Multiple Therapies for Advanced Penile Cancer

(InPACT Trial)

Recruiting at 16 trial locations

Overseen By UK - InPACT Senior Trial Manager

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: Institute of Cancer Research, United Kingdom

Disqualifiers: Verrucous carcinoma, Nonsquamous malignancy, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

Trial Summary

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Inguinal Lymph Node Dissection (ILND) for advanced penile cancer?

ILND is used for the treatment of metastatic penile cancer and has been associated with significant morbidity, but recent modifications aim to reduce complications while optimizing cancer outcomes. ^{1 2 3 4 5}

Is inguinal lymph node dissection (ILND) generally safe for humans?

Inguinal lymph node dissection (ILND) often has a high rate of complications, especially wound-related issues, when used for treating penile cancer and other conditions. ^{1 2 4 6 7}

How is the treatment with Ifosfamide and ILND different for advanced penile cancer?

This treatment combines Ifosfamide, a chemotherapy drug, with ILND (inguinal lymph node dissection), a surgical procedure, to target advanced penile cancer. The combination is unique because it addresses both the cancer cells with chemotherapy and the affected lymph nodes surgically, which is important since there is no standard treatment for this rare condition. ^{1 2 3 8 9}

Research Team

Steve Nicholson

Principal Investigator

Mid and South Essex NHS Foundation Trust

Curtis Pettaway

Principal Investigator

University of Texas M.D. Anderson Cancer Center ; 713-792-3250 ; [e-mail]

Eligibility Criteria

This trial is for individuals with squamous cell carcinoma of the penis, who have palpable lymph nodes but no distant metastasis (M0), and are in a decent physical state (ECOG 0-2). They must have measurable disease and not have received prior chemo or chemoradiotherapy. Those with pure verrucous carcinoma, urethral cancer, other recent malignancies except certain skin cancers, or non-squamous penile cancer cannot join.

Inclusion Criteria

I have been diagnosed with penile squamous cell carcinoma.

Written informed consent

My cancer is at a stage where it has spread to my lymph nodes but not to other parts of my body.

Exclusion Criteria

I haven't had treatment for cancer other than skin cancer in the last 3 years.

I have had chemotherapy or chemoradiotherapy before.

My cancer has spread to other parts of my body.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Patients receive one of three initial treatments: standard surgery, neoadjuvant chemotherapy followed by surgery, or neoadjuvant chemoradiotherapy followed by surgery.

5-12 weeks

Surgery

Inguinal Lymph Node Dissection (ILND) is performed, followed by risk assessment for recurrence.

1 day

Adjuvant Treatment

High-risk patients may receive prophylactic pelvic lymph node dissection (PLND) or adjuvant chemoradiotherapy.

Varies

Follow-up

Participants are monitored for overall survival, disease-free survival, and other secondary outcomes.

up to 5 years

Treatment Details

Interventions

• Cisplatin
• Ifosfamide
• ILND - Inguinal Lymph Node Dissection
• Intensity modulated radiation treatment (IMRT)
• Paclitaxel
• Prophylactic PLND - pelvic lymph node dissection

Trial Overview The study tests different sequences of treatments for penile cancer. Patients may receive standard surgery alone (ILND), chemotherapy before surgery (neoadjuvant chemotherapy + ILND), or chemoradiotherapy before surgery (neoadjuvant chemoradiotherapy + ILND). High-risk patients post-ILND may also be randomized to get prophylactic pelvic lymph node dissection or not.

Participant Groups

Group I: Arm P - prophylactic PLND Experimental Treatment 1 Intervention

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: 1. Any macroscopic tumour or pathological lymph nodes 2. Electively to external iliac nodes in patient with high disease burden Patients who have had neoadjuvant chemoradiotherapy will have prophylactic PLND alone.

Group II: Arm C - neoadjuvant chemoradiotherapy Experimental Treatment 2 Interventions

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.

Group III: Arm B - neoadjuvant chemotherapy Experimental Treatment 3 Interventions

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

Group IV: Arm Q - Surveillance no prophylactic PLND Active Control 1 Intervention

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

Group V: Arm A - Standard Surgery (ILND) Active Control 1 Intervention

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.

Ifosfamide is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ifex for:

• Testicular cancer
• Ovarian cancer
• Soft tissue sarcoma
• Ewing's sarcoma
• Non-Hodgkin's lymphoma

Approved in European Union as Ifex for:

• Testicular cancer
• Ovarian cancer
• Soft tissue sarcoma
• Ewing's sarcoma
• Non-Hodgkin's lymphoma

Approved in Canada as Ifex for:

• Testicular cancer
• Ovarian cancer
• Soft tissue sarcoma
• Ewing's sarcoma
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Institute of Cancer Research, United Kingdom

Lead Sponsor

Trials

167

Recruited

136,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

ECOG-ACRIN Cancer Research Group

Collaborator

Trials

122

Recruited

160,000+

Canadian Cancer Trials Group

Collaborator

Trials

135

Recruited

70,300+

Findings from Research

Inguinal lymph node dissection (ILND) for penile cancer showed a high rate of postoperative complications, with 44% experiencing fluid collections and 36% developing leg lymphoedema, particularly in radical lymphadenectomies.

Despite the high morbidity associated with ILND, major complications were rare (only 4%), suggesting that while the procedure is risky, it provides significant oncological benefits that must be carefully weighed against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Morbidity and risk factors for complications of inguinal lymph node dissection in penile cancer. Jeanne-Julien, A., Bouchot, O., De Vergie, S., et al.[2023]

Inguinal lymph node dissection (ILND) for penile cancer has historically had a very high complication rate of 80-100%, but recent surgical modifications have significantly reduced this risk, with current rates showing 19% minor and 27% major complications for diagnostic ILND, and 29% minor and 24% major complications for therapeutic ILND.

