Ivosidenib for Relapsed Or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation Kelly J

$Ivosidenib for Relapsed Or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation Kelly J$

Published OnlineFirst January 28, 2019; DOI: 10.1158/1078-0432.CCR-18-3749

CCR Drug Updates Clinical Cancer Research FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation Kelly J. Norsworthy1, Lola Luo1, Vicky Hsu1, Ramadevi Gudi1, Sarah E. Dorff1, Donna Przepiorka1, Albert Deisseroth1, Yuan-Li Shen1, Christopher M. Sheth1, Rosane Charlab1, Gene M. Williams1, Kirsten B. Goldberg2, Ann T. Farrell1, and Richard Pazdur2

Abstract

The FDA approved ivosidenib (Tibsovo; Agios), a small- 33% [95% confidence interval (CI), 26–40], median duration molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July of response was 8.2 (95% CI, 5.6–12) months, and conversion 20, 2018, for treatment of adults with relapsed or refractory from TD to TI occurred in 37% of patients. These endpoints acute myeloid leukemia (R/R AML) with susceptible IDH1 reflect short-term benefit in patients with an unmet medical mutation as detected by an FDA-approved test. The efficacy of need; long-term efficacy outcomes were not assessed. Serious ivosidenib was established on the basis of complete remission adverse reactions (AR) in 5% of patients were differentiation (CR) þ CR with partial hematologic recovery (CRh) rate, syndrome (10%), leukocytosis (10%), and QT interval pro- duration of CR þ CRh, and conversion from transfusion longation (7%). Common (20%) ARs of any grade were dependence (TD) to transfusion independence (TI) in Study fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, AG120-C-001, a single-arm trial. With median follow-up of nausea, mucositis, QT interval prolongation, rash, pyrexia, 8.3 months for 174 adults with IDH1-mutated R/R AML cough, and constipation. Assessment of long-term safety of treated with 500 mg ivosidenib daily, the CR þ CRh rate was ivosidenib is a condition of this approval.

Introduction and older, refractory, or multiple relapsed patients have even Despite advancements in molecular pathogenesis and novel poorer outcomes. The use of high-dose cytarabine or investi- therapeutics in acute myeloid leukemia (AML), treatment of gator's choice on large, phase III studies in R/R AML resulted in patients with relapsed or refractory AML (R/R AML) remains CR rates of 12% to 18% and median overall survivals (OS) of challenging without a "one-size-fits-all" approach. Tradition- 3.3 to 6.3 months (3, 4). Thus, there is a clear need for new ally, eligible patients will undergo intensive salvage chemo- treatments for patients with R/R AML. therapy followed by hematopoietic stem cell transplantation Isocitrate dehydrogenase (IDH) enzymes catalyze the oxida- (HSCT) provided a CR is achieved. Patients who can tolerate tive decarboxylation of isocitrate to a-ketoglutarate (a-KG) intensive chemotherapy may achieve CR rates of roughly 30% during cellular metabolism. Mutations of the IDH1 isoform to 70% (1). In a large analysis, about half of younger adults in are found in 6% to16% of patients with AML (5). These first relapse achieved a second CR in the absence of prior HSCT, mutations are typically heterozygous and confer new ability and 5-year survival of patients in second CR who underwent of the enzyme to catalyze production of 2-hydroxyglutarate (2- HSCT was about 40% (2). However, many patients with HG). Increased cellular 2-HG levels inhibit a-KG–dependent relapsed AML cannot tolerate intensive salvage chemotherapy, enzymes important for DNA demethylation, and consequently, impair normal differentiation (5). Patients with R/R IDH1- mutated AML may benefit from a novel therapy that specifically targets the IDH1 mutation. 1 Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Ivosidenib, also known as AG-120, is a small-molecule inhib- Silver Spring, Maryland. 2Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland. itor of mutant IDH1. Herein, we provide a summary of the FDA review of the marketing application for ivosidenib for treatment Note: Supplementary data for this article are available at Clinical Cancer of adults with R/R AML with a susceptible IDH1 mutation as Research Online (http://clincancerres.aacrjournals.org/). detected by an FDA-approved test. This is a U.S. Government work. There are no restrictions on its use. Corresponding Author: Kelly J. Norsworthy, U.S. Food and Drug Administration, WO22 Room 2387, 10903 New Hampshire Avenue, Silver Spring, MD 20993. Mechanism of Action Phone 301-348-1937; Fax: 301-796-9909; E-mail: On the basis of the nonclinical data submitted, ivosidenib [email protected] inhibits a variety of IDH1 R132 mutants (R132C, R132G, doi: 10.1158/1078-0432.CCR-18-3749 R132H, R132S, and R132L) at much lower concentrations than 2019 American Association for Cancer Research IDH1 wild-type (WT) enzymes in vitro (6, 7). Ivosidenib showed no

