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Pembrolizumab Combined With Cisplatin-based Chemotherapy as First-line Systemic Therapy in Advanced Penile Cancer (HERCULES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04224740
Recruitment Status : Recruiting
First Posted : January 13, 2020
Last Update Posted : December 9, 2021
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Latin American Cooperative Oncology Group

Brief Summary:

This is a phase II clinical trial evaluating activity, safety and patients reported outcomes of first-line pembrolizumab plus cisplatin (or carboplatin) plus 5-FU for patients with advanced penile squamous cell carcinoma.

The primary endpoint is overall responsa rate according to RECIST v1.1 at week 24.

Condition or disease Intervention/treatment Phase
Penile Carcinoma Drug: Pembrolizumab Drug: Standard of care therapy Phase 2

Detailed Description:
Advanced penile squamous cell carcinoma is associated with dismal survival rates and a major impact on the quality of life. To date, unresectable or metastatic disease is managed by systemic therapy with platinum-based chemotherapy for patients with good performance status. The median PFS and OS on first-line platinum-based chemotherapy vary between 3-4 and 7-15 months, respectively. Chemotherapy induces objective responses in only 20-30% of penile cancer patients with rare complete responses and systemic treatment has not changed for decades. Therefore, this study's rationale is to explore the efficacy and safety of pembrolizumab combined with standard-of-care cisplatin(or carboplatin) plus 5-fluorouracil as part of the first-line therapy. Patients will receive pembrolizumab 200mg IV every three weeks with a maximum duration of 2 years (34 cycles-counting the combination with chemotherapy) in case of no progressive disease or intolerance. The investigators hypothesized that the combination of immunotherapy with standard cytotoxic chemotherapy may improve the overall response rate by RECIST v1.1 in this patient population.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Pembrolizumab Combined With Cisplatin-based Chemotherapy as First-line Systemic Therapy in Advanced Penile Cancer: LACOG 0218 HERCULES Trial
Actual Study Start Date : June 15, 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Pembrolizumab plus standard of care chemotherapy

-Pembrolizumab combined with standard of care therapy

  • Standard of care therapy: ciplastin 70mg/m² IV D1(or carboplatin AUC 5) plus 5-Fluouracil 1000mg/m²/day IV( continuous infusion on Days 1-4) Q3W for 6 cycles
Drug: Pembrolizumab
Patients will receive pembrolizumab at the dose of 200mg IV Q3W with maximum duration of 2 years (34 cycles-counting the part combined with chemotherapy)

Drug: Standard of care therapy
Ciplastin 70mg/m² IV D1(or carboplatin AUC 5) plus 5-Fluouracil 1000mg/m²/day IV( continuous infusion on Days 1-4) Q3W for 6 cycles
Other Name: Cisplatin(or Carboplatin), 5-fluouracil

Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: 24 weeks ]
    Proportion of patients with partial or complete response by investigator-assessed RECIST v1.1

Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 24 months ]
    Time from enrollment to progression by investigator-assessed RECIST 1.1 or death

  2. Overall survival (OS) [ Time Frame: 36 months ]
    Time from enrollment to death due to any cause.

  3. Clinical Benefit Rate (CBR) [ Time Frame: 24 weeks ]
    Proportion of patients who have complete, partial response or stable disease by investigator-assessed RECIST v1.1

  4. Health Related Quality of Life (QoL) [ Time Frame: 24 weeks ]
    Comparison of initial and final scores of the European Organization for Research and Treatment (EORTC) C30 questionnaires.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No


  1. Male participants who are at least 18 years of age on the day of signing informed consent will be enrolled in this study.
  2. Patients with penile squamous cell carcinoma with either:

    • metastatic disease (de novo or recurrent), or
    • recurrent locally advanced disease not amenable to curative intent therapy (e.g. surgery, radiotherapy, chemoradiotherapy, etc), or
    • anyT N3 M0 or T4 anyN M0 (stage IV - AJCC 8th) not amenable to curative-intent therapy (e.g. surgery, radiotherapy, chemoradiotherapy, etc).
  3. Histologically confirmed diagnosis of penile squamous cell carcinoma (PSCC).
  4. Patients with advanced or metastatic PSCC without prior treatment or that progressed after 12 months of (neo) adjuvant chemotherapy completion.
  5. Participant must agree to use a contraception.
  6. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
  7. Have measurable disease based on RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

    Newly obtained biopsies are preferred to archived tissue.

  9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of enrollment.
  10. Have adequate organ function (see Table 1). Specimens must be collected within 10 days prior to the start of study treatment.
  11. Have a life expectancy of at least 12 weeks.


  1. Primary tumor arising from urethra.
  2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
  3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to enrollment.
  4. Has received prior radiotherapy within 3 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  5. Has received a live vaccine within 30 days prior to the first dose of study drug.
  6. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
  7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
  8. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of non-penile skin or carcinoma in situ that have undergone potentially curative therapy are not excluded.
  9. Has known symptomatic uncontrolled CNS metastases and/or carcinomatous meningitis.
  10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
  11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  13. Has an active infection requiring systemic therapy.
  14. Has a known history of Human Immunodeficiency Virus (HIV).
  15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.
  16. Has a known history of active TB (Bacillus Tuberculosis).
  17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  19. Is expecting to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
  20. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subject who are MSD employees directly involved in the conduct of the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04224740

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Contact: Gustavo Werutsky, MD +55 51 3384 5334
Contact: Laura Voelcker +55 51 3384 5334

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Instituto do Câncer do Ceará Recruiting
Fortaleza, Ceará, Brazil, 60430-230
Contact: João Paulo Holanda Soares, MD    558532884576      
Oncocentro Recruiting
Fortaleza, CE, Brazil
Contact: Karine Trindade         
Hospital Universitário de Brasília Recruiting
Brasília, Distrito Federal, Brazil, 70840-901
Contact: Fernando Sabino, MD    55 61 33466248      
Clínica Oncológica Brasil Active, not recruiting
Belém, PA, Brazil
Hospital Erasto Gaertner Recruiting
Curitiba, PR, Brazil
Contact: Murilo Luz         
Centro de Pesquisa em Oncologia Not yet recruiting
Porto Alegre, Rio Grande Do Sul, Brazil, 90619900
Contact: Andre Fay, MD         
Contact    55 51 3320.3039      
INCA Recruiting
Rio De Janeiro, RJ, Brazil
Contact: Victor Marcondes         
Beneficência Portuguesa Recruiting
São Paulo, SP, Brazil
Contact: Fernando Maluf         
Fundação Pio XII - Hospital de Amor Recruiting
Barretos, São Paulo, Brazil, 14780-360
Contact: Luis Eduardo Rosa Zucca, MD    55 1791077997      
Fundação Doutor Amaral Carvalho Recruiting
Jaú, São Paulo, Brazil, 17210-070
Contact: Patricia Medeiros Milhomen Beato, MD    55 1436021399      
Instituto do Câncer do Estado de São Paulo Recruiting
São Paulo, Brazil, 01246-000
Contact: Diogo Bastos, MD         
Sponsors and Collaborators
Latin American Cooperative Oncology Group
Merck Sharp & Dohme Corp.
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Responsible Party: Latin American Cooperative Oncology Group Identifier: NCT04224740    
Other Study ID Numbers: LACOG 0218
First Posted: January 13, 2020    Key Record Dates
Last Update Posted: December 9, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Latin American Cooperative Oncology Group:
Penile Neoplasms
Additional relevant MeSH terms:
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Penile Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Penile Diseases
Antineoplastic Agents
Antineoplastic Agents, Immunological