The purpose of this study is to evaluate the efficacy and safety of Cetuximab in metastatic penile carcinoma
Penile carcinoma is a rare cancer type, particularly in our industrialized countries. Incidence is not well established but is estimated around 26000 annual new cases all around the world \[1\]. We don't have accurate estimation for France but regarding data from the literature, incidence rates in developed countries vary from 0.7 to 1.0/100000 men \[2\]. The mean age at diagnosis is about 60 years \[3\]. Different causes have been identified like history of Human PapillomaVirus (essentially HPV16), phymosis, absence of circumcision, tobacco use, and history of condyloma \[1\]. In addition, a lot of molecular genetic alterations are also responsible for penile cancer occurrence and development \[4\]. Histologically, most of these tumors are epidermoid cancers. Tumor spreads into inguinal lymphnodes, then into pelvic lymphnodes. Then retroperitoneal lymphnodes are involves before metastatic dissemination, often in lungs, liver and bones. According to the French urology recommendations, treatment of localized penis cancer should be conservative, as far as possible \[5\]; Even if local recurrences rate varies from 15% to 30% of patients, no reduction of overall survival is observed in these patients \[7\]. The investigations regarding involvement of inguinal lymphnodes and distant organs are a key-point. Among the 10% of patients with loco regional recurrence \[6\], lymphadenectomy should be preferred to chemotherapy which should be recommended for metastatic patients or unresectable patients with regional lymphnodes involvement \[5\]. Numbers of treatments (monotherapy or associations) have been tested in penis cancer but the rarity of these tumors is a major obstacle to clinical research, due to small samples of patients. The best results seem to be obtained with platinum-based treatments (ORR up to 32.5% with a combination of cisplatin, methotrexate and bleomycine) \[8\] \[9\], but even if response rates are very promising, overall survival is still very short (median OS = 28 weeks) and treatment-related toxicities can be very important, even lethal \[9\]. The histological type of squamous cells carcinoma, which is the large majority of penile cancer, led Pagliaro et al. \[10\] to explore a combination of Paclitaxel, Ifosfamide and Cisplatin (TIP) as neoadjuvant treatment of locally advanced penile tumors. This association of chemotherapy agents had previously proven its efficacy in squamous cell carcinoma of the head and neck. Even if this study included a small number of patients (N=30) with penile carcinoma, it showed very promising results on primary objective (objective response rate = 50% with 10% of complete responses). Despite these results and all previous researches, no chemotherapy agent has been submitted to health authority's approval in France. It results that there is no market approval for treatment of metastatic penile carcinoma. However, based on the results of Pagliaro et al., the TIP is now considered by the French physicians as the recommended standard of care for patients with metastatic penile carcinoma \[5\]. From a biological point of view, Epidermal Growth Factor Receptor (EGFR) and K-ras status have been widely explored in the past few years in penile carcinoma. EGFR seem to present high expression levels in such tumors, whatever the stage of disease. Among 17 patients studied by Lavens et al., expression of EGFR was 3+ (which is the highest grade of expression) in 14 cases and 2+ in 3 cases \[11\]. Andersson et al. analyzed 28 penis tumors and found a somatic mutation in 39% (n=11). Mutations have been detected in the following genes: PIK3CA (29%), HRAS (7%) and K-ras (3%) \[12\]. Dorff et al. studied EGFR expression and K-ras status in 28 other penile carcinomas. They noted an over expression of EGFR in all the samples but didn't find any K-ras mutation \[13\] while Valverde et al. found 22% of K-ras muted carcinomas (N=28) \[14\]. When present, K-ras mutations have been identified on exon 2 (codons 12 and 13) but rarely on exon 3 (codon 61). Mutational status can be easily explored by Polymerase Chain Reaction amplification. EGFR expression seems to be correlated with differentiation grade while K-ras mutation seems to be correlated to the stage of disease \[13\] \[14\]. Cetuximab is a human/mouse chimeric monoclonal antibody. It has a specific and competitive binding to the extracellular domain of EGFR, leading to inactivation of self-phosphorylation of the receptor and inhibition of all the following intracellular signal chains. This has an antiproliferative effect on cancer cells, inhibits angiogenesis, reduces cells mobility and restores apoptosis. Cetuximab has been widely studied in cancers with overexpression of Epidermal Growth Factor Receptors (EGFR), in particular in squamous cancers of head and neck \[15\], colorectal \[16\] and lung cancers \[17\]. Phases I studies showed that a dose in the range of 200mg/m² to 400mg/m² led to a good EGF receptor saturation \[18\]. Association of Cetuximab and radiation therapy showed an improvement on overall survival in patients with locally advanced head and neck cancers (median overall survival = 49 months versus 29 months in the radiotherapy-alone group) \[19\]. Cetuximab has also been associated to platinum-based chemotherapies (Cisplatin or Carboplatin) and 5-Fluorouracile in patients with head and neck cancer. Median overall survival was significantly better on the group of patients with Cetuximab (10.1 months vs 7.4 months; p=0.04). However, 82% of patients with Cetuximab experienced Commom Terminology Criteria for Adverse Event (CTCAE) grade 3/4 toxicities versus 76% in the other group \[20\]. Adverse events commonly noted with Cetuximab are cutaneous events, hypomagnesaemia, infection and grade 3/4 anorexia. Cetuximab has also been studied as monotherapy in head and neck patients with responses rate of 13% and disease control rate of 46%. Cutaneous events were still the main toxicities \[21\]. One preliminary experience has been conducted in a patient with penile carcinoma, treated with an association of a taxane (Docetaxel) and Cetuximab. This treatment led to imaging and clinical signs of efficacy (decrease of 