Clinical genitourinary cancer · 2025
Dose-Dense Docetaxel and Radium-223 in Bone-Dominant Metastatic Castration-Resistant Prostate Cancer.
Клиническое исследование I фазыСтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Connell Brendan, Hwang Clara, Folefac Edmund, Lawlor Christian, Koethe Benjamin, Mathew Paul
Аннотация
BACKGROUND: Disease progression in castration-resistant prostate cancer (CRPC) remains bone-dominant and docetaxel-responsive. Docetaxel and radium-223 would be a logical combination but myelosuppression is dose-limiting. Dose-dense schedules of docetaxel have comparable activity to bolus dosing with mitigated myelosuppression. We hypothesized that dose-dense docetaxel with standard radium-223 would be a feasible, safe and effective combination in bone-dominant metastatic CRPC.
METHODS: Subjects had progressive bone-predominant CRPC. Design was dose escalation plus expansion with 28-day cycles. Docetaxel was given every 2 weeks in a 4-week lead-in, then with Radium-223 every 4 weeks up to 6 cycles. Dose-levels (DL) included 1: docetaxel 40 mg/m2; 1a: docetaxel 40 mg/m2 with G-CSF on Day 16, 2a: docetaxel 50 mg/m2 with G-CSF on Day 16. The maximum tolerated dose (MTD) was defined as the highest (DL) of docetaxel achieved without dose-limiting toxicity (DLT). Markers of safety and efficacy were annotated.
RESULTS: Forty-three subjects were enrolled (NCT03737370). The patient population included 21% black, 9% Asians, 93% had prior intensified hormonal therapy, 67% had bone pain, and 76% had ≥ 4 bone metastases. Seven patients dropped out during the 4-week docetaxel lead in. Neutropenia at DL 1 limited combination therapy. No (DLT) occurred at DL 1a (n = 6) or DL 2a (n = 5). Twenty-two patients were enrolled to an expansion cohort with docetaxel 50 mg/m2 with G-CSF on Day 16 (DL 2a), the designated MTD. Among 35 patients treated with the combination, there were no febrile neutropenia events. One patient had dose-limiting Grade 3 anemia. PSA50 response was 51.4% and PSA90 was 25.7%. Median progression-free survival was 11.7 months, and median overall survival was 20.1 months.
CONCLUSIONS: A lead-in cycle and a dose-dense schedule of docetaxel with G-CSF enabled the combination with radium-223 in standard dose-intensities with minimal hematological toxicity. The regimen will likely combine logically and safely with hormone-intensification for study in high-risk/high-volume castration-sensitive metastatic disease.
METHODS: Subjects had progressive bone-predominant CRPC. Design was dose escalation plus expansion with 28-day cycles. Docetaxel was given every 2 weeks in a 4-week lead-in, then with Radium-223 every 4 weeks up to 6 cycles. Dose-levels (DL) included 1: docetaxel 40 mg/m2; 1a: docetaxel 40 mg/m2 with G-CSF on Day 16, 2a: docetaxel 50 mg/m2 with G-CSF on Day 16. The maximum tolerated dose (MTD) was defined as the highest (DL) of docetaxel achieved without dose-limiting toxicity (DLT). Markers of safety and efficacy were annotated.
RESULTS: Forty-three subjects were enrolled (NCT03737370). The patient population included 21% black, 9% Asians, 93% had prior intensified hormonal therapy, 67% had bone pain, and 76% had ≥ 4 bone metastases. Seven patients dropped out during the 4-week docetaxel lead in. Neutropenia at DL 1 limited combination therapy. No (DLT) occurred at DL 1a (n = 6) or DL 2a (n = 5). Twenty-two patients were enrolled to an expansion cohort with docetaxel 50 mg/m2 with G-CSF on Day 16 (DL 2a), the designated MTD. Among 35 patients treated with the combination, there were no febrile neutropenia events. One patient had dose-limiting Grade 3 anemia. PSA50 response was 51.4% and PSA90 was 25.7%. Median progression-free survival was 11.7 months, and median overall survival was 20.1 months.
CONCLUSIONS: A lead-in cycle and a dose-dense schedule of docetaxel with G-CSF enabled the combination with radium-223 in standard dose-intensities with minimal hematological toxicity. The regimen will likely combine logically and safely with hormone-intensification for study in high-risk/high-volume castration-sensitive metastatic disease.