A Phase 2 clinical trial of Pembrolizumab in combination with Carboplatin and Cabazitaxel in Aggressive Variant Metastatic Castration Resistant Prostate Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundación Oncosur

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12], Diseases [C] - Neoplasms [C04]

Trial duration

5 May 2023 → ongoing

Decision date (initial)

2022-10-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Efficacy and safety of pembrolizumab in combination with carboplatin and cabazitaxel according to 6 months Radiographic Progression-Free Survival rate (rPFS) according to the Prostate Cancer Working Group 3 (PCWG3).

Secondary objectives 8

1. To determine radiographic Progression Free-Survival at 12 months
2. To evaluate response rate by PCWG modified RECIST 1.1
3. To evaluate PSA response (when PSA is evaluable)
4. To determine PSA progression-free survival (PSA-PFS)
5. To determine progression-free survival (PFS)
6. To determine overall survival (OS)
7. Correlation of efficacy endpoints with AVPC- Molecular- Classification (MC) defined as the presence of tumour mutations in two of the following genes: P53, PTEN or RB
8. Correlation of efficacy endpoints with neuroendocrine signature in the ctDNA methylation pattern

Conditions and MedDRA coding

Aggressive Variant Metastatic Castration Resistant Prostate Cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Male participants who are at least 18 years of age on the day of signing informed consent.
2. Histologically confirmed diagnosis of adenocarcinoma and/or neuroendocrine carcinoma of the prostate will be enrolled in this study.
3. Presence of metastatic disease documented on imaging studies (bone scan, computed tomography (CT) and/or magnetic resonance imaging (MRI) scans
4. 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).
5. 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
6. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
7. 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.
8. 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.
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 first dose of study intervention.
10. 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.
11. 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 20

1. 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).
2. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to informed consent signature.
3. Has received previous treatment with cabazitaxel or carboplatin.
4. 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
5. 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.
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 intervention.
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. 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.
9. 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.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, carboplatin or cabazitaxel 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 and is allowed.
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
13. Has an active infection requiring systemic therapy
14. Has congestive Heart failure NYHA ≥2.
15. Has hypoacusis grade ≥2.
16. Has a known history of Human Immunodeficiency Virus (HIV) infection
17. 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.
18. 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.
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
20. Has had an allogenic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Radiographic Progression-free survival (rPFS) rate at 6 months. Radiographic Progression-Free Survival is defined from the date of first dose of study treatment to the date of radiographic confirmed progression or death (from any cause), whichever occurs first
2. Incidence of adverse events (AEs) graded according to NCI-CTCAE v 5.0 criteria

Secondary endpoints 12

1. Radiographic Progression free-survival at 12 months
2. Response rate by PCWG3 modified RECIST 1.1
3. PSA response (when PSA is evaluable)
4. PSA progression-free survival
5. Progression-free survival
6. Overall survival
7. Abnormalities in vital signs, laboratory test values, and ECG data
8. Treatment modifications
9. Patients’ withdrawals for safety reasons
10. Exploratory biomarkers (including but not limited to proteins, tumor tissue-derived DNA and circulating cell-free DNA) will be collected before treatment, during treatment and at disease progression
11. We will determine androgen receptor N-terminus (AR441, Carpinteria, CA, USA), androgen receptor C-terminus (SP242, Abcam, Cambridge, UK) and Ki67 (M724001-2, Dako, Glostrup, Denmark).
12. We will collect and analyze tumor tissue, whole blood and plasma nucleic acids (DNA and RNA) in future research.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundación Oncosur

Sponsor organisation

Fundación Oncosur

Address

Gran Vía Marques De Turia N. 65, 3-11 3-11

City

Valencia

Postcode

46005

Country

Spain

Scientific contact point

Organisation

Fundación Oncosur

Contact name

José Gallo

Public contact point

Organisation

Fundación Oncosur

Contact name

José Gallo

Third parties 1

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications