Enfortumab vedotin plus avelumab as first-line treatment for advanced penile cancer

DEPECA-1 - DEfeating PEnile Cancer 1 - A Phase II Study to Evaluate a First-line Systemic Therapy With Enfortumab Vedotin Plus Avelumab for Advanced and Metastatic Penile Carcinoma

This trial tests whether combining enfortumab vedotin with avelumab helps men with advanced or metastatic penile squamous cell carcinoma as first-line treatment.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years and up
• Sex: Male
• Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest (Academic / other)
• Drugs / interventions: enfortumab, avelumab, prednisone
• Locations: 7 sites (Dresden and 6 other locations)
• Trial ID: NCT07110038 on ClinicalTrials.gov

What this trial studies

This Phase II open-label trial gives enfortumab vedotin (an antibody–drug conjugate) together with avelumab (a PD-L1 inhibitor) to men with locally advanced or metastatic penile squamous cell carcinoma who are not candidates for curative surgery. Participants receive the combination as first-line systemic therapy and are followed with regular imaging and clinical visits to measure tumor response, progression-free survival, and overall survival. The multicenter study is conducted at several German university hospitals with scheduled safety monitoring and adverse-event reporting. The goal is to determine the anti-tumor activity and tolerability of this combination in a rare cancer with limited treatment options.

Who should consider this trial

Good fit: Men aged 18 or older with histologically confirmed penile squamous cell carcinoma that is locally advanced or metastatic and deemed unsuitable for curative surgery are eligible.

Not a fit: Patients who are candidates for curative surgical management, who have non-squamous penile tumors, or who have received prior systemic therapy for metastatic disease are unlikely to receive benefit from this first-line study treatment.

Why it matters

Potential benefit: If successful, this combination could produce higher tumor response rates and longer survival than currently available first-line systemic options for advanced penile cancer.

How similar studies have performed: Enfortumab vedotin combined with immune checkpoint inhibitors has shown promising activity in urothelial carcinoma and other tumors, but this combination is largely untested specifically in penile carcinoma.

Eligibility criteria

Inclusion Criteria:

1. Patient has ability to understand and the willingness to sign a written informed consent.
2. Patient is ≥ 18 years of age at time of signing the written informed consent.
3. Male patients with histologically confirmed diagnosis of penile squamous cell carcinoma.
4. Patients must be considered non-eligible for curative surgical management. Eligibility for trial inclusion should be based on the presence of either distant metastatic disease (M1) or at least one of the following scenarios based on the UICC/AJCC 8th edition TNM clinical and pathological classification of penile cancer:

   1. Stage 3 (cT3) disease with a single lymph node involved (N1).
   2. Stage 4 disease (cT4).
   3. Any T stage with either N2 (involvement of multiple or bilateral inguinal nodes) or N3 (fixed inguinal nodal mass or pelvic lymphadenopathy) disease. Patients without distant metastases are eligible if multidisciplinary team review concludes that they are unsuitable for curative surgery.
5. Tumor material (archival or current) is available for local pathology testing (PD-L1, HPV).
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
7. Measurable disease per RECIST 1.1 criteria.
8. No prior systemic therapy for metastatic or locally advanced PeCa in the palliative setting. NOTE: (Neo)adjuvant systemic therapy (without IO) is allowed at least 6 months before study enrollment.
9. Patients has adequate blood count, liver-enzymes, and renal function:

   1. ANC (Absolute neutrophil count) \> 1,500 cells/μL without the use of hematopoietic growth factors.
   2. Platelet count ≥ 100 x 109/L (\>100,000 per mm3).
   3. Hemoglobin ≥ 9 g/dL.
   4. Serum total bilirubin ≤ 1.5x institutional upper normal limit (ULN).
   5. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN (or ≤ 5 x ULN if liver metastases are present).
   6. Creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft- Gault equation (or local institutional standard method).
10. No other active malignancy within the past 3 years, except for adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin.
11. No history of significant cardiovascular disease (e.g., myocardial infarction, unstable angina) within the last 6 months.
12. Life expectancy of at least 3 months.
13. Willingness to comply with study requirements, including follow-up visits and procedures.
14. Patients with female partners of childbearing potential must agree to use an effective method of contraception during the study and for 4 months after the last dose of enfortumab vedotin or for at least 30 days after last avelumab treatment administration, whichever occurs last.

Exclusion Criteria:

1. Previous systemic therapy for metastatic or locally advanced PeCa in the palliative setting.
2. Previous treatment with investigational drugs or devices within 30 days prior to the first dose of trial treatment.
3. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
4. Active, known, or suspected autoimmune disease requiring systemic treatment within the past 2 years. Patients with controlled autoimmune d disease not requiring systemic immunosuppressive treatment including diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases are eligible.
5. Has ongoing sensory or motor neuropathy Grade 2 or higher.
6. Has a history of uncontrolled diabetes (HbA1c \> 8%).
7. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
8. Active infection requiring systemic therapy. The following exceptions apply:

   1. Patients with an HIV infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction.
   2. Patients with evidence of chronic HBV infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have ALT, AST, and total bilirubin levels \< ULN, and provided there is no expected drug-drug interaction.
   3. Patients with a history of HCV infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels \< ULN.
9. History of other malignancies within the past 3 years, with the exception of adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin.
10. Severe hepatic impairment (Child-Pugh Class C).
11. Severe renal impairment or requirement for dialysis.
12. History of keratitis and corneal ulceration in the last two years.
13. Active pneumonia, pneumonitis or pulmonary fibrosis.
14. Active tuberculosis.
15. Known prior severe hypersensitivity to the study drugs or any component of their formulations, known severe hypersensitivity reactions to monoclonal antibodies (NCT CTCAE Grade ≥ 3).
16. Inability or unwillingness to comply with study requirements, including follow-up visits and procedures.
17. Inability to provide informed consent.
18. Use of immunosuppressive medication within 14 days prior to the first dose of study treatment, with the exception of intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection), systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent, or steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
19. Prior organ transplantation including allogenic stem-cell transplantation.
20. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
21. Persisting toxicity related to prior therapy (NCI CTCAE Grade \> 1); however, alopecia or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
22. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
23. Patient participated in another interventional clinical study according to Medicines Act within 28 days prior to study enrollment or participation in a clinical study according to Medicines Act at the same time as this study unless it is an observational / non-interventional study or during the follow- up period of an interventional study.

Where this trial is running

Dresden and 6 other locations

• Universitätsklinikum Carl Gustav Carus — Dresden, Germany (Recruiting)
• University Medical Center of Johannes Gutenberg-University — Mainz, Germany (Recruiting)
• University Hospital Mannheim — Mannheim, Germany (Recruiting)
• Technical University of Munich, University Hospital Munich — Munich, Germany (Recruiting)
• Caritas St. Josef Medical Center — Regensburg, Germany (Recruiting)
• Rostock University Medical Center — Rostock, Germany (Recruiting)
• University Hospital Tübingen — Tübingen, Germany (Recruiting)

Study contacts

• Study coordinator: Igor Tsaur, Prof. Dr.

Conditions Penile Squamous Cell Carcinoma