Abstract P5-20-03: A phase 2, double-blind, randomized, placebo-controlled, dose-finding study of sotatercept for the treatment of patients with chemotherapy-induced anemia and metastatic breast cancer.

Abstract Background: Sotatercept is a recombinant activin receptor IIA (ActRIIA) ligand trap and is comprised of the extracellular domain of ActRIIA linked to the Fc domain of human IgG1 (ActRIIA-IgG1). Results of preclinical and early clinical studies provide evidence that sotatercept increases the concentration of hemoglobin (Hb) in blood and may constitute a novel treatment for chemotherapy-induced anemia (CIA), a condition that results in significant morbidity. Methods: This study evaluated the safety of, and hematopoietic response to, sotatercept in patients with CIA and metastatic breast cancer (MBC). Response was defined as increase in Hb ≥1 g/dL for ≥28 consecutive days during treatment or ≤2 months following the last dose, in the absence of red blood cell (RBC) transfusion or treatment with an erythropoiesis stimulating agent (ESA). If RBC transfusion or treatment with an ESA was required, no Hb measurements within 28 days of the RBC transfusion or administration of ESA were used to determine the Hb response. Subjects were randomized to subcutaneous injection of sotatercept (0.1, 0.3, or 0.5 mg/kg) or placebo and were treated on day 1 of each of four 28-day cycles. Results: Thirty (30) subjects were enrolled and treated (5 placebo, 25 sotatercept). Increases in mean Hb in the 0.3 and 0.5 mg/kg groups were greater than in 0.1 mg/kg and placebo groups. Increases peaked approximately 15 days following treatment and declined over the remaining interval between treatments. Among 23 subjects with confirmed CIA and administered ≥1 dose and followed for ≥57 days (per-protocol analysis), 5/18 (28%) administered sotatercept responded (0/5 [0%] at 0.1 mg/kg; 3/9 [33%] at 0.3 mg/kg; 2/4 [50%] at 0.5 mg/kg) vs 1/5 [20%] administered placebo. Among 13 nonresponders administered sotatercept, 5 (39%) experienced ≥1 dose interruption/reduction, as per protocol, due to elevated Hb. The incidence of adverse events (AEs) was consistent with that reported in patients with MBC. No dose-limiting or dose-related toxicity was observed. Conclusions: Sotatercept demonstrated dose-dependent hematopoietic activity in subjects with CIA and MBC. The safety findings were generally consistent with the known safety profile of sotatercept. These data suggest that a greater dose of sotatercept or a dose interval &amp;lt;28 days might result in a more sustained, and greater rate of, hematopoietic response. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-03.</jats:p

P3-16-18: Phase 2, Open-Label Study of EZN-2208 (PEG-SN38) in Patients with Previously Treated Metastatic Breast Cancer.

Abstract Background EZN-2208 is a water-soluble PEGylated conjugate of SN38 that results in parenteral delivery, increased solubility, higher exposure, and longer apparent half-life of SN38, as well as more profound deoxyribonucleic acid (DNA) damage and inhibition of angiogenesis. EZN-2208 results in prolonged exposure of tumors to SN38 via preferential accumulation of EZN-2208 in the tumor and prolonged release of SN38 in the blood. Methods: This trial evaluated EZN-2208 delivered as a 1-h IV infusion weekly for 3 wks in 4-wk cycles. The primary objective was to determine the overall response rate (RR) in female patients with metastatic breast cancer (MBC) who had received prior adjuvant or metastatic therapy with either 1) anthracycline and taxane (AT) or 2) anthracycline, taxane, and capecitabine (Xeloda®) (ATX). Secondary objectives included evaluation of RR based on tumor receptor status, duration of response, progression-free survival (PFS), overall survival (OS), and safety and toxicity. Response was evaluated using RECIST (v1.1). Results: 148 patients received EZN-2208 in the AT (n=65; median age = 56 y [31-84 y]) or ATX (n=83; median age = 55 y [36-83 y]) cohorts. All 65 patients in the AT cohort had received 0–2 lines of prior cytotoxic therapy for MBC; for the ATX cohort, 31 patients (37%) had received 0–2 prior lines of cytotoxic therapy for MBC, 50 patients (60%) had received 3–4 prior lines, and 2 patients (2%) had received 5 prior lines. Preliminary results follow; final data will be presented at the meeting. Median (range) cycles of EZN-2208 was 2.3 (0.3-14) for AT and 2 (0.3-15) for ATX. Best overall response is shown in the table. RR (PR+uPR) was 22% for AT and 10% for ATX. Median (95% CI) time to progression was 3.8 mo (3.6−7.4) for AT and 3.3 mo (1.8−3.7) for ATX. Median (95% CI) duration of response was 4.0 mo (3.7−5.6) for AT and 5.2 mo (1.9-..) for ATX. 6-mo PFS (95% CI) was 34% (19%-50%) for AT and 19% (9%-29%) for ATX. Median PFS (95% CI) was 3.8 mo (2.7−5.6) for AT and 2.9 mo (1.83.7) for ATX. Median OS (95% CI) was 9.1 mo (6.1−12.7) for AT and 7.9 mo (6.4−12.9) for ATX. Grade 3 or 4 drug-related adverse events (&amp;gt;10% of patients in either arm) included neutropenia (43%, 33%), diarrhea (11%, 8%), and leukopenia (11%, 6%). Conclusions: EZN-2208 is active in patients with previously treated MBC. The activity is similar regardless of ER status and is promising in the TNBC population. The safety profile of EZN-2208 is acceptable with good tolerability in most patients. Further evaluation of EZN-2208 in this population is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-18.</jats:p

