Citations

Background:Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ∼4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory (R/R) AML. Through inhibition of mIDH1, IVO suppresses production of the oncometabolite 2‐hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.Aims:To report safety and efficacy data from patients with R/R MDS enrolled in the first‐in‐human, phase 1, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839).Methods:This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of IVO. Enrollment was completed on May 8, 2017. In dose escalation, patients received single‐agent IVO orally (dose range, 200–1200 mg daily) in 28‐day cycles. The MTD was not reached and 500 mg QD was selected as the dose for expansion. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR (mCR) according to International Working Group 2006 criteria for MDS. Exploratory biomarker assessments included baseline co‐occurring mutations (next‐generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02–0.04%).Results:Baseline characteristics of the 12 patients with R/R MDS who received 500 mg IVO once daily were: 9 men/3 women; median age 72.5 years (range 52–78), and 42% were ≥75 years of age; median number of prior therapies 1 (range 1–3). As of Nov 2, 2018, 3 of 12 (25.0%) patients remained on treatment; 9 (75.0%) had discontinued (one for allogeneic stem cell transplantation). Median duration of exposure to IVO was 11.4 months (range 3.3–42.5). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n = 4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n = 3 each, 25.0%). No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome was observed in 1 of 12 (8.3%) patients (grade 2). Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient). Five of 12 patients achieved CR (41.7%; 95% CI 15.2%, 72.3%), 1 achieved PR (8.3%), and 5 achieved mCR (41.7%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median duration of CR was not estimable (NE) at the time of datacutoff and the median duration of response was 21.4 months (95% CI 2.3, NE). At 12 months, 60.0% of patients remained in CR. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for ≥56 consecutive days on treatment. Baseline co‐occurring mutations and changes in mIDH1 VAF levels will be presented.Summary/Conclusion:In patients with mIDH1 R/R MDS, IVO monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.

Abstract Background: Combining cyclin dependent 4/6 kinase inhibitors (CDK4/6i) with endocrine therapy (ET) has resulted in clinically significant improvements in progression-free survival (PFS) in persons with hormone-receptor (HR)-positive metastatic breast cancer (MBC). However, nearly all patients will progress on CDK4/6i and ET and the mechanisms associated with primary and secondary resistance are mostly unknown. The identification of biomarkers associated with response to CDK4/6i is therefore a major research priority. PROMISE is a multicenter prospective cohort study designed to perform a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify alterations in molecular or cellular features associated with primary endocrine resistance (e.g. disease progression ≤ 12 months on treatment) and acquired resistance to CDK4/6i. Additionally, patient derived xenografts (PDX) and organoids are generated to test new drug strategies designed to reverse resistance to CDK4/6i and ET. Methods: Eligible participants include women for whom palbociclib is recommended in combination with either letrozole (first-line) or fulvestrant (second-line) therapy for HR-positive MBC. As of July 2018, 14 patients have been enrolled; the target accrual is 250 patients, who will be followed over the course of 36 months and followed for at least 12 months after the close of enrollment. Blood and tumor biopsies are obtained at baseline, at the end of cycle 2, and at progression. Whole exome sequencing (germline and tumor) and RNAseq (whole transcriptome) are performed on tumor samples in a CAP/CLIA lab (TEMPUS) and results will be provided back to all patients for later use. Additionally, PDX and organoids are generated from tumor biopsies at baseline and during progression. Blood, stool, and urine samples are collected for additional correlative studies. The primary objective of this trial is to identify novel genomic variants and pathways associated with early progression (≤ 12 months) among women with advanced HR-positive breast cancer treated with palbociclib and ET. Secondary objectives include identification of the biomolecular features within the gut (stool) microbiome and exploration of the metabolomics and proteomics of ER-positive MBC. Results from the interrogation of these biospecimens will be critical to gain insights into treatment resistance. Funding is provided by Mayo Clinic Center for Individualized Medicine, TEMPUS, and an ASCO Career Development Award (COS). ClinicalTrials.gov Identifier: NCT03281902. Citation Format: O'Sullivan CC, Suman VJ, Kalari KR, Moyer A, Sung J, Moreno-Aspitia A, Northfelt DW, Liu MC, Haddad TC, Chumsri S, Couch FJ, Weinshilboum RM, Wang L, Goetz MP. Genetic analysis in blood, urine, stool and tumor samples from patients with advanced or metastatic estrogen receptor positive and HER2 negative breast cancer receiving palbociclib and endocrine therapy (PROMISE) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-08.

OBJECTIVE To determine whether burden of multiple chronic conditions (MCCs) influences the risk of receiving inappropriate vs appropriate device therapies. DESIGN Retrospective cohort study. SETTING Seven US healthcare delivery systems. PARTICIPANTS Adults with left ventricular systolic dysfunction receiving an implantable cardioverter‐defibrillator (ICD) for primary prevention. MEASUREMENTS Data on 24 comorbid conditions were captured from electronic health records and categorized into quartiles of comorbidity burden (0‐3, 4‐5, 6‐7 and 8‐16). Incidence of ICD therapies (shock and antitachycardia pacing [ATP] therapies), including appropriateness, was collected for 3 years after implantation. Outcomes included time to first ICD therapy, total ICD therapy burden, and risk of inappropriate vs appropriate ICD therapy. RESULTS Among 2235 patients (mean age = 69 ± 11 years, 75% men), the median number of comorbidities was 6 (interquartile range = 4‐8), with 98% having at least two comorbidities. During a mean 2.2 years of follow‐up, 18.3% of patients experienced at least one appropriate therapy and 9.9% experienced at least one inappropriate therapy. Higher comorbidity burden was associated with an increased risk of first inappropriate therapy (adjusted hazard ratio [HR] = 1.94 [95% confidence interval {CI} = 1.14‐3.31] for 4‐5 comorbidities; HR = 2.25 [95% CI = 1.25‐4.05] for 6‐7 comorbidities; and HR = 2.91 [95% CI = 1.54‐5.50] for 8‐16 comorbidities). Participants with 8‐16 comorbidities had a higher total burden of ICD therapy (adjusted relative risk [RR] = 2.12 [95% CI = 1.43‐3.16]), a higher burden of inappropriate therapy (RR = 3.39 [95% CI = 1.67‐6.86]), and a higher risk of receiving inappropriate vs appropriate therapy (RR = 1.74 [95% CI = 1.07‐2.82]). Comorbidity burden was not significantly associated with receipt of appropriate ICD therapies. Patterns were similar when separately examining shock or ATP therapies. CONCLUSIONS In primary prevention ICD recipients, MCC burden was independently associated with an increased risk of inappropriate but not appropriate device therapies. Comorbidity burden should be considered when engaging patients in shared decision making about ICD implantation.

AbstractVenous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and T/B cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.