International Penile Advanced Cancer Trial (International Rare Cancers Initiative Study)

Study Overview
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Brief Summary
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This is an international phase III trial, with a Bayesian design, incorporating two sequential randomisations. It efficiently examines a series of questions that routinely arise in the sequencing of treatment. The study design has evolved from lengthy international consultation that has enabled us to build consensus over which questions arise from current knowledge and practice. It will enable potential randomisation for the majority of patients with inguinal lymph node metastases and will provide data to inform future clinical decisions. InPACT-neoadjuvant patients are stratified by disease burden as assessed by radiological criteria. Treatment options are then defined according to the disease burden strata. Treatment is allocated by randomisation. Patients may be allocated to one of three initial treatments: A. standard surgery (ILND); B. neoadjuvant chemotherapy followed by standard surgery (ILND); or C. neoadjuvant chemoradiotherapy followed by standard surgery (ILND). After ILND, patients are defined as being at low or high risk of recurrence based on histological interpretation of the ILND specimen. Patients at high risk of relapse are eligible for InPACT-pelvis, where they are randomised to either: P. prophylactic PLND Q. no prophylactic PLND

Official Title
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International Penile Advanced Cancer Trial (International Rare Cancers Initiative Study)

Conditions
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Squamous Cell Carcinoma of the Penis, Usual Type