Coral Reef Community Composition in the Context of Disturbance History on the Great Barrier Reef, Australia

Much research on coral reefs has documented differential declines in coral and associated organisms. In order to contextualise this general degradation, research on community composition is necessary in the context of varied disturbance histories and the biological processes and physical features thought to retard or promote recovery. We conducted a spatial assessment of coral reef communities across five reefs of the central Great Barrier Reef, Australia, with known disturbance histories, and assessed patterns of coral cover and community composition related to a range of other variables thought to be important for reef dynamics. Two of the reefs had not been extensively disturbed for at least 15 years prior to the surveys. Three of the reefs had been severely impacted by crown-of-thorns starfish outbreaks and coral bleaching approximately a decade before the surveys, from which only one of them was showing signs of recovery based on independent surveys. We incorporated wave exposure (sheltered and exposed) and reef zone (slope, crest and flat) into our design, providing a comprehensive assessment of the spatial patterns in community composition on these reefs. Categorising corals into life history groupings, we document major coral community differences in the unrecovered reefs, compared to the composition and covers found on the undisturbed reefs. The recovered reef, despite having similar coral cover, had a different community composition from the undisturbed reefs, which may indicate slow successional processes, or a different natural community dominance pattern due to hydrology and other oceanographic factors. The variables that best correlated with patterns in the coral community among sites included the density of juvenile corals, herbivore fish biomass, fish species richness and the cover of macroalgae. Given increasing impacts to the Great Barrier Reef, efforts to mitigate local stressors will be imperative to encouraging coral communities to persist into the future

Early-phase dynamics in coral recovery following cyclone disturbance on the inshore Great Barrier Reef, Australia

Coral recovery (the restoration of abundance and composition of coral communities) after disturbance is a key process that determines the resilience of reef ecosystems. To understand the mechanisms underlying the recovery process of coral communities, colony abundance and size distribution were followed on reefs around Pelorus Island, located in the inshore central region of the Great Barrier Reef, following a severe tropical cyclone in 2011 that caused dramatic loss of coral communities. Permanent quadrats (600m2) were monitored biannually between 2012 and 2016, and individual coral colonies were counted, sized and categorized into morphological types. The abundance of coral recruits and coral cover were also examined using permanent quadrats and random line intercept transects, respectively. The number of colonies in the smallest size class (4–10 cm) increased substantially during the study period, driving the recovery of coral populations. The total number of coral colonies 5 yr post-cyclone reached between 73 and 122% of pre-cyclone levels though coral cover remained between 16 and 31% of pre-cyclone levels, due to the dominance of small coral colonies in the recovering communities. Temporal transitions of coral demography (i.e., colony-size distributions) illustrated that the number of recently established coral populations overtook communities of surviving colonies. Coral recruits (<4cm in size) also showed increasing patterns in abundance over the study period, underscoring the importance of larval supply in coral recovery. A shift in morphological composition of coral communities was also observed, with the relative abundance of encrusting corals reduced post-cyclone in contrast to their dominance prior to the disturbance. This study identifies the fine-scale processes involved in the initial recovery of coral reefs, providing insights into the dynamics of coral demography that are essential for determining coral reef resilience following major disturbance