Platelets from patients with myeloid leukaemia showed reduced aggregation with collagen or thrombin. These platelets also had a lower capacity to bind thrombin. This lower thrombin binding is due to a decrease in the total quantity of receptors available and not because of a change in the affinity. In the presence of the patients' plasma, the aggregation behaviour of normal platelets induced by thrombin as well as the clotting time of fibrinogen remained unchanged. The results suggest that the platelet dysfunction in myeloid leukaemia is partially due to a membrane defect involving the thrombin receptors which leads to an impaired induction of the initial stimulation.
1028 Background: Current therapeutic efforts in the management of HER2+ MBC focus on targeting the HER receptor family, however co-inhibition of targets downstream of the HER2 pathway, such as cyclin D-CDK 4/6, could enhance therapeutic efficacy. We conducted a phase 1b study of the CDK4/6 inhibitor ribociclib and T-DM1 in patients (pts) with HER2+ MBC. The primary objective was to determine the recommended phase 2 dose (RP2D) of ribociclib plus T-DM1. Secondary objectives included safety, PK assessments, and efficacy. Methods: Pts with HER2+ MBC who previously received at least 1 taxane and trastuzumab-containing regimen in any setting were eligible. Pts with previous CDK4/6 inhibitor exposure, QTcF > 450msec, or unstable brain metastases were excluded. Ribociclib was given orally for 2 weeks of a 21-day cycle (days 8-21), with T-DM1 given at 3.6 mg/kg every 3 weeks on day 1. A standard 3+3 dose escalation design was used to evaluate various doses of ribociclib in combination with T-DM1 to determine the RP2D. Results: From 5/2016 – 10/2018, 10 pts (8/10 ER+) were enrolled with a median age of 53 (38-72) and median of 1 (0-2) prior therapies for MBC. During dose-escalation, pts received doses of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 1). No DLTs were observed. The most common treatment related grade 3 or higher AEs were neutropenia (50%), infection (20%), anemia (10%), and thrombocytopenia (10%). 4/10 pts had dose reductions due to toxicity. The average concentration of ribociclib at steady state was similar at each dose level, ranging from 273 to 413 ng/mL. Among 9 evaluable pts, the ORR was 33% (3/9) and the other 6 pts had stable disease. After a median follow-up time of 10.9 months, the median PFS was 12.5 months (95% CI [10.5. 20.9]). Biomarker results will be presented at the meeting. Conclusions: Co-targeting HER2 and CDK4/6 with the combination of ribociclib with T-DM1 was well tolerated with evidence of clinical activity. Based on PK analysis and dose reductions, 400 mg is the RP2D. Further evaluation is warranted for patients with HER2+ MBC. Clinical trial information: NCT02657343.
In this study we have explored the interaction of thrombin with platelets from human and rat. Compared to human platelets, rat platelets suspended in plasma required a higher concentration of thrombin for aggregation. This difference in sensitivity to thrombin was maintained when platelets were washed and suspended in buffer. Platelets from both mammals bound thrombin and showed a similar number of binding sites. However, the apparent dissociation constant of thrombin binding for rat platelets was approximately 15-fold higher than that for human. Thus, the decreased aggregation response of rat platelets may be due to a reduced binding of thrombin to its receptor. It is known that the thrombin receptor is located on the platelet surface. Gel electrophoresis of platelets followed by specific staining as well as fluorography showed significant differences in the surface glycoproteins of human and rat platelets. Human platelets showed labeled components corresponding to 210,000 and 160,000 daltons, whereas rat platelets showed glycoproteins with molecular weights of 240,000 and 190,000. A 135,000-dalton component was present in platelets from both sources. These results suggest that either or both glycoproteins of 210,000 and 160,000 daltons may be involved in the interaction of thrombin with human platelets.
Background: Metastatic breast cancer (MBC) accounts for most breast cancer deaths. In 2018, two Poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib and talazoparib, were approved for the treatment of MBC patients with germline BRCA1 or 2 mutations based on the OlympiAD and EMBRACA trials (Robson, NEJM, 2017 and Litton, NEJM, 2018), which demonstrated improvement in progression-free survival (PFS) with PARP inhibitors compared to chemotherapy. These landmark findings have triggered much interest in studying PARP inhibitors in MBC, but germline BRCA mutations only account for 5-10% of breast cancer patients. A critical question is whether PARP inhibitors may also be beneficial in MBC with somatic BRCA1 or 2 mutations, similar to somatic BRCA mutant ovarian cancer where they are effective(George, Oncotarget, 2017). Liquid biopsies via circulating cell-free DNA (cfDNA) may unveil somatic mutations. We previously demonstrated (Vidula, SABCS, PD1-13, 2017) that a subset of MBC patients have detectable somatic cfDNA BRCA1 or 2 mutations, in the absence of germline BRCA mutations, highlighting the role of liquid biopsies for detection of somatic BRCA mutations in MBC. Based on our preliminary data, we hypothesize that we can utilize liquid biopsies to detect somatic BRCA1 or 2 mutations and guide therapy selection with a PARP inhibitor in patients with MBC. Methods: In this single arm phase II clinical trial we will evaluate the efficacy and safety of a PARP inhibitor, talazoparib, in patients with somatic BRCA mutant MBC (N=30). Patients will undergo cfDNA screening to identify cfDNA somatic BRCA1 or 2 deleterious mutations. Patients without known BRCA germline mutations who have cfDNA BRCA1 or 2 mutations will be enrolled at the Massachusetts General Hospital and University of California San Francisco. The study will enroll both patients with hormone receptor positive/HER2 negative breast cancer and triple-negative breast cancer whose disease has progressed on at least 1 prior line of endocrine therapy and at least 1 prior line of chemotherapy for MBC, respectively. Patients may have received any number of prior lines of therapy. Eligible patients will be treated with talazoparib 1 mg daily until progression (evaluated with serial CT chest/abdomen/pelvis and bone scan) or unacceptable toxicity. The primary endpoint is to determine PFS by RECIST 1.1. Patients will be enrolled in a two-stage design, providing 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety/tolerability (NCI CTCAE v5.0). Serial cfDNA will be collected at baseline and during treatment to evaluate for changes in the BRCA cfDNA mutant allelic fraction in response to therapy. The impact of pre-existing resistance mutations in baseline cfDNA, particularly BRCA reversion mutations that can occur with prior platinum exposure (Weigelt, CCR, 2017), on outcomes will be studied. Paired liquid biopsies (pre- and post-treatment) will be compared to generate hypotheses about potential novel targets for future combination studies with talazoparib to improve response(exploratory objective). This study may help expand the applicability of talazoparib in MBC. This study was activated in July 2019. Funding support for the clinical trial is provided by a Pfizer ASPIRE award. (NCT03990896). Citation Format: Neelima Vidula, Nora Horick, Erin Basile, Sara Sutherland, Ruth Fax, Daniel Haber, Leif Ellisen, Hope S. Rugo, Aditya Bardia. Evaluation of talazoparib, a PARP inhibitor, in patients with somatic BRCA mutant metastatic breast cancer: Genotyping based clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-03-03.
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