Abstract P1-16-03: An open-label, multicenter phase 1b trial of radium-223 + paclitaxel in cancer patients with bone metastases: Safety results from the breast cancer patient subgroup
Authors: Danson SJ , Perets R , Lopez J , Joensuu H , Peer A , Harris SJ , Souza F , Ploeger B , Pereira KMC , Geva R 
Published: February 2018

Abstract
Background: Taxanes have an established role in treating breast cancer (BC), and combination with radium-223 (Ra-223) may be an option in patients (pts) with bone metastases. Both therapies impact hematologic parameters, but myelosuppression risk in combination is unknown. A phase 1b trial (NCT02442063) in cancer pts with bone metastases studied Ra-223+paclitaxel (PTX) safety and mode of interaction regarding myelosuppression; BC subgroup safety results are presented.
Methods: Eligible pts had a malignant solid tumor with ≥2 bone metastases and were PTX candidates. Treatment (tx) was 7 PTX cycles (90 mg/m2/wk IV per local standard of care, 3 wk on/1wk off) + 6 Ra-223 cycles (55 kBq/kg IV; 1 injection q4wk, starting at PTX cycle 2). Primary endpoint was % pts with neutropenia and thrombocytopenia during Ra-223+PTX (cycles 2, 3) vs PTX alone (cycle 1). A dose-exposure-response model describing time course of Ra-223+PTX–induced suppression of absolute neutrophil counts was used to evaluate Ra-223+PTX mode of interaction (additive or synergistic) in the total population.
Results: 15/22 enrolled pts were treated (total population); 7 had BC (BC subgroup). Baseline characteristics of the 2 groups were similar; ECOG PS was better in BC pts (Table). Fewer BC pts had prior taxane therapy (29% vs 53%), but rates of ≥3 prior chemotherapy regimens were similar (43% vs 47%). BC pts, vs total population, had slightly longer median tx duration for Ra-223 (6 vs 5.5 cycles) and PTX (7 vs 6 cycles), and more pts who completed 6 Ra-223 doses (57% vs 47%). Tx discontinuation related to disease progression in 29% of BC pts vs 33% in total population. Table shows TEAEs. In the BC subgroup, all 7 pts completed cycle 3 and Gr 3 neutropenia rates were 43% in cycle 2 and 14% in cycle 3, vs 29% in cycle 1; there was no Gr 4 neutropenia or Gr 3/4 thrombocytopenia. In the total population, 13 pts completing cycle 3 were in the pharmacodynamics analysis. Their Gr 3 neutropenia rates were 31% in cycle 2 and 8% in cycle 3, vs 23% in cycle 1; there was no Gr 4 neutropenia or Gr 3/4 thrombocytopenia. Myelosuppression model for the total population showed an additive effect of Ra-223 to PTX-induced neutropenia, with an additional 10% average decrease in absolute neutrophil count vs PTX alone. BC subgroup modeling was not feasible due to small sample size.
Total Population n=15BC Subgroup n=7Median age (range), y61(45-76)58(45-68)Tumor type, n (%) Breast7(47)7(100)Prostate4(27)0Bladder1(7)0Non-small cell lung1(7)0Other2(13)0ECOG score, n (%) 06(40)5(71)18(53)1(14)Prior taxane therapy, n (%)8(53)2(29)≥3 prior chemotherapy regimens, n (%)7(47)3(43)TEAEs, n (%) Gr 3/49(60)2(29)Serious6(40)2(29)Gr 3/4 TEAEs, n (%)* Neutrophil count decreased6(40)3(43)White blood cell count decreased4(27)2(29) TEAE=treatment-emergent adverse event.*In &gt;15% of patients.
Conclusions: Ra-223 was well tolerated when combined with PTX in pts with solid tumors and bone metastases. The BC subgroup vs total population had slightly higher hematologic AE rates, but fewer Gr 3/4 and serious TEAEs; more BC pts also completed study tx. The combination should be explored further in pts with bone metastases.
Citation Format: Danson SJ, Perets R, Lopez J, Joensuu H, Peer A, Harris SJ, Souza F, Ploeger B, Pereira KMC, Geva R. An open-label, multicenter phase 1b trial of radium-223 + paclitaxel in cancer patients with bone metastases: Safety results from the breast cancer patient subgroup [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-03.