ALSYMPCA Trial Research Articles

A phase I/IIa study of the safety and efficacy of radium-223 chloride (Ra-223) with docetaxel (D) for castration-resistant prostate cancer (CRPC) patients with bone metastases.

TPS4694 Background: Ra-223is a first-in-class alpha-pharmaceutical that targets bone metastases (mets) with high energy alpha-particles of short range (< 100 μm). In the ALSYMPCA trial, Ra-223 plus best standard of care (BSC) significantly improved OS vs placebo plus BSC in CRPC patients (pts) with bone mets (Parker et al. ECCO/ESMO 2011), and was shown to have an excellent safety profile. Since D is an approved chemotherapy with demonstrated survival benefit for pts progressing after castrating hormone therapy, it is logical to explore combining Ra-223 plus D in pts with CRPC and bone mets. This study is being conducted in the Prostate Cancer Clinical Trials Consortium with an aim to establish the safe dose of Ra-223 and D when used in combination in pts with bone mets with CRPC. Methods: This ongoing phase I/IIa trial (NCT01106352) is enrolling pts with bone mets from CRPC intended for treatment with D. D naïve pts are preferred, although up to 10 previous infusions of D are acceptable if D was well tolerated and the patient is in good condition and fulfills all eligibility criteria at study entry. Phase I dose-escalation study: minimum of 9 pts (max. 18 pts) will be included if no dose limiting toxicity (DLT) is observed. Dose escalation will follow a ‘3+3’ design, with no intra-patient dose escalation or overlapping of cohorts permitted. Ra-223 doses are 25 or 50 kBq/kg, with number of Ra-223 injections (inj) (2, 4, 5, or 10) and interval between inj (3 or 6 wks) varying by escalation schema; D doses are 60 or 75 mg/m2 q3wk. DLT will be assessed when 6 wks post-inj safety data are available after 1st Ra-223 +D inj. Phase IIa open-label expanded safety study: pts will be randomized 2:1 to the recommended dose of Ra‑223 to be used with D or to treatment with D alone (approx. 42 pts will be included). Primary endpoint is to assess safety of combining Ra-223 with D. Exploratory efficacy endpoints for the open-label expanded safety portion of the study include change in disease-related biomarkers, time to 1st radiological or clinical progression, CTC and pain assessment. Enrollment in dose-escalation portion of the study is complete; expanded safety cohort to begin enrolling in March 2012.

New mechanistic insights into possible radiobiologic and pathophysiologic explanations for unexpectedly impressive outcomes data observed for hormone-refractary metastatic prostate cancer patients treated with radium 223.

10623 Background: The ALSYMPCA Trial of 223Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223Ra plus SOC vs best SOC. This trial was stopped early after 922 patients enrolled at over 100 centers achieved primary (overall survival) and all secondary endpoints including median survived (14 vs 11.2 m) time to first SRE (13.6 m vs 8.4 m) and time to PSA progression.These unexpectedly positive results prompted us to review some of the unique aspects of alpha-particle radiobiology and ultra-short range molecular targeting capabilities. Methods: Literature analysis. Results: The highly energetic alpha particles such as those released during decay of 223Ra (T1/2 = 11.4 mins) display unique radiobiologic and dosimetric aspects. The nuclear dose required in vitro for approximately 90% target cell kill is less than 1 Gy and electron micrographs shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. Bovine aortic endothelial cells exposed to alpha particle radiation indicate that the radiobiologic effects depend heavily on cell culture condition with nonuniform DNA strand break damage observed in isolated detached cells. The subcellular alpha particle path length appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. 223Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be effective in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing subcellular damage accumulation to target cell groups.

Management of natural forest in the semiarid areas of Africa: J. Fries, Ambio, 20(8), 1991, p 395–400

Symptomatic skeletal events (SSEs) commonly occur in patients with bone metastases, often leading to hospitalisations and decreased quality-of-life. In the ALSYMPCA trial, radium-223 significantly improved overall survival (hazard ratio 0.70, 95% confidence interval [CI] 0.58–0.83, P < 0.001) and prolonged time to first SSE (hazard ratio 0.66, 95% CI 0.52–0.83, P = 0.00037) and subsequent SSE (hazard ratio 0.65, 95% CI 0.51–0.83, P = 0.00039) versus placebo in patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Health care resource use (HCRU), including hospitalisation events and days, were prospectively collected in ALSYMPCA. We assessed health care resource use for the first 12 months post-randomisation. Significantly fewer radium-223 (218/589; 37.0%) versus placebo patients (133/292; 45.5%) had at least one hospitalisation event (P = 0.016). However, mean number of hospitalisation events per patient was similar (radium-223 0.69 versus placebo 0.79, P = 0.226), likely due to the significantly longer follow-up time for radium-223 (7.82 months versus 6.92 months for placebo; P < 0.001). There were significantly fewer hospitalisation days per patient for radium-223 (4.44 versus 6.68, respectively, P = 0.004). The reduction in hospitalisation days with radium-223 was observed both before first SSE (2.35 days versus 3.36 days, respectively) and after SSE (7.74 days versus 9.19 days, respectively). Our data suggest that this reduced hospital days along with the survival benefit and reduction in time to SSEs with radium-223 treatment may contribute to improvements in health-related quality-of-life in patients with castration-resistant prostate cancer with symptomatic bone metastases (ALSYMPCA ClinicalTrials.gov number, NCT00699751.).