| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced squamous carcinoma of the penis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally advanced penis cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10034299 |
| E.1.2 | Term | Penile cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary research objectives in the management of patients with regionally advanced squamous carcinoma of the penis are as follows:
1. (a) Is there a role for neoadjuvant therapy and, if so, (b) does chemotherapy or chemoradiotherapy produce superior outcomes (either for survival endpoints or for morbidity/quality of life endpoints)?
2. Does prophylactic pelvic lymph node dissection (PLND) improve survival in patients at high risk of recurrence following ILND?
These questions are addressed through sequential randomisations (Randomisation 1 in "InPACT-neoadjuvant" and Randomisation 2 in "InPACT-pelvis") at two key decision points in the clinical management pathway. |
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| E.2.2 | Secondary objectives of the trial |
In InPACT-neoadjuvant (Randomisation 1):
• Can neoadjuvant therapy prior to surgery (ILND) reduce regional recurrence rates?
• Which is the more active of neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy?
• What is the operative/post-operative complication rate following neoadjuvant therapy of both types?
• Is neoadjuvant chemoradiotherapy feasible in this setting?
In InPACT‐pelvis (Randomisation 2):
• What is the rate of additional complications for the combination of PLND and chemoradiotherapy?
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for InPACT-neoadjuvant
1. Male, aged 18 years or older.
2. Histologically-proven squamous cell carcinoma of the penis.
3. Stage:
- any T, N1 (i.e. a palpable mobile unilateral inguinal lymph node OR a single radiologically-abnormal inguinal lymph node with no evidence of extra-nodal extension), M0 or;
- any T, N2 (i.e. palpable mobile multiple or bilateral inguinal lymph nodes OR radiologically evident multiple or bilateral inguinal nodes with no evidence of extra-nodal extension), M0 or;
- any T, N3 (i.e. fixed inguinal nodal mass or any pelvic lymphadenopathy), M0
4. Patients being considered for InPACT-neoadjuvant must have either:
- measurable disease as determined by RECIST (version 1.1) criteria or;
- a single, unilateral lymph node that does not meet RECIST criteria for measurable disease, but that is either palpable or radiologically abnormal, and with histological/cytological evidence of metastatic involvement. This applies only to low disease burden patients who would then be eligible for direct entry into arm A.
*Patients with radiological evidence of macroscopic pelvic node involvement are eligible for randomisation in InPACT-neoadjuvant but are not be eligible for entry into InPACT-pelvis.
5. Performance Status ECOG 0, 1 or 2.
6. Patient is fit to receive the randomisation options for which he is being considered.
7. Haematology/biochemistry (as dictated by local hospital practice) should indicate fitness for randomisation options and parameters should be in line with considerations specified in the summary of product characteristics. Haematological parameters should not be supported by transfusion to enable entry into the trial. Liver function and renal function tests must form part of the pre-treatment assessment for patients who may be randomised to receive TIP chemotherapy e.g. patients with impaired renal function may not be considered for arms B and C of InPACT-neoadjuvant (see section 5.5.2 of the protocol for full details) but may be considered for arm A.
8. Nodal disease burden must be assessable, with all patients stratified into one of three categories (low / intermediate / high disease burden) in accordance with physical examination and Graafland radiological criteria (see Section 5.5.1).
9. Glomerular filtration rate (GFR) must be assessed for all patients (see Section 5.5.2). Requirements for GFR vary with treatment eligibility:-
- GFR ≥50 mL/min: eligible for all treatment options
- GFR 45–49 mL/min: eligible for surgery alone (arm A) and for synchronous chemoradiotherapy (arm C); not eligible for neoadjuvant TIP chemotherapy
- GFR < 45 mL/min eligible for surgery alone (arm A) or radiotherapy (arm C with cisplatin omitted)
10. Willing and able to comply with follow-up schedule.
11. Written informed consent.
Inclusion criteria for InPACT-pelvis
1. Patient has met eligibility criteria for InPACT-neoadjuvant.
2. Patient has completed ILND within arms A, B or C of InPACT-neoadjuvant.
3. There must be no radiological evidence of residual inguinal disease on cross-sectional imaging performed after therapeutic inguinal lymph node dissection.
