overall survival (OS), and progression-free survival (PFS).
* To assess the tolerability and safety profile of this regimen.
* To assess the role of PET for staging and outcome prediction (for those patients who had PET following local standards).

Eligibility Criteria:
Inclusion Criteria:

* Histologically/pathologically confirmed squamous-cell carcinoma of the anal canal
* Stage II-IIIB (T2-4, N any, M0) disease
* Previously untreated disease
* Age ≥ 18 years at time of consent
* Life expectancy of at least 2 years
* ECOG performance status (PS) of 0 to 1
* Adequate bone marrow, liver and renal functions as assessed by the following laboratory requirements to be conducted within 14 days prior to registration.

  * Hemoglobin ≥ 90 g/l without transfusion requirement in the prior 4 weeks
  * Absolute neutrophil count (ANC) ≥1.5 x 109/L
  * Platelet count ≥ 100 x 109/L
  * Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
  * ALT and AST ≤ 2.5 x ULN
  * Alkaline phosphatase \< 4 x ULN
  * PT/PTT \< 1.5 x ULN (patients who receive anticoagulation treatment with an agent such as warfarin or heparin will be allowed to participate; for patients on warfarin, close monitoring of at least weekly evaluations will be performed until INR is stable based on a measurement at predose, as defined by the local standard of care.
  * Serum creatinine clearance ≤ 1.5 x ULN (≥ 60 ml/min calculated using the Cockcroft-Gault formula)
* Patients with stable HIV infection (i.e. undetectable viral load over the past 6 months while on HIV treatment and with CD4 count \> 200 /ml) can be included.
* Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations

Exclusion Criteria:

* Prior treatment with capecitabine or mitomycin
* Prior or concurrent chemotherapy, or any antitumoral hormonal therapy
* Prior treatment with panitumumab or other EGFR inhibitors
* Prior biologic therapy or immunotherapy, e.g. anti-TNF treatment etc.
* Less than 24 hours since prior granulocyte colony-stimulating factors
* Any other concurrent anticancer therapy, including experimental medications
* Receipt of any investigational agent within 4 weeks of study registration
* Concurrent alternative medicine, vitamin supplements unless approved by the investigator
* Prior radiation therapy to the pelvis
* Prior surgery for anal canal cancer except biopsy
* Evidence of metastatic disease
* Prior or concurrent malignancy other than the study disease unless treated with curative intent and with no evidence of disease
* Any of the following within 6 months prior to study drug administration: severe/ unstable angina (symptoms at rest), new onset angina (began within the last 3 months) or myocardial infarction, congestive heart failure, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
* Known active Hepatitis B or C
* Active clinically serious infection \> NCI-CTCAE v4.0 grade 3
* Known or suspected allergy to panitumumab or any agent given in the course of this trial
* Any condition that impairs patient's ability to swallow whole pills
* Symptomatic pulmonary fibrosis
* History of collagen vascular disease
* Other severe, acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study
* Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate contraception during the course of the trial and three months after the completion of trial
* 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 patient before registration in the trial