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inhibition of IDH2 mutant or IDH2WT enzymes at concentrations patients with advanced hematologic malignancies harboring >100 mmol/L. In vitro studies in cell lines expressing IDH1 muta- an IDH1 mutation. The trial included a dose-escalation phase tions showed that ivosidenib can reduce 2-HG levels with IC50 utilizing a standard 3 þ 3 design to determine the MTD and/ values ranging from 2 to 20 nmol/L. In an ex vivo assay with primary or recommended phase II dose (RP2D) followed by expan- humanAML blastsharboring the IDH1 R132C mutation, treatment sion arms to further evaluate safety, tolerability, and clinical with ivosidenib for up to 7 days reduced 2-HG levels by 98% activity of ivosidenib in different patient populations. The relative to controls and IDH1WT, decreased viable AML blasts, and pivotal portion of the trial consisted of adults with R/R AML induced cellular differentiation. In addition, in a xenograft model with an IDH1 mutation as identifiedbyalocalorcentral using primary human AML cells with an IDH1 R132H mutation, diagnostic test and confirmed retrospectively using the Abbott treatment with ivosidenib dose-dependently decreased 2-HG levels RealTime IDH1 Assay, which identifies the IDH1 mutations (>96%) in plasma, spleen, and bone marrow, and increased R132C, R132G, R132H, R132L, and R132S. þ þ percentages of human CD14 and CD15 cells in the peripheral The primary efficacy endpoint was the rate of CR þ CR with blood, suggesting induction of cellular differentiation. Overall, the partial hematologic recovery (CRh, where CRh is defined as CR nonclinical pharmacology studies demonstrated that ivosidenib but with platelets >50 Gi/L and ANC >0.5 Gi/L). Response was inhibited the gain-of-function enzymatic activity of mutated IDH1 assessed throughout the trial, with bone marrow and peripheral and led to differentiation of leukemic blasts. blood assessments on day 29 of cycle 1, every 28 days through month 12, and every 56 days thereafter. The objective was to test Clinical Pharmacology the hypothesis that the rate of CR þ CRh was >10%. With the planned sample size of 125 patients and a true response rate of Pharmacokinetics 20%, the study had 89% power to exclude a 10% response rate The FDA reviewed subject-level pharmacokinetic data collected with a one-sided type I error rate of 2.5%. Additional patients with on the pivotal trial and several healthy volunteer studies to char- R/R AML beyond the minimum sample size for the primary acterize pharmacokinetics, food effect, and drug–drug interac- analysis were accrued as prespecified in the protocol. tions (6). Following oral administration on Study AG120-C-001, median time to peak ivosidenib plasma concentration was 3 hours. Ivosidenib mean elimination half-life was 93 hours. Steady-state Treatment plan plasma levels were reached within 14 days. A single-dose food effect Ivosidenib was administered at a dose of 500 mg orally once study in healthy subjects indicatedthat a high-fatmeal increased the daily until disease progression, development of unacceptable mean peak plasma concentration by 98%. Thus, the prescribing toxicity, or HSCT. Dose adjustment was possible in case of adverse information (PI) instructs not to administer ivosidenib with a high- events (AE). Supportive care measures included the use of dexa- fat meal. No clinically meaningful effects on pharmacokinetics were methasone for differentiation syndrome (DS) and hydroxyurea or observed on the basis of age, sex, race, body weight, mild or leukapheresis for leukocytosis. moderate renal impairment (RI), or mild hepatic impairment (HI). The pharmacokinetics of ivosidenib in patients with severe RI, RI Disposition and demographics requiring dialysis, moderate or severe HI is unknown. Protocol AG120-C-001 accrued and treated 258 patients inter- Ivosidenib is metabolized primarily by CYP3A4, and thus, nationally, including 179 patients with R/R AML treated at the concomitant strong CYP3A4 inhibitors and inducers will increase recommended dose. At the time of the primary efficacy analysis, and decrease ivosidenib plasma concentrations, respectively. The 125 patients with R/R AML treated at the recommended dose PI recommends dose reduction with concomitant strong CYP3A4 completed at least 6 months of therapy or discontinued earlier; a inhibitors and to avoid use with concomitant strong CYP3A4 subsequent analysis was performed once all 179 patients com- inducers. Ivosidenib induces CYP3A4, and thus, will decrease pleted 6 months of therapy or discontinued earlier. Five patients plasma concentrations of sensitive CYP3A4 substrate drugs. The without confirmed IDH1 mutation per the RealTime IDH1 Assay PI recommends avoiding use with sensitive CYP3A4 substrates. were excluded from the efficacy analysis. The demographics of the Notably, it is important to not administer ivosidenib with azole remaining 174 patients are shown in Table 1. Twenty-one (12%) antifungals that are CYP3A4 substrates (i.e., itraconazole and patients proceeded to HSCT after treatment with ivosidenib. ketoconazole) due to expected loss of antifungal efficacy. Also, the PI recommends avoidance of QTc-prolonging drugs, but if Efficacy results unavoidable, to monitor patients for increased risk of QTc interval For the analysis of the primary endpoint, the rate of CR þ CRh prolongation. was 30% of the primary analysis population of 125 patients with fi Pharmacodynamics R/R AML, with a lower 95% con dence interval (CI) boundary of þ The pharmacodynamic (PD) effects observed in the patient 23%. Thus, the primary objective of excluding a CR CRh rate of population included inhibition of 2-HG in the blood and bone 10% was met. Considering the entire population of patients with N ¼ þ marrow. Ivosidenib dosed at 500 mg once daily showed near R/R AML ( 179), the CR CRh rate was 33% (Table 2). The maximal inhibition of 2-HG by cycle 2, day 1, with no addi- results for the primary endpoint were largely consistent across the tional 2-HG inhibition at doses above 500 mg daily (6, 8). subpopulations tested. However, a trend toward lower response rates was observed for patients with poor risk cytogenetics, prior fi HSCT, baseline transfusion dependence (TD), 2 or more prior Assessment of Ef cacy therapies, and the R132H mutation (Supplementary Fig. S1). Clinical trial overview Key secondary endpoints were used to inform the regulatory Study AG120-C-001 was a multicenter, open-label, single- decision-making process (Table 2). For patients with a CR þ CRh arm, dose-escalation and expansion trial of ivosidenib in response, median duration of response (DOR) was 8.2 months.