4. There must be no radiological evidence of pelvic lymphadenopathy on cross-sectional imaging performed after therapeutic inguinal lymph node dissection.
*Any patient who underwent synchronous ispilateral pelvic lymph node dissection at the time of inguinal lymph node dissection is automatically ineligible for InPACT Pelvis.
5. Patient must be at high risk of relapse following ILND, risk of relapse being assigned on the basis of histological assessment of the ILND specimen. High-risk disease is defined as any patient where ILND reveals either: extranodal extension, bilateral nodal involvement, or 3 or more involved nodes. These patients should be considered at high risk of harbouring occult micrometastatic disease in the ipsilateral pelvic nodes.
6. Performance Status ECOG 0, 1 or 2.
7. Patient is fit to receive the randomisation options for which he is being considered.
8. Haematology/biochemistry (as dictated by local hospital practice) should indicate fitness for randomisation options and parameters should be in line with considerations specified in the summary of product characteristics. Haematological parameters should not be supported by transfusion to enable entry into the trial.
9. Willing and able to comply with follow-up schedule.
10. Written informed consent.
|
|
| E.4 | Principal exclusion criteria |
Patients who have any of the following are not eligible:
1. Pure verrucous carcinoma of the penis.
2. Non-squamous malignancy of the penis.
3. Squamous carcinoma of the urethra.
4. Stage M1.
5. Previous chemotherapy or chemoradiotherapy outside of the InPACT trial.
6. Any absolute contraindication to chemotherapy if eligible for a chemotherapy/chemoradiotherapy randomisation.
7. 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.
8. Patients who are sexually active and unwilling to use effective contraception (if they are not already surgically sterile).
9. Radiological evidence of macroscopic pelvic lymph node disease on post-ILND cross-sectional imaging
10. Patients with regionally advanced (N1-3, M0) penile cancer with disease burden that is considered unresectable by the accredited InPACT surgeon* utilising standard inguinal, ilioinguinal lymphadenectomy resection and reconstructive techniques. For example, where procedures would require circumferential resection of the femoral or iliac vessels, or the requirement for hemipelvectomy.
* InPACT surgeon should consider reviewing the case with their National InPACT surgical lead where resectablity is unclear.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure (all patients) is survival time. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This is defined in whole days as the time from the date of randomisation to the date of death from any cause |
|
| E.5.2 | Secondary end point(s) |
Secondary outcome measures for the trial as a whole (all patients) are:
- Disease-specific survival time.
- Disease-free survival time with subsidiary outcomes of locoregional recurrence free survival time and distant
metastasis free survival time.
- Toxicity and specifically the occurrence of at least one grade 3 or 4 adverse event.
- Occurrence of surgical complication.
- Feasibility of pathological nodal assessment after chemotherapy.
- Quality of life (in participating patients).
Secondary outcome measures for InPACT-neoadjuvant are:
- Occurrence of pathological complete remission.
- Operability.
- Feasibility of on-schedule delivery of neoadjuvant therapy.
Secondary outcome measures for InPACT-pelvis are:
- Occurrence of lower limb/scrotal oedema. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Disease-specific survival time defined in whole days from the date of randomisation to date of death from penis cancer
• Disease-free survival time defined in whole days as time from date of randomisation to date of either locoregional recurrence, distant metastasis or death from penis cancer, whichever occurs first
• Toxicity where all events experienced by patients are recorded and graded using CTCAE v4 and specifically occurrence of at least one grade 3 or 4 event
• Occurrence of surgical complication recorded as whether or not a surgical complication was experienced according to the Modifed Clavien-Dindo criteria.
• Feasibility of pathological nodal assessment after chemotherapy
• QL measured pre-randomisation, 3-monthly in yr 1, 6-monthly in yr 2 and at 36mths. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Surgery (ILND, PLND), Neo adjuvant and adjuvant Chemoradiotherapy (25 Fr/5wks, weekly ciplatin) |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study end date is deemed to be the date of the last data capture. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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