SummaryBackground: Strong P2Y12 blockade, as can be achieved with novel anti-platelet agents such as prasugrel, has been shown in vitro to inhibit both ADP and thromboxane A2-mediated pathways of platelet aggregation, calling into question the need for the concomitant use of aspirin. Objective: The present study investigated the hypothesis that aspirin provides little additional anti-aggregatory effect in a group of healthy volunteers taking prasugrel. Study participants/methods: In all, 9 males, aged 18 to 40 years, enrolled into the 21-day study. Prasugrel was loaded at 60 mg on day 1 and maintained at 10 mg until day 21. At day 8, aspirin 75 mg was introduced and the dose increased to 300 mg on day 15. On days 0, 7, 14 and 21, platelet function was assessed by aggregometry, response to treatments was determined by VerifyNow™ and urine samples were collected for quantification of prostanoid metabolites. Results: At day 7, aggregation responses to a range of platelet agonists were reduced and there was only a small further inhibition of aggregation to TRAP-6, collagen and epinephrine at days 14 and 21, when aspirin was included with prasugrel. Urinary prostanoid metabolites were unaffected by prasugrel, and were reduced by the addition of aspirin, independent of dose. Conclusions: In healthy volunteers, prasugrel produces a strong anti-aggregatory effect, which is little enhanced by the addition of aspirin. The addition of aspirin as a dual-therapy with potent P2Y12 receptor inhibitors warrants further investigation.
Background: Triple-negative breast cancer (TNBC) comprises about 15% of all breast cancer types, and has a particularly aggressive course. Following first-line therapy, the median PFS is <3 months, and OS is <10 months. Therefore, new treatment strategies are needed. Since Trop-2 is expressed in >90% of TNBC, as measured by IHC, we conducted a trial to evaluate the safety and efficacy of a humanized anti-Trop-2 monoclonal antibody conjugated to a high concentration of SN-38, a camptothecin that is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan, with 2-3 logs higher potency than the prodrug. Methods: After establishing the optimal repeated dose in a Phase I trial (ClinicalTrials.gov, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC. Patients received 8 or 10 mg/kg IMMU-132 i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible. Results: As of May 10, 2015, 58 patients with TNBC, with a median of 4 prior therapies (range, 1-11), were treated with IMMU-132. Grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%). No patient developed antibodies to SN-38 or the antibody, and no patient discontinued therapy due to toxicity. Tumor responses were defined as ORR (CR+PR) in 31% of 49 evaluated patients, including 2 with CR, and a clinical benefit ratio (CR+PR+SD>6 mo) of 49% (63% with SD>4 mo; 23 patients continuing treatment after 1st assessment). The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient. Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining. Conclusions: The Trop-2-targeting IMMU-132, delivering cytotoxic doses of the topoisomerase I inhibitor, SN-38, shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This ADC appears to have a high therapeutic index in heavily pretreated patients. Citation Format: Bardia A, Diamond JR, Mayer IA, Starodub AN, Moroose RL, Isakoff SJ, Ocean AJ, Guarino MJ, Berlin JD, Messersmith WA, Thomas SS, O'Shaughnessy JA, Kalinsky K, Maurer M, Chang JC, Forero A, Traina T, Gucalp A, Wilhelm F, Wegener WA, Maliakal P, Sharkey RM, Goldenberg DM, Vahdat LT. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-06.
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