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Table 1. Characteristics of the patients in protocol AG120-C-001 with IDH1- provided. Thus, in addition to investigator-reported cases of mutated R/R AML DS, the FDA performed a comprehensive analysis of AEs, Number of patients 174 laboratory, and vital sign data to determine its true inci- Median age (range) 67 (18, 87) dence (10). The FDA determined that 19% of patients had 65 years 111 (64%) Gender any-grade DS and 13% had grade 3 or higher DS. Of 34 patients Male 88 (51%) who experienced DS, 27 (79%) recovered after treatment or Female 86 (49%) after dose interruption of ivosidenib. Race QTc prolongation was another serious toxicity associated with White 108 (62%) ivosidenib, both in nonclinical testing and the clinical trial. Over a Black or African American 10 (6%) quarter of patients treated with ivosidenib on the pivotal trial Asian 6 (3%) Other/not provided 50 (29%) experienced any-grade QTc elevation, which was typically observed ﬁ Disease status in the rst month of therapy but occurred throughout the treatment Primary refractory 64 (37%) period. A total of 7% required treatment interruption, and 1% Refractory relapse 45 (26%) required a dose reduction, but no patient discontinued ivosidenib Untreated relapse 65 (37%) as a result. Ventricular arrhythmias were rare (<1%). Relapse number Ivosidenib was interrupted in 38% of patients and discontin- 0 64 (37%) 1 83 (48%) ued prematurely in 13% due to an AE. The most common reasons 2 21 (12%) leading to dose interruption were QT prolongation, DS, dyspnea, 3 6 (3%) and leukocytosis. ARs leading to permanent withdrawal in more Median prior therapies (range) 2 (1, 6) than one patient included Guillain–Barre syndrome, rash, sto- Prior HSCT 40 (23%) matitis, and creatinine increased. IDH1 mutation Ten deaths on or within 28 days after the last dose of ivosidenib R132C 102 (59%) R132H 43 (25%) were concluded to have resulted potentially from a direct toxicity n ¼ R132G 12 (7%) of ivosidenib. Proximate causes of death included infection ( R132S 10 (6%) 4), DS (n ¼ 2), and one case each of aspiration pneumonia, R132L 7 (4%) myocardial infarction, ventricular arrhythmia, and thrombotic Transfusion-dependent baseline 110 (63%) stroke. The rate of 30-day all-cause mortality was 7% (95% CI, 4%–11%).

