A Phase 2 Clinical Study to Assess Efficacy of Induction Carboplatin/Paclitaxel + Pembrolizumab for Locoregionally Advanced Penile Cancer: PRIAM
Overview
- Phase
- Phase 2
- Intervention
- Carboplatin/Paclitaxel
- Conditions
- Urologic Neoplasms
- Sponsor
- The Netherlands Cancer Institute
- Enrollment
- 27
- Locations
- 2
- Primary Endpoint
- Pathological complete response (pCR)
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
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
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
- •Histologically confirmed diagnosis of squamous cell carcinoma of the penis.
- •Patients have one of the following disease stages:
- •cTxN2-3 or
- •cTxN1 in case of central nodal necrosis and/or an irregular nodal border, or node \>3cm, or
- •Inguinal or pelvic lymph node recurrence that is potentially resectable. Any of the disease stages above, in combination with oligometastatic disease with a maximum of 2 distant metastases is allowed, as long as these metastases can be treated by resection or radiotherapy. This should be established in the multidisciplinary tumor board before enrolment.
- •Archival tumor tissue sample or newly obtained \[core, incisional or excisional\] biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
- •A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Evaluation of ECOG is to be performed within 14 days prior to the first dose of study intervention.
Exclusion Criteria
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
- •Has received prior systemic anti-cancer therapy including investigational agents, or an investigational device, within 4 weeks prior to registration.
- •Has received prior radiotherapy within 4 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids.
- •Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- •Known additional malignancy that is progressing or has required active treatment within the past 3 years.
- •Exceptions: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
- •Has known active or treated CNS metastases and/or carcinomatous meningitis.
- •Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- •Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid). Patients with vitiligo, psoriasis or other mild skin disease can still be included.
Arms & Interventions
Induction chemo-immunotherapy combination followed by consolidative surgical resection
Patients receive three cycles of induction carboplatin+paclitaxel on days 1, 22 and 43, with two concurrent cycles of fixed-dose pembrolizumab on days 1 and 43. Within 3-9 weeks after the last cycle of induction chemo-immunotherapy, patients undergo complete resection of remaining tumor tissue. Patients start subsequent adjuvant immunotherapy with fixed-dose pembrolizumab for up to seven 6-week cycles between 3-9 weeks after surgery.
Intervention: Carboplatin/Paclitaxel
Induction chemo-immunotherapy combination followed by consolidative surgical resection
Patients receive three cycles of induction carboplatin+paclitaxel on days 1, 22 and 43, with two concurrent cycles of fixed-dose pembrolizumab on days 1 and 43. Within 3-9 weeks after the last cycle of induction chemo-immunotherapy, patients undergo complete resection of remaining tumor tissue. Patients start subsequent adjuvant immunotherapy with fixed-dose pembrolizumab for up to seven 6-week cycles between 3-9 weeks after surgery.
Intervention: Pembrolizumab
Induction chemo-immunotherapy combination followed by consolidative surgical resection
Patients receive three cycles of induction carboplatin+paclitaxel on days 1, 22 and 43, with two concurrent cycles of fixed-dose pembrolizumab on days 1 and 43. Within 3-9 weeks after the last cycle of induction chemo-immunotherapy, patients undergo complete resection of remaining tumor tissue. Patients start subsequent adjuvant immunotherapy with fixed-dose pembrolizumab for up to seven 6-week cycles between 3-9 weeks after surgery.
Intervention: Partial or total penectomy with inguinal and/or pelvic lymph node dissection
Outcomes
Primary Outcomes
Pathological complete response (pCR)
Time Frame: Immediately after surgery
Pathological complete response defined as pT0N0 in all evaluable patients
Secondary Outcomes
- Drug toxicity(Drug-related serious adverse events will be noted from day of registration until 90 days after the last protocol treatment/administration.)
- Overall survival (OS)(Through study completion, at a minimum of 24 months)
- Tumor tissue PD-L1 expression in relation to treatment response(12 weeks after last patient first visit)
- Evaluation of changes in patient reported outcome regarding Quality of Life (QoL)(From screening until end of treatment visit (30 days after last adjuvant treatment))
- Progression-free survival (PFS)(Through study completion, at a minimum of 24 months)
- Tumor tissue HPV status in relation to treatment response(12 weeks after last patient first visit)
- Assessment of correlation between clinical endpoints and tumor characteristics(Tumor tissue will be collected at baseline and during resection procedure. Clinical endpoints of pCR, PFS and OS will be determined as mentioned above)