Intervention / Treatment
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* Procedure: ILND - Inguinal Lymph Node Dissection
* Drug: Paclitaxel
* Drug: Ifosfamide
* Drug: Cisplatin
* Radiation: Intensity modulated radiation treatment (IMRT)
* Procedure: Prophylactic PLND - pelvic lymph node dissection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Measurable disease as determined by RECIST (version 1.1) criteria; Histologically-proven squamous cell carcinoma of the penis, Stage: any T, N1 (i.e. a palpable mobile unilateral inguinal lymph node), M0 or; any T, N2 (i.e. palpable mobile multiple or bilateral inguinal lymph nodes), M0 or; any T, N3 (i.e. fixed inguinal nodal mass or any pelvic lymphadenopathy), M0 Performance Status ECOG 0, 1 or 2. Exclusion Criteria: Pure verrucous carcinoma of the penis, Nonsquamous malignancy of the penis, Squamous carcinoma of the urethra, Stage M1, Previous chemotherapy or chemoradiotherapy, Concurrent malignancy (other than SCC or Basal Cell Carcinoma of non-penile skin) that has required surgical or non-surgical treatment in the last 3 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A - Standard Surgery (ILND)<br>Part of randomisation 1. The total treatment duration (Inguinal Lymph Node Dissection (ILND)) is estimated to be over 1 day for those patients allocated to Arm A - standard surgery. | Procedure: ILND - Inguinal Lymph Node Dissection<br>* Surgery to remove the lymph nodes in the groin near to where the cancer first appeared.<br>|
| Experimental: Arm B - neoadjuvant chemotherapy<br>Part of randomisation 1. Patients will receive up to 4 cycles of Paclitaxel, Ifosfamide, and Cisplatin (TIP). Administration on an outpatient basis: Paclitaxel 175 mg/m2, day 1, Ifosfamide 900 mg/m2, days 2-5, Cisplatin 15 mg/m2, days 1-5 Administration on an inpatient basis: Paclitaxel 175 mg/m2, day 1, Ifosfamide 1200 mg/m2, days 1-3, Cisplatin 25 mg/m2, days 1-3 | Drug: Paclitaxel<br>* Dose 175mg/m2 as part of TIP regimen.<br>* Other names: Taxol;Drug: Ifosfamide<br>* Dose 900mg/m2 as part of TIP regimen.<br>* Other names: Mitoxana;Drug: Cisplatin<br>* Dose 15mg/m2 as part of TIP regimen (neoadjuvant chemotherapy arm) Dose 40mg/m2 for use concurrently with raditotherapy (chemoradiotherapy arm)<br>|
| Experimental: Arm C - neoadjuvant chemoradiotherapy<br>Part of randomisation 1. Radiotherapy dose is 45Gy in 25 fractions over 5 weeks using 6-10 MV photons to all regions. Concurrent cisplatin 40mg/m2 will be given weekly, subject to GFR>45mls/min. | Drug: Cisplatin<br>* Dose 15mg/m2 as part of TIP regimen (neoadjuvant chemotherapy arm) Dose 40mg/m2 for use concurrently with raditotherapy (chemoradiotherapy arm)<br>Radiation: Intensity modulated radiation treatment (IMRT)<br>* Treatment with very high energy X-rays (radiotherapy).<br>|
| Experimental: Arm P - prophylactic PLND<br>Part of randomisation 2. Prophylactic pelvic lymph node dissection (PLND) - The total treatment duration is estimated to be over 1 day. Patients who have NOT received neoadjuvant chemoradiotherapy will receive adjuvant chemoradiotherapy: Cisplatin 40mg/m2 will be given weekly, subject to GFR>45mls/min. Groin: One or both groins may be boosted up to 54Gy in 25 fractions. An IMRT boost of up to 57 Gy can be given to recurrent or residual macroscopic tumour Pelvis: the dose is limited to 45Gy unless IMRT is available. An IMRT boost of up to 54Gy in 25 fractions is applied to: Any macroscopic tumour or pathological lymph nodes Electively to external iliac nodes in patient with high disease burden Patients who have had neoadjuvant chemoradiotherapy will have prophylactic PLND alone. | Procedure: Prophylactic PLND - pelvic lymph node dissection<br>* Surgery to remove the lymph nodes deeper in the pelvis, further away from where the cancer first appeared, that are at high risk of harbouring cancer.<br>|
| No Intervention: Arm Q - Surveillance no prophylactic PLND<br>no prophylactic PLND Part of randomisation 2. For patients who have NOT received neoadjuvant chemoradiotherapy: Groin: One or both groins may be boosted up to 54Gy in 25 fractions. An IMRT boost of up to 57 Gy can be given to recurrent or residual macroscopic tumour Pelvis: the dose is limited to 45Gy unless IMRT is available. An IMRT boost of up to 54Gy in 25 fractions is applied to: Any macroscopic tumour or pathological lymph nodes Electively to external iliac nodes in patient with high disease burden | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The primary outcome measure that will be measured for all trial patients is survival time. This is defined in whole days as the time from the date of randomisation to the date of death from any cause; for those who have not been reported as dead at the time of analysis, the survival time will be censored at the date of last follow-up. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease specific survival time | Disease-specific survival time which is defined in whole days as the time from the date of randomisation to the date of death specifically from disease; for those who have not been reported as dead at the time of analysis, the survival time will be censored at the date of last follow-up and for those whose death is reported as non-disease specific then the survival time will be censored at date of death. | up to 5 years | 
| Number of patients experience a grade 3 or 4 toxicity |  | up to 5 years | 
| Disease-free survival time | Disease-free survival time (DFST) which is defined in whole days as the time from date of randomisation to the date of either locoregional recurrence, distant metastasis or death from disease, whichever occurs first; for those who have not been reported as experiencing any of these events, the DFST will be censored at the date last known to be alive and free of disease or date of non-disease-specific death. A supplementary exploratory outcome measure will also be calculated taking date of penectomy as the origin rather than date of randomisation. Subsidiary outcome measures will be locoregional recurrence free survival time (LRFST). distant metastases free survival time (DMFST). A supplementary exploratory outcome measure will also be calculated taking date of penectomy as the origin for all these outcome measures rather than date of randomisation. | up to 5 years | 
| Occurrence of surgical complication |  | up to 5 years | 
| Is it possible to achieve pathological nodal assessment after chemotherapy | Feasibility of pathological nodal assessment after chemotherapy which is recorded as whether or not it was possible to achieve a pathological nodal assessment after chemotherapy. | 12 weeks | 
| Quality of life | Measured using the EORTC-QLQC30 and Lymphodema-QL | Baseline, 3, 6, 9, 12, 18, 24 and 36 months | 
| Occurrence of Pathological complete remission | Measured for all patients in InPACT-neoadjuvant: Absolute absence of disease on histological examination | Time to complete remission after randomisation | 
| Operability | Measured for all trial patients in InPACT-neoadjuvant. Operability which will be recorded as whether or not the planned inguinal node dissection was undertaken and the reasons if it did not occur. | 2-6 weeks | 
| Occurrence of Lower limb/scrotal oedema | Occurrence of Lower limb/scrotal oedema which is recorded as whether or not the patient experiences a lower limb or scrotal oedema | up to 5 years | 
| On-schedule delivery of neoadjuvant therapy | Feasibility of on-schedule delivery of neoadjuvant therapy | After randomisation up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Penis cancer, Chemotherapy, Chemoradiotherapy, Surgery, Phase III