CR was achieved by 25% of patients and duration of CR was 10.1 months. Thus, it was concluded that the responses were reason- Regulatory Insights ably durable. Study AG120-C-001 provided substantial evidence of efficacy and safety to support approval of ivosidenib for treatment of Assessment of Safety adults with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test. The durable CR þ CRh rate Nonclinical toxicology of 33% supported by data on conversion to transfusion indepen- In repeat dose-studies of oral ivosidenib in rats and monkeys, dence (TI) and a tolerable safety profile justified regular approval toxicities included liver dysfunction, increased hematopoiesis, of ivosidenib based on a transfusion benefit to patients. There decreased hemoglobin, stomach erosions/ulceration, prolonga- were several regulatory considerations when making the decision tion of QTc interval, and ventricular bigeminy. These findings to grant regular approval based on a single-arm study. were consistent with the increased transaminases, leukocytosis, anemia, mucositis, and QTc prolongation observed in the clinical study. Table 2. Efficacy results in patients with IDH1-mutated R/R AML on Study AG120-C-001 Ivosidenib 500 mg daily Safety events in the intended population Endpoint N ¼ 174 Safety was assessed in 179 patients with R/R AML treated with CR þ CRh n (%) 57 (32.8) ivosidenib at a dose of 500 mg daily. A treatment-emergent AE was 95% CI (25.8, 40.3) experienced by 99% of patients and the event was grade 3 for Median DOR (months) 8.2 79%. The most common (10%) treatment-emergent adverse 95% CI (5.6, 12) reactions (AR) that occurred on or within 28 days after the last CR n (%) 43 (24.7) dose of ivosidenib are listed in Table 3. The most common grade 95% CI (18.5, 31.8) Median DOR (months) 10.1 3 ARs were DS (13%), electrocardiogram QT prolonged (10%), 95% CI (6.5, 22.2) dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome CRh n (%) 14 (8.0) (6%). Two patients (<1%) had Guillain–Barre syndrome that 95% CI (4.5, 13.1) could not be attributed to a cause other than ivosidenib. Median DOR (months) 3.6 DS is a clinical syndrome characterized by dyspnea, unex- 95% CI (1, 5.5) n plained fever, weight gain, unexplained hypotension, acute Conversion from TD to TI (%) 41/110 (37) Maintenance of TI n (%) 38/64 (59) kidney injury, and pulmonary infiltrates, or pleuropericardial Abbreviations: DOR, duration of response; TD, TD at baseline, defined as effusion, which can be fatal if not treated (9). Although the receiving any transfusion within 56 days prior to the first dose of ivosidenib; fi protocol provided guidelines for the identi cation and man- TI, transfusion independence postbaseline, defined as being independent of both agement of DS, definitive criteria for its diagnosis were not red blood cell and platelet transfusions during any 56-day postbaseline period.

