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

Sponsor

Institute of Cancer Research, United Kingdom (Other)

Overall Status

Unknown status

CT.gov ID

NCT02305654

Collaborator

National Cancer Institute (NCI) (NIH), ECOG-ACRIN Cancer Research Group (Other), Canadian Cancer Trials Group (Other)

400

Enrollment

Locations

Arms

61.6

Anticipated Duration (Months)

23.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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:

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:

prophylactic PLND Q. no prophylactic PLND

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Penis, Usual Type	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	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 12, 2017

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jul 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Overall survival [up to 5 years]
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.

Secondary Outcome Measures

Disease specific survival time [up to 5 years]
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.
Number of patients experience a grade 3 or 4 toxicity [up to 5 years]
Disease-free survival time [up to 5 years]
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.
Occurrence of surgical complication [up to 5 years]
Is it possible to achieve pathological nodal assessment after chemotherapy [12 weeks]
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.
Quality of life [Baseline, 3, 6, 9, 12, 18, 24 and 36 months]
Measured using the EORTC-QLQC30 and Lymphodema-QL
Occurrence of Pathological complete remission [Time to complete remission after randomisation]
Measured for all patients in InPACT-neoadjuvant: Absolute absence of disease on histological examination
Operability [2-6 weeks]
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.
Occurrence of Lower limb/scrotal oedema [up to 5 years]
Occurrence of Lower limb/scrotal oedema which is recorded as whether or not the patient experiences a lower limb or scrotal oedema
On-schedule delivery of neoadjuvant therapy [After randomisation up to 12 weeks]
Feasibility of on-schedule delivery of neoadjuvant therapy

Other Outcome Measures

Acceptability of randomisation [up to 5 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
2	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Grady Health System	Atlanta	Georgia	United States	30303
5	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
6	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
9	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
10	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
11	University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030
12	Velindre NHS Trust	Cardiff		United Kingdom	CF14 2TL
13	University Hospitals of Leicester NHS Trust	Leicester		United Kingdom	LE1 5WW
14	The Royal Marsden NHS Foundation Trust	London		United Kingdom	SM2 5PT
15	St George's Hospital NHS Foundation Trust	London		United Kingdom	SW17 0QT
16	Norfolk and Norwich University Hospitals NHS Foundation Trust	Norwich		United Kingdom	NR4 7UY
17	Swansea Bay University Health Board	Swansea		United Kingdom	SA6 6NL

Sponsors and Collaborators

Institute of Cancer Research, United Kingdom
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Canadian Cancer Trials 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