Fractionated docetaxel (D) and radium 223 (Ra223) in metastatic castrationresistant prostate cancer (CRPC): A modular phase I trial

Document Type

Conference Proceeding

Publication Date

5-29-2024

Publication Title

J Clin Oncol

Keywords

docetaxel, granulocyte colony stimulating factor, prostate specific antigen, radium, adult, adverse drug reaction, aged, anorexia, bone marrow suppression, bone metastasis, Caucasian, cerebrovascular accident, clinical article, clinical trial, conference abstract, controlled study, drug combination, drug dose regimen, drug therapy, failure to thrive, fatigue, febrile neutropenia, Food and Drug Administration, human, infusion related reaction, male, maximum tolerated dose, metastasis, neutropenia, phase 1 clinical trial, prostate cancer, quality of life, response evaluation criteria in solid tumors, side effect, special situation for pharmacovigilance, thrombocytopenia, visceral metastasis

Abstract

Background: Disease progression following novel hormonal therapy in CRPC remains bonedominant and D-responsive. D+ Ra223 would be a logical combination but myelosuppression is dose-limiting. Prior combinations have required a reduction in dose intensity (DI) in both agents. Fractionated schedules of D Q2weekly (DQ2) have comparable activity to D 75mg/m2 Q3weekly with mitigated myelosuppression. We hypothesized that a fractionated schedule of DQ2 with standard Ra223 dosing would be feasible while preserving DI. Methods: Subjects had progressive bone-metastatic CRPC, ECOG PS 0-2, and no bulky visceral disease. Design was phase I, 6+6, dose escalation plus expansion with 28-day cycles. DQ2 was given in a 4-week lead-in, then with Ra223 every 4 weeks. Dose-level (DL) 1: D 40mg/m2; if neutropenia, then 1a: D 40mg/m2 with G-CSF on Day 16, 2a: D 50mg/m2 with G-CSF on Day 16. Up to 6 cycles of the combination were given. Primary objective was the feasibility and maximum tolerated DL explored (MTD). Secondary objectives included PSA response, ORR, PFS, OS, and quality of life. Results: 43 patients (pts) enrolled including 34.9% non-white pts and 76.7% with ≥ 4 bony mets. 8 dropped out during the D lead in (1 each neutropenia, stroke, failure to thrive, anorexia/ fatigue, thrombocytopenia, infusion reaction and 2 hospitalized for other reasons). At DL1, 2 of 3 had DLT (both neutropenia). No DLT occurred at DL1a (n=5) or DL2a (n=5). MTD was DL2a. 22 subjects enrolled to expansion cohort at DL2a. Of the 35 pts treated with D + Ra223, adverse events of interest listed in the table. No febrile neutropenia, fractures, or G5 toxicity were seen. 19/35 completed all 6 cycles of combination therapy. PSA50 response was seen in 18 (51.4%) and PSA90 in 9 (25.7%) pts. Of 31 pts with evaluable data, best response (RECIST 1.1) was 1 CR, 5 PR, 23 SD, 2 PD. Median PFS was 50.0 weeks (95% CI: 37.3-86.1) and OS was 86.1 weeks (95% CI: 60.0-130.9). 10 pts progressed exclusively in nodal/visceral metastases compared to 6 in bone only. Quality of life measures remained stable on study. Conclusions: Utilizing a D lead-in strategy, combination DQ2 and Ra223 was feasible and well tolerated, with a favorable PFS and evidence of preferential control of osseous metastases. Dose-intensity for both docetaxel and Ra223 was preserved and comparable to the FDA-approved dose-schedules for each of the single agents. The lead-in design and use of G-CSF contributes significantly to the feasibility.

PubMed ID

Not assigned.

Volume

42

Issue

16

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