A Phase 2 clinical trial of Pembrolizumab in combination with Carboplatin and Cabazitaxel in Aggressive Variant Metastatic Castration Resistant Prostate Cancer
- Trial ID
- 2022-501139-17-01
- Protocol
- PEAPOD-FOS04/2022
- Sponsor
- Fundacion Oncosur
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 clinical trial is to assess the **efficacy** and safety of pembrolizumab in combination with carboplatin and cabazitaxel in patients with Aggressive Variant Metastatic Castration Resistant Prostate Cancer. This is evaluated through the 6-month Radiographic Progression-Free Survival (rPFS) rate, as defined by the Prostate Cancer Working Group 3 (PCWG3). The clinical relevance of this objective lies in its potential to provide a new therapeutic option for a challenging and aggressive form of prostate cancer, where current treatment options are limited.
Secondary objectives include: - Determining radiographic Progression-Free Survival at 12 months. - Evaluating response rate by PCWG modified RECIST 1.1. - Evaluating PSA response when PSA is evaluable. - Determining PSA progression-free survival (PSA-PFS). - Determining progression-free survival (PFS). - Determining overall survival (OS). - Correlating efficacy endpoints with AVPC-Molecular-Classification, defined by the presence of tumor mutations in two of the following genes: P53, PTEN, or RB. - Correlating efficacy endpoints with neuroendocrine signature in the ctDNA methylation pattern.
Participants
The clinical trial focuses on evaluating the **efficacy and safety** of pembrolizumab in combination with carboplatin and cabazitaxel for patients with **Aggressive Variant Metastatic Castration Resistant Prostate Cancer**. The study population consists exclusively of male participants, aged 18 years and older, who have a histologically confirmed diagnosis of adenocarcinoma and/or neuroendocrine carcinoma of the prostate. Participants must have documented metastatic disease and meet at least one of the Aggressive Variant Prostate Cancer criteria. The trial does not include female subjects, and the population is not considered vulnerable. Participants are required to have adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. They must also provide a tumor tissue sample and agree to use contraception during the study. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of **pembrolizumab** in combination with **carboplatin** and **cabazitaxel** in patients with Aggressive Variant Metastatic Castration Resistant Prostate Cancer. This is a Phase 2, randomized, double-blind, controlled trial with an estimated duration extending until January 2027. The primary objective is to assess the 6-month Radiographic Progression-Free Survival (rPFS) rate, with secondary endpoints including 12-month rPFS, response rate by PCWG3 modified RECIST 1.1, and overall survival, among others.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and disease characteristics. Following successful screening, participants will be randomized to receive the study treatment. The treatment period will involve regular follow-up visits to monitor safety and efficacy, with assessments including imaging studies, laboratory tests, and evaluation of adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 108 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are required to adhere to study protocols, including the use of contraception and compliance with scheduled visits and assessments. The trial aims to provide valuable insights into the treatment of this aggressive form of prostate cancer, contributing to the advancement of therapeutic strategies in this field.
Treatment
The clinical trial involves the administration of **Carboplatin**, an antineoplastic agent, which is utilized in its pharmaceutical form as a concentrate for solution for infusion. The active substance, carboplatin, is of chemical origin and is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg/m² over a treatment period of up to 18 weeks. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.
**Pembrolizumab**, marketed as Keytruda, is another investigational product in this trial. It is provided as a 25 mg/mL concentrate for solution for infusion. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, administered through **intravenous use**. The maximum daily dose is set at 400 mg, with a cumulative maximum dose of 7200 mg over a treatment period of up to 108 weeks. The administration schedule is designed to optimize therapeutic outcomes while monitoring participant compliance closely.
**Cabazitaxel** is also included in the trial as an antineoplastic agent, provided in the form of a concentrate for solution for infusion. The active substance, cabazitaxel, is of chemical origin and is administered via **intravenous infusion**. The dosing is based on body surface area, with a maximum daily dose of 25 mg/m² and a total maximum dose of 150 mg/m² over a treatment period of up to 18 weeks. Participant adherence to the dosing regimen is monitored to ensure protocol compliance.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The focus is on evaluating the efficacy and safety of the combination of pembrolizumab, carboplatin, and cabazitaxel in patients with aggressive variant metastatic castration-resistant prostate cancer, with the primary objective being the assessment of radiographic progression-free survival rate at six months.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Radiographic Progression-Free Survival** (rPFS) rate at 6 months. This endpoint is defined as the time from the first dose of study treatment to the date of radiographic confirmed progression or death from any cause, whichever occurs first. The rPFS will be evaluated according to the Prostate Cancer Working Group 3 (PCWG3) criteria. Secondary efficacy endpoints include the rPFS at 12 months, response rate by PCWG3 modified RECIST 1.1, PSA response, PSA progression-free survival, progression-free survival, and overall survival. Additionally, exploratory biomarkers, including proteins, tumor tissue-derived DNA, and circulating cell-free DNA, will be collected before treatment, during treatment, and at disease progression. Specific biomarkers such as androgen receptor N-terminus, androgen receptor C-terminus, and Ki67 will be determined. Tumor tissue, whole blood, and plasma nucleic acids (DNA and RNA) will also be collected and analyzed for future research.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male participants who are at least 18 years of age on the day of signing informed consent.
- Histologically confirmed diagnosis of adenocarcinoma and/or neuroendocrine carcinoma of the prostate will be enrolled in this study.
- Presence of metastatic disease documented on imaging studies (bone scan, computed tomography (CT) and/or magnetic resonance imaging (MRI) scans
- At least one of the following Aggressive Variant Prostate Cancer (AVPC) Criteria a. Histologically proven small cell (neuroendocrine) prostate cancer b. Exclusive visceral metastases c. Predominantly lytic bone metastases d. Bulky lymph nodes (≥ 5 cm in longest dimension) or high-grade pelvic/prostatic masses e. Low PSA (≤10 ng/ml) at initial presentation in the presence of extensive disease (≥20 metastases) f. Elevated serum LDH (≥2 x ULN) or CEA (≥2 x ULN) or 7) g. Short time to castration-resistance (≤6 months).
- A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least after the last dose of study treatment and refrain from donating sperm during this period
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
- Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- Have provided archival tumor tissue sample obtained in the previous year since 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.
- 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 first dose of study intervention.
- Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the start of study intervention.
- Criteria for known Hepatitis B and C positive subjects a. Hepatitis B and C screening tests are not required unless: • Known history of HBV or HCV infection • As mandated by local health authority b. Hepatitis B positive subjects • Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. • Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. c. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. • Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
Exclusion Criteria
- 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 (e.g., CTLA-4, OX 40, CD137).
- Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to informed consent signature.
- Has received previous treatment with cabazitaxel or carboplatin.
- Has received prior radiotherapy within 2 weeks of start of study intervention. 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
- Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
- 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 intervention.
- 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.
- Known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
- Has severe hypersensitivity (≥Grade 3) to pembrolizumab, carboplatin or cabazitaxel and/or any of its excipients.
- 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 and is allowed.
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy
- Has congestive Heart failure NYHA ≥2.
- Has hypoacusis grade ≥2.
- Has a known history of Human Immunodeficiency Virus (HIV) infection
- Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Has had an allogenic tissue/solid organ transplant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Dec 2022 | 42 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 400 | 108 | PRD4323105 |
CARBOPLATIN | Test | PHF00230MIG | INTRAVENIOUS INFUSION | 400 | 18 | SCP28192792 |
CABAZITAXEL | Test | — | INTRAVENIOUS INFUSION | 25 | 18 | SUB31282 |