This is a Phase I, open-label, single-center study evaluating the safety, tolerability, and recommended Phase II dose of docetaxel when combined with a fixed dose of 177-Lutetium-PSMA-I&T in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Patients will receive standard androgen deprivation therapy, docetaxel at escalating doses (50 mg/m², 60 mg/m², 75 mg/m² every 3 weeks), and 177Lu-PSMA-I&T at a fixed dose of 7.4 GBq every 6 weeks (up to 4 cycles). A 3+3 dose escalation design will be employed. Secondary endpoints include safety profile, treatment-limiting toxicities, treatment completion rate, and delayed toxicity. Exploratory endpoints include PSA response, radiographic progression-free survival (rPFS), and PERCIST-based response rate.

This is a Phase I, open-label, single-center study designed to evaluate the safety, tolerability, and to determine the recommended Phase II dose (RP2D) of docetaxel when combined with a fixed dose of 177Lu-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (mCRPC) who have not previously received chemotherapy for castration-resistant disease.

All participants will continue receiving androgen deprivation therapy (ADT) throughout the study. The treatment regimen includes docetaxel administered intravenously every 3 weeks at escalating doses of 50 mg/m², 60 mg/m², and 75 mg/m² (up to 10 cycles), combined with 177Lu-PSMA-I&T at a fixed dose of 7.4 GBq every 6 weeks, for up to 4 cycles. A traditional 3+3 dose-escalation design will be used, allowing sequential patient enrollment and assessment of dose-limiting toxicities (DLTs) during the first 3 weeks to establish the optimal docetaxel dose for future studies.

Treatment will continue until completion of 10 cycles of docetaxel and 4 cycles of 177Lu-PSMA-I&T, or until disease progression, unacceptable toxicity, or withdrawal of consent. Imaging exams, including SPECT, will be performed after each lutetium administration for dosimetry assessment.

The primary endpoint is the determination of the RP2D of docetaxel when combined with 177Lu-PSMA-I&T. Secondary endpoints include evaluation of the overall safety profile, incidence of DLTs, treatment completion rate, and monitoring of late toxicities. Exploratory endpoints include PSA response (≥50% decline), radiographic progression-free survival (rPFS), and response rate based on PERCIST criteria using PSMA-PET.

Patients will undergo imaging assessments every 6 weeks (±7 days), including PSMA-PET/CT, FDG-PET/CT, CT scans, and bone scintigraphy. Laboratory tests will be performed every 3 weeks during treatment and every 6 weeks during the post-treatment follow-up, for up to 24 weeks.

Key inclusion criteria include: male patients aged 18 years or older, histologically confirmed adenocarcinoma of the prostate, documented metastatic disease by conventional imaging, castration-resistant disease with testosterone levels <50 ng/mL, ECOG performance status of 0-1, adequate organ function, and positive 68Ga-PSMA-PET/CT uptake according to protocol-defined parameters.

Key exclusion criteria include: presence of small-cell or neuroendocrine tumor components, prior chemotherapy or radiopharmaceuticals for castration-resistant disease, recent or active second malignancies, significant discordance between FDG-PET/CT and PSMA-PET/CT, visible brain metastases, severe urinary incontinence, or any clinical condition that, in the investigator's judgment, would contraindicate the use of docetaxel or 177Lu-PSMA-I&T. Full details of inclusion and exclusion criteria are provided in the study protocol.

This study aims to establish the optimal dose of docetaxel in combination with 177Lu-PSMA-I&T and to generate preliminary safety and efficacy data for treating patients with metastatic castration-resistant prostate cancer.

Inclusion Criteria:

1. Men aged 18 years or older.

2. Histological or cytological diagnosis of prostate adenocarcinoma. The presence of intraductal or cribriform carcinoma will be allowed.

3. Presence of metastatic disease on conventional imaging exams (bone scintigraphy and/or CT scan or MRI).

4. Patients with castration-resistant disease, defined as testosterone <50 ng/mL in the context of prior orchiectomy or ongoing androgen deprivation therapy (ADT) with LHRH agonists or antagonists, plus at least one of the criteria below:

5. PSA ≥2.0 ng/mL with at least two consecutive PSA rises at intervals of at least 1 week.

6. Radiologic progression defined by the investigator.

7. Clinical progression defined by the investigator.

8. Performance status per the Eastern Cooperative Oncology Group (ECOG) equal to 0 or 1.

9. Willingness to continue ongoing ADT.

10. Adequate organ function as defined below:

    • Parameter Requirement
    • Neutrophils ≥ 1,500/µL
    • Hemoglobin ≥ 12 g/dL
    • Platelets ≥ 100,000/µL
    • Creatinine ≤ 1.5 x upper limit of normal
    • Potassium > 3.5 mmol/L and <5.0 mmol/L
    • Total Bilirubin ≤ ULN (unless Gilbert's disease)
    • AST (TGO) ≤ 2.5 x ULN
    • ALT (TGP) ≤ 2.5 x ULN

11. 68Ga-PSMA-PET/CT performed during the screening phase showing metastatic (extraprosthetic and extrapelvic) disease with radiotracer uptake and:

12. SUVmax ≥20 in at least one site;

13. SUVmax >10 in all other measurable metastatic sites.

14. Lesions with uptake at least 1.5 times greater than hepatic background will be considered measurable.

Exclusion Criteria:

1. Presence of any small-cell or neuroendocrine component of prostate carcinoma.
2. Prior receipt of chemotherapy or radiopharmaceuticals in the castration-resistant setting.
3. Presence of another active malignancy requiring treatment or a cancer diagnosis within the past 5 years. Carcinoma in situ of any site, squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or papillary bladder tumors will be allowed if previously treated.
4. Severe urinary incontinence at the investigator's discretion.
5. 18F-FDG-PET/CT will be performed during screening and will be considered exclusionary if there is discordance with the 68Ga-PSMA-PET/CT. Discordance is defined as FDG-hypermetabolic lesions with absent or low PSMA uptake (SUVmax <10) in more than 50% of measurable metastatic lesions.
6. Patients with brain metastases visible on 68Ga-PSMA-PET/CT.

It has been decided not to share individual participant data (IPD) related to the study for several reasons. Protecting the privacy of participants is a priority.

Sharing IPD may expose sensitive information that, even when de-identified, can be traced back to individuals. Furthermore, the complexity of the data makes sharing challenging without the risk of misunderstandings or misinterpretations, which could compromise the integrity of the research. Sharing IPD without the explicit consent of participants may violate ethical principles of respect and protection. There is also a need to comply with regulatory guidelines governing data sharing to avoid potential legal issues. Finally, the focus will be on disseminating aggregated results that can benefit the scientific community and the public without compromising individual privacy.