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

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

Study Overview

• Status: Recruiting
• Conditions: Squamous Cell Carcinoma of the Penis, Usual Type
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: UK - InPACT Senior Trial Manager; Phone Number: 02087224261; Email: InPACT-icrctsu@icr.ac.uk
• Study Contact Backup: Name: US/Canada - InPACT DA for EA8134; Phone Number: (857)504-2900

Study Locations

• United Kingdom
  • Cardiff, United Kingdom, CF14 2TL
    • Recruiting
    • Velindre NHS Trust
    • Contact: Dr James Barber
  • Leicester, United Kingdom, LE1 5WW
    • Recruiting
    • University Hospitals of Leicester NHS Trust
    • Contact: Dr Christopher Kent
  • London, United Kingdom, SW17 0QT
    • Recruiting
    • St George's Hospital NHS Foundation Trust
    • Contact: Mr Nick Watkin
  • London, United Kingdom, SM2 5PT
    • Active, not recruiting
    • The Royal Marsden NHS Foundation Trust
  • Norwich, United Kingdom, NR4 7UY
    • Recruiting
    • Norfolk and Norwich University Hospitals NHS Foundation Trust
    • Contact: Mr Vivekanandan Kumar
  • Swansea, United Kingdom, SA6 6NL
    • Active, not recruiting
    • Swansea Bay University Health Board
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC / Norris Comprehensive Cancer Center
      • Contact: Sia Daneshmand; Phone Number: 323-865-3700; Email: daneshma@usc.edu
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Los Angeles County-USC Medical Center
      • Contact: Anne Schuckman; Phone Number: 323-865-3700; Email: anne.schuckman@med.usc.edu
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
      • Contact: Phil Spiess; Phone Number: 813-745-8343; Email: Philippe.spiess@moffitt.org
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University Hospital/Winship Cancer Institute
      • Contact: Viraj Master; Phone Number: 404-778-4898; Email: vmaster@emory.edu
    • Atlanta, Georgia, United States, 30303
      • Active, not recruiting
      • Grady Health System
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Active, not recruiting
      • University of Chicago Comprehensive Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Contact: Lance Pagliaro; Email: pagliaro.lance@mayo.edu
      • Contact: Stephen Boorjian /Jeffrey Karnes (karnes.r@mayo.edu); Phone Number: (507)284-4015 / (507)266-9968; Email: boorjian.stephen@mayo.edu
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Active, not recruiting
      • Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Active, not recruiting
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Active, not recruiting
      • Fox Chase Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas M.D. Anderson Cancer Center
      • Contact: Curtis Pettaway; Phone Number: 713-792-3250; Email: cpettawa@mdanderson.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent
2. Measurable disease as determined by RECIST (version 1.1) criteria;
3. Histologically-proven squamous cell carcinoma of the penis,

4. 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
5. Performance Status ECOG 0, 1 or 2.

Exclusion Criteria:

1. Pure verrucous carcinoma of the penis,
2. Nonsquamous malignancy of the penis,
3. Squamous carcinoma of the urethra,
4. Stage M1,
5. Previous chemotherapy or chemoradiotherapy,
6. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A - Standard Surgery (ILND); 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; Surgery to remove the lymph nodes in the groin near to where the cancer first appeared.
Experimental: Arm B - neoadjuvant chemotherapy; 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; Dose 175mg/m2 as part of TIP regimen.; Other Names: Taxol; Drug: Ifosfamide; Dose 900mg/m2 as part of TIP regimen.; Other Names: Mitoxana; Drug: Cisplatin; Dose 15mg/m2 as part of TIP regimen (neoadjuvant chemotherapy arm) Dose 40mg/m2 for use concurrently with raditotherapy (chemoradiotherapy arm)
Experimental: Arm C - neoadjuvant chemoradiotherapy; 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; Dose 15mg/m2 as part of TIP regimen (neoadjuvant chemotherapy arm) Dose 40mg/m2 for use concurrently with raditotherapy (chemoradiotherapy arm); Radiation: Intensity modulated radiation treatment (IMRT); Treatment with very high energy X-rays (radiotherapy).
Experimental: Arm P - prophylactic PLND; 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; 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.
No Intervention: Arm Q - Surveillance no prophylactic PLND; 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?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of randomisation	In addition to the outcome measures, the acceptability of both randomisations will be monitored based on the proportion of eligible patients approached for randomisation, the proportion of approached patients consenting to randomisation and the proportion of randomised patients receiving their allocated treatment. This will provide ongoing information regarding the feasibility of the trial successfully completing to target.	up to 5 years

Collaborators and Investigators

• Sponsor: Institute of Cancer Research, United Kingdom
• Collaborators: National Cancer Institute (NCI); ECOG-ACRIN Cancer Research Group
• Investigators: Study Chair: Steve Nicholson, Mid and South Essex Nhs Foundation Trust; Study Chair: Curtis Pettaway, University of Texas M.D. Anderson Cancer Center ; 713-792-3250 ; cpettawa@mdanderson.org

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2017
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: November 27, 2014
• First Posted (Estimated): December 2, 2014

Study Record Updates

• Last Update Posted (Estimated): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Surgery; Phase III; Chemotherapy; Chemoradiotherapy; Penis cancer
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Paclitaxel; Ifosfamide
• Other Study ID Numbers: ICR CTSU/2014/10048; CRUK/13/005 (Other Grant/Funding Number: Cancer Research UK); 13580965 (Registry Identifier: ISRCTN); EA8134 (Other Grant/Funding Number: NCI); IRCI004 (Other Identifier: IRCI); 2015-001199-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No