This is a single-armed, single-centre, non-blinded phase II trial to assess efficacy of induction chemo-immunotherapy for resectable node-positive squamous cell carcinoma of the penis
This is a phase II study in which fifty adult patients with cTxN1-3 locoregionally advanced squamous cell penile cancer (LRAPC), suitable for resection will be included. Patients with recurrence in lymph nodes are suitable for inclusion if they have not received prior systemic treatment. Patients with cN1 are only included in case of central nodal necrosis and/or an irregular nodal border, or node \>3cm on CT. A maximum of 2 supraregional or distant metastases is allowed if local treatment (i.e. irradiation or resection) is feasible. Patients will be treated with three 21-day cycles of induction chemotherapy, carboplatin AUC5 (max 750 mg) and paclitaxel 175 mg/m2, with additional fixed-dose 400mg pembrolizumab on the first and third cycle. Response to induction therapy will be evaluated by CT scan, ca. 2 weeks after the last cycle. Subsequent consolidative treatment will consist of surgical resection of all visible and/or suspected disease. In 3-9 weeks after surgery, patients will enter the adjuvant phase, consisting of 7 cycles of pembrolizumab 400 mg every 6 weeks. Focused physical examination, registration of adverse-events and monitoring of, amongst others, TSH, FT4, liver enzymes via blood tests, is performed at the start of every cycle. End of treatment visit will be set 30 days after receiving the last cycle of pembrolizumab. Disease status will be monitored by CT-scan at 3, 6, 9, 12, 18 and 24 months from resection, after which imaging will follow standard follow-up protocols. QoL will be assessed at 3,6,12, 18 and 24 months using using the EORTC QLQ-C30 questionnaire. Following 24 months after resection subsequent follow-up visits for survival and anti-cancer therapy will be planned every 6 months, until death, withdrawal of consent or the end of the study, whichever occurs first. The primary endpoint is efficacy, defined as pathological complete response (pCR). Secondary endpoints are grade 3-4 toxicity (by CTCAE 5.0), PFS and OS at 2 years after surgery, correlation of clinical endpoints (pCR, PFS, OS) with high-risk HPV (hrHPV) and PD-L1 immunohistochemistry, and quality of life.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Induction: three cycles of intravenous carboplatin AUC5 (max 750 mg) and paclitaxel 175 mg/m2, during cycle 1, 2 and 3 (day 1, 22, 43)
Induction: two cycles of intravenous pembrolizumab 400 mg during cycle 1 and 3 (day 1 and 43) Adjuvant: up to seven cycles of fixed-dose intravenous pembrolizumab 400 mg, on day 1 every 6 weeks within 3-9 weeks after surgery
Resection of part or all of the penis with complete removal of suspect lymphnodes in the inguinal and/or pelvic area
UZ Leuven
Leuven, Belgium
RECRUITINGNKI-AVL
Amsterdam, North Holland, Netherlands
RECRUITINGPathological complete response (pCR)
Pathological complete response defined as pT0N0 in all evaluable patients
Time frame: Immediately after surgery
Drug toxicity
Safety in terms of chemotherapy and immunotherapy-related adverse events of grade 3 or higher according to version 5.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria.
Time frame: Drug-related serious adverse events will be noted from day of registration until 90 days after the last protocol treatment/administration.
Progression-free survival (PFS)
PFS is defined as time from start of therapy until an event. Events include: * Histologically or cytologically established recurrence after surgery * Omission of surgery as a result of progressive disease. * Unequivocal radiological progression. In case of equivocal results, radiological evaluation may continue. When unequivocal progression is established, the event date will be the first tumor assessment where new lesions were noted. * Switch to another systemic therapy. Note: in case a radiologically responding patient refuses surgery and elects other locoregional therapy (e.g. (chemo)radiotherapy), this is not considered a progression event. PFS will be estimated using the Kaplan-Meier method. The median PFS and 95% confidence interval will be reported.
Time frame: Through study completion, at a minimum of 24 months
Overall survival (OS)
OS is defined as the time between the date of enrollment and the date of death. OS will be estimated using the Kaplan-Meier method. The median OS and 95% confidence interval will be reported.
Time frame: Through study completion, at a minimum of 24 months
Assessment of correlation between clinical endpoints and tumor characteristics
Tumor tissue gathered from patients at baseline via biopsy and, in case of non complete response, at surgery will be tested via a comprehensive analysis of the tumor microenvironment (TME) using state of the art multiparameter techniques to determine the TME composition and activation status in responders vs non-responders. Additional analyses on clinical endpoints (i.e. pCR, PFS and OS) will be carried out between patient groups defined by tumor characteristics.
Time frame: Tumor tissue will be collected at baseline and during resection procedure. Clinical endpoints of pCR, PFS and OS will be determined as mentioned above
Tumor tissue HPV status in relation to treatment response
HPV, or human papilloma virus, status of pre-treatment (baseline) tumor tissue will be determined. Tumor tissue will be tested for HPV status (present or not) to determine a possible (prior) infection with a "high-risk" HPV serotype. High-risk meaning a serotype associated with a higher risk for developing neoplasms. High-risk HPV status will be related to pCR, PFS and OS as they are described above. Baseline tumor tissue will be requested from a referring hospital or gathered from each individual patient during screening.
Time frame: 12 weeks after last patient first visit
Tumor tissue PD-L1 expression in relation to treatment response
PD-L1 expression of pre-treatment (baseline) tumor tissue will be determined. PD-L1 tumor proportion score (TPS; 0%-100%) will be assessed via immunohistochemical staining of tumor tissue. PD-L1 TPS ≥50% will be related to pCR, PFS and OS as they are described above. Baseline tumor tissue will be requested from a referring hospital or gathered from each individual patient during screening.
Time frame: 12 weeks after last patient first visit
Evaluation of changes in patient reported outcome regarding Quality of Life (QoL)
QoL will be measured by the European Organization for the Research and Treatement of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in all patients who were registered for the study and started treatment. This questionnaire will be used to evaluate changes from baseline in QoL, with patient-reported QoL scored in various domains on a scale of 0-100.
Time frame: From screening until end of treatment visit (30 days after last adjuvant treatment)
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