Efficacy and Safety of Cetuximab in Metastatic Penile Carcinoma (PENILANE)

INCLUSION CRITERIA :

* Male older than 18 years-old,
* Squamous cell carcinoma of the penis of clinical stages N3 and/or M1,
* Central Histological confirmation of diagnosis of wild-type K-ras penis cancer (histological documentation of the mutational status prior to each patient's registration).

Nota Bene: an archival tumor sample must be available.

* At least one measurable lesion according to the RECIST version 1.1. In case of relapsing patient, documented progression as per RECIST version 1.1,
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2,
* Life expectancy ≥ 6 months,
* Adequate organs functions defined as the following (transfusion is not allowed within 7 days prior to lab test performed to assess the eligibility):

  * Hemoglobin ≥ 9 mg/dL,
  * Absolute Neutrophils Count ≥ 1,5 Gi/l,
  * Platelets ≥ 100 Gi/l,
  * Creatinine ≤ 1,5 x Upper Limit of Normal (ULN) and Creatinine clearance ≥ 60 ml/min (calculated with Cockcroft formula or Modification of Diet in Renal Disease (MDRD) formula for patients older than 65 years old)
  * Aspartate aminotransferase (ASAT) and Alanine aminotransferase (ALAT) ≤ 2,5 x ULN (≤ 5 x ULN in presence of liver metastasis)
  * Total bilirubin ≤ 1,5 x ULN,
* Willingness to use effective contraceptive method during the whole treatment period and up to 4 months after the last study drug administration,
* Affiliated to the French social security system,
* Subjects must provide written informed consent prior to perform any study-specific procedures or assessments and must be willing to comply with treatment and follow up.

EXCLUSION CRITERIA :

* Symptomatic metastases of Central nervous system (CNS) requiring or having required steroids or enzyme-inducing anticonvulsants within 4 weeks before inclusion,
* Previous treatment with paclitaxel, or ifosfamide, or cetuximab, or any monoclonal antibody, and or any drug targeting EGF Receptor,
* Local and/or resectable disease,
* Prior history of other malignancies other than penis cancer (except for basal cell or squamous cell carcinoma of the skin and superficial bladder carcinoma) unless the subject has been free of the disease for at least 3 years,
* No resolution of specific toxicities related to any prior anti-cancer therapy to Grade ≤1 according to the CTCAE v.4.0 (except lymphopenia and alopecia),
* Active peripheral or motor neuropathy of any CTCAE grade and due to any cause,
* Known hypersensitivity or allergy or contraindication to at least one of the study drugs
* In case of previous chemotherapy, wash out period of less than 5 half-lives of treatment before study entry,
* Clinically significant cardiovascular disease including:

  * Myocardial infarction within 3 months,
  * Congestive heart failure of the New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening Left Ventricular Ejection Fraction (LVEF) assessment ≥ 45%,
  * Prolonged QT interval defined as screening corrected QT interval (QTc) \> 470 ms (Fridericia correction formula),
  * History of clinically significant ventricular arrhythmia (e.g., ventricular tachycardia, ventricular fibrillation, ...),
  * History of Mobitz II 2nd degree or 3rd degree heart block without a permanent pacemaker in place,
  * Hypotension (systolic BP \< 86 mmHg) or bradycardia with a heart rate \< 50 bpm,
  * Uncontrolled hypertension as indicated by a resting systolic BP \> 170 mmHg or diastolic BP \> 105 mmHg despite an optimal treatment,
* Major surgery or radiation therapy within 4 weeks prior first study drug administration or already planned during the study,
* Any pulmonary, thyroid, renal, hepatic severe/uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol,
* Active uncontrolled viral, fungal or bacterial infection,
* Patient who cannot abstain from vaccine against yellow fever, prophylactic use of phenytoin or derivate, or any drug which can strongly interfere with the sub-units 2C8 and/or 3A4 of the cytochrome P450 (Cf. appendix 5) Nota Bene: in case of poor interference with these sub-units, treatments with a narrow therapeutic index should be avoided.
* Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements (participants must agree to refrain from substance abuse use during the entire course of the study),
* Concomitant participation to another clinical trial with active agent during the study (concomitant non interventional study will be allowed).