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (18-FDG) uptake, necrosis of metastatic mass, improvement of pain and performance status). The tolerance profile has been characterized by neutropenia and mild skin toxicity \[22\]. Another key-point is that the efficacy of Cetuximab is closely related to the presence of mutation on the gene coding for K-ras. Van Cutsem et al. showed that patients with wild-type K-ras colorectal cancers are much better responders to Cetuximab than patients with mutation \[23\]. K-ras mutation leads to a constitutive activation of the Ras pathway independently and can bypass the EGFR-driven signaling cascade and impair the clinical efficacy of EGFR. K-ras status should always be determined before Cetuximab initiation and it would be interesting to know EGFR expression rates in order to correlate with responses to Cetuximab. Finally, immunogenicity is a class effect of monoclonal chimeric antibodies; the incidence of Human Anti-Chimeric Antibodies (HACA) formation has been observed around 3.7% of patients treated with cetuximab. However, no apparent effect on the safety or antitumor activity of cetuximab has been observed in these patients \[Summary of Product Characteristics of Cetuximab\]. Given the fact that, * the association of Paclitaxel, Ifosfamide and Cisplatin is efficient for the treatment of metastatic penile carcinoma and considered as the new "standard" of care in France, * squamous cell carcinoma of the penis expresses EGF receptor, * cetuximab has anti-tumor properties in EGF mediated cancers, * response rates to cetuximab is much better in patient with wild-type K-ras, We postulate that: \- the combination of Paclitaxel, Ifosfamide, Cisplatin with Cetuximab, will enable to provide a better Objective Response Rate (ORR) than the same combination used without Cetuximab. As promising results obtained by Pagliaro are not resulting from a comparative phase III with a reference treatment, it cannot be considered as a validated new standard of care. The proposed Phase 2 study will explore the optimal way to treat patients with metastatic penile carcinoma between two experimental schemes using a Simon's selection "pick the winner" randomized design.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Cetuximab treatment will be administered on specific days within a 21-days-cycle and for a maximum of 6 cycles as follow : CETUXIMAB I.V infusion of 400 mg/m2 on cycle 1 Day 0 for 2 hours, then 250 mg/m2 for subsequent infusions for 1 hour on Day 8, Day 15 and next cycles Day1, Day8, Day15. In case of documented toxicities, 2 drugs doses reductions are allowed according specific algorithms indicated in protocol
The TIP combination of treatments will be administered on specific days within a 21-days-cycle and for a maximum of 6 cycles as follow : PACLITAXEL I.V infusion of 175 mg/m2, for 3 hours, on Day 1 of the cycle. IFOSFAMIDE I.V infusion of 1200 mg/m2, for 2 hours, on Day 1, Day 2, Day 3 of the cycle. CISPLATINE I.V infusion of 25 mg/m2, for 1 hour, on Day 1, Day 2, Day 3. In case of documented toxicities, 2 drugs doses reductions are allowed according specific algorithms indicated in protocol
CHRU Strasbourg
Strasbourg, Bas Rhin, France
Institut Paoli Calmettes
Marseille, Bouches du Rhône, France
Institut Bergonié
Bordeaux, Gironde, France
Institut Claudius Regaud
Toulouse, Haute Garonne, France
Evaluation of the antitumor activity of Cetuximab treatment in terms of Objective Response Rate (ORR) at the end of treatment
Patients will be treated by TIP +/- Cetuximab for 1 cycle of 21 days. Subsequent treatment cycles will be performed only if patients meet correct biological analyses as defined by protocol, with a maximum of 5 more cycles of 21 days. Thus, the treatment duration will vary between patients from 3 weeks to 18 weeks. The treatment efficacy will be evaluated 28 days after the day 1 of the last cycle administered. Thus ORR will be evaluated between 4 weeks to 20 weeks after randomization, according to the amount of administered cycles. ORR is defined as the proportion of patients with best response consisting in a Complete Response (CR) or a Partial Response (PR) from the date of randomization to the date of the end of treatment visit (i.e 6 cycles of treatment as maximum) evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time frame: 4 weeks after the day 1 of the last cycle administered (i.e between 4 weeks to 20 weeks after randomization, according to the amount of administered cycles)
Evaluation of the Safety Profile of Cetuximab treatment
Safety profile is assessed throughout the study by incidence and intensity of Adverse Events displayed by patients using the CTCAE version 4.0
Time frame: From patient randomization up to the end of study i.e 28 months maximum after first patient inclusion
Evaluation of the antitumor activity of Cetuximab treatment in terms of Overall Survival (OS) at the end of the study
OS is defined as the time from the date of randomization to the date of death due to any cause. If a patient is not known to have died at the time of the analysis, OS will be censored at the date of last contact.
Time frame: From patient randomization up to the end of study i.e 28 months maximum after first patient inclusion
Evaluation of the antitumor activity of Cetuximab treatment in terms of Progression-Free Survival (PFS) at the end of the study
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Centre Léon Bérard
Lyon, Rhône, France
Institut Curie
Paris, Île-de-France Region, France
APHP Hôpital Saint Louis
Paris, Île-de-France Region, France
PFS is defined as the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event at the time of the analysis, PFS will be censored at the date of last adequate tumor assessment.
Time frame: From patient randomization up to the end of study i.e 28 months maximum after first patient inclusion
Evaluation of Quality of Life during the Cetuximab treatment
Quality of life is assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30. It will be evaluated at Screening, at the beginning of cycle 4, and at the end of treatment i.e after 6 cycles maximum
Time frame: From patient randomization up to the end of treatment (i.e between 4 weeks to 20 weeks after randomization, according to the amount of administered cycles)