Dynamic sentinel lymph node biopsy, used for staging in clinically node-negative patients, has a much lower complication rate of 7%, highlighting its potential as a safer alternative to traditional ILND.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contemporary inguinal lymph node dissection: minimizing complications. Spiess, PE., Hernandez, MS., Pettaway, CA.[2021]

Inguinal lymph node dissection (ILND) is a crucial procedure for treating metastatic penile squamous cell carcinoma (SCC), and recent advancements have led to a reduction in the associated morbidity of the surgery.

Contemporary ILND techniques not only optimize oncological outcomes but also have the potential to render appropriately selected patients disease-free, making the procedure justifiable despite its risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update in the surgical principles and therapeutic outcomes of inguinal lymph node dissection for penile cancer. Ercole, CE., Pow-Sang, JM., Spiess, PE.[2013]

Inguinal lymph node dissection (ILND) has a wound complication rate of 14.6%, with similar rates across different cancer types (penile cancer, vulvar cancer, and melanoma), indicating a significant risk associated with this procedure.

Factors such as a body mass index (BMI) of 30 or higher, longer operative times, and the need for additional pelvic lymph node dissection are strong predictors of increased wound complications, suggesting that these patients may benefit from modified surgical techniques to reduce risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wound Complication Rates after Inguinal Lymph Node Dissection: Contemporary Analysis of the NSQIP Database. Chua, KJ., Balraj, V., Patel, HV., et al.[2023]

Fine needle aspiration cytology is recommended for all patients with suspected penile cancer, and if positive, therapeutic inguinal lymph node dissection (ILND) should be performed, highlighting the importance of accurate diagnosis and timely intervention.

In patients with varying risk levels for inguinal metastases, tailored approaches such as surveillance, sentinel node biopsy, or ILND are recommended, ensuring that treatment is based on individual risk assessments to optimize outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of the lymph nodes in penile cancer. Heyns, CF., Fleshner, N., Sangar, V., et al.[2010]

Inguinal lymph node dissection (ILND) is associated with significant perioperative adverse events (AEs), with 52.7% of patients experiencing at least one postoperative AE, particularly lymphatic complications.

High body mass index (BMI), presence of comorbidities, and diabetes are identified as independent predictors of AEs following ILND, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment and Reporting of Perioperative Adverse Events and Complications in Patients Undergoing Inguinal Lymphadenectomy for Melanoma, Vulvar Cancer, and Penile Cancer: A Systematic Review and Meta-analysis. Cacciamani, GE., Medina, LG., Sayegh, AS., et al.[2023]

In a study of 237 inguinal lymph node dissections (ILND) performed on 163 patients with penile cancer, 58% of procedures resulted in at least one complication, with 10% classified as severe, highlighting the high complication rates associated with this surgery.

Factors such as higher body mass index (BMI), sartorius muscle transposition, and bilateral dissection were identified as significant risk factors for moderate to severe complications, indicating that these clinical characteristics may help predict patient outcomes after ILND.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early wound complications after inguinal lymphadenectomy in penile cancer: a historical cohort study and risk-factor analysis. Stuiver, MM., Djajadiningrat, RS., Graafland, NM., et al.[2013]

The robotic-assisted single-port inguinal lymph node dissection (ILND) technique demonstrated comparable effectiveness in nodal yield to traditional open surgery while significantly reducing postoperative complications, as shown in a case involving a 54-year-old man with penile cancer.

The procedure was completed with minimal blood loss (<30 mL) and no complications, allowing for the patient's discharge on the first postoperative day with only minor pain and leg swelling, highlighting the safety and efficiency of this robotic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-port robotic inguinal lymph node dissection: A safe and feasible option for penile cancer. Patel, AS., Isharwal, S.[2022]

A 55-year-old male with advanced penile cancer and inguinal metastases showed a significant response to neoadjuvant chemotherapy using paclitaxel, ifosfamide, and cisplatin (TIP), with marked reduction in metastases after 4 treatment cycles.

Despite experiencing some side effects like grade 3 neutropenia and peripheral neuropathy, the patient underwent successful surgery with no viable cancer cells found post-treatment, and remains cancer-free 8 months later, suggesting TIP chemotherapy is a promising option for advanced penile cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dramatic response of penile cancer with inguinal lymph node metastases to neoadjuvant chemotherapy with paclitaxel, ifosfamide and cisplatin : a case report]. Kubota, Y., Nakano, M., Nagai, S., et al.[2015]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Morbidity and risk factors for complications of inguinal lymph node dissection in penile cancer. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Contemporary inguinal lymph node dissection: minimizing complications. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Update in the surgical principles and therapeutic outcomes of inguinal lymph node dissection for penile cancer. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Wound Complication Rates after Inguinal Lymph Node Dissection: Contemporary Analysis of the NSQIP Database. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Management of the lymph nodes in penile cancer. [2010]

6. United States pubmed.ncbi.nlm.nih.gov

Assessment and Reporting of Perioperative Adverse Events and Complications in Patients Undergoing Inguinal Lymphadenectomy for Melanoma, Vulvar Cancer, and Penile Cancer: A Systematic Review and Meta-analysis. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Early wound complications after inguinal lymphadenectomy in penile cancer: a historical cohort study and risk-factor analysis. [2013]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Single-port robotic inguinal lymph node dissection: A safe and feasible option for penile cancer. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

[Dramatic response of penile cancer with inguinal lymph node metastases to neoadjuvant chemotherapy with paclitaxel, ifosfamide and cisplatin : a case report]. [2015]