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Table 3. Treatment-emergent ARs in the safety populationa not known whether younger patients with R/R IDH1-mutated Preferred termb Any grade Grade 3 AML may benefit from a more intensive treatment paradigm. Fatigue 69 (39%) 6 (3%) Thus, future trials are warranted to investigate the comparative Leukocytosis 68 (38%) 15 (8%) efficacy of ivosidenib to other therapies in R/R AML and/or the Arthralgia 64 (36%) 8 (4%) Diarrhea 60 (34%) 4 (2%) combination of ivosidenib with intensive salvage chemotherapy. Dyspnea 59 (33%) 16 (9%) The FDA approved ivosidenib for patients with R/R AML and Edema 57 (32%) 2 (1%) a susceptible IDH1 mutation as per an FDA-approved test. Of Nausea 56 (31%) 1 (1%) note, the FDA recently issued a guidance on targeted therapies Mucositis 51 (28%) 6 (3%) in low-frequency molecular subsets, providing information on Electrocardiogram QT prolonged 46 (26%) 18 (10%) how to handle rare molecular subsets that may not have been Rash 46 (26%) 4 (2%) Pyrexia 41 (23%) 2 (1%) represented on the pivotal trial (13). Given that there are IDH1 Cough 40 (22%) 1 (<1%) mutations that do not confer the pathogenic gain-of-function Constipation 35 (20%) 1 (1%) or that are not inhibited by ivosidenib (14), the FDA made it Differentiation syndrome 34 (19%) 23 (13%) clear in the PI that the approval is specifically for patients with Decreased appetite 33 (18%) 3 (2%) susceptible mutations that are pathogenic and inhibited by Myalgia 33 (18%) 1 (1%) ivosidenib. Susceptible mutations are defined in the PI as those Vomiting 32 (18%) 2 (1%) Abdominal pain 29 (16%) 2 (1%) leading to increased levels of 2-HG in leukemia cells and where fi Headache 28 (16%) 0 ef cacy is predicted by clinically meaningful remissions with Pleural effusion 23 (13%) 5 (3%) the recommended dose of ivosidenib and/or inhibition of Chest pain 29 (16%) 5 (3%) mutant IDH1 enzymatic activity at concentrations of ivoside- Hypotension 22 (12%) 7 (4%) nib sustainable at the recommended dosage according to Neuropathy 21 (12%) 2 (1%) validated methods. The most common of such mutations are a N ¼ 179 adults with R/R AML treated with ivosidenib using the dose of 500 mg R132H and R132C substitutions, but others include R132G, daily. R132L, and R132S. bIncludes grouped terms. See Supplementary Table S1 for further information. Ivosidenib is a small-molecule inhibitor of mutant IDH1 that induces cellular differentiation. Thus, DS was recognized CR rate has traditionally been viewed as a surrogate endpoint early in the drug's development and was the major toxicity reasonably likely to predict clinical benefit for purposes of accel- resulting in a boxed warning in the PI. Serious and fatal erated approval in leukemia (11). In acute leukemia settings toxicities occurred, and thus, close monitoring and early treat- without intent to cure, the FDA has considered durable CR þ ment with steroids are essential. To minimize risks in practice, CRh as a direct measure of clinical benefit for regulatory-decision the FDA required a Medication Guide for patients. QT pro- making (12), based on recovery of adequate blood counts to longation and Guillain–Barre syndrome were other potentially protect against infection and avoid transfusions, preferably with life-threatening toxicities identified by the FDA that resulted in corroborating evidence. The submission for ivosidenib contained Warnings and Precautions in the PI. Despite the risk of these evidence showing that patients with CR/CRh responses had lower severe toxicities, the drug was generally well tolerated, with rates of severe infection and febrile neutropenia and higher rates only 3% of patients requiring a dose reduction and 13% of TI than patients with lesser responses, including CR with discontinuing therapy due to toxicity. The tolerable safety incomplete count recovery and CR with incomplete platelet profile was critical when performing the benefit-risk assess- recovery (6). The Study AG120-C-001 statistical analysis plan ment. However, given median follow-up of only 8.3 months, specified CR þ CRh rate as the primary efficacy endpoint and there is a postmarketing requirement to provide long-term conversion and maintenance of TI as secondary endpoints. CRh safety follow-up from the ongoing Study AG120-C-001. responses were less durable than CR responses, at 3.6 versus 10.1 months, respectively, but provided a transient benefit to patients nonetheless. Conclusions Data on achievement and maintenance of TI for a period of at In AG120-C-001, ivosidenib 500 mg orally once daily led to a least 56 days postbaseline provided support for the use of durable CR þ CRh rate of 33% (95% CI, 26%–40%) with a median DOR CR þ CRh as a measure of palliative benefit to patients with IDH1- of 8.2 months (95% CI, 5.6–12 months) in adults with R/R IDH1- mutated R/R AML. Over a third of patients who were TD at mutated AML. A transfusion benefit was also observed, in that baseline achieved TI on therapy, and most patients who were TI 37% of patients went from TD to TI for at least 56-days postbase- at baseline maintained TI. Of patients with CR/CRh responses, the line. Thus, ivosidenib provided meaningful, short-term, clinical majority who were TD at baseline achieved TI postbaseline, and benefit to a subset of patients with R/R IDH1-mutated AML. The all patients who were TI at baseline maintained TI. It is worth single-arm trial with limited follow-up does not determine wheth- mentioning that, while the FDA considered TI for a period of at er there is long-term benefit to ivosidenib or an effect on survival. least 56 days postbaseline to be clinically meaningful in this Ivosidenib was well tolerated, with the most serious risk, DS, able application, we would be interested to assess even longer periods to be mitigated with appropriate monitoring and treatment. of TI as treatments improve. Long-term safety follow-up data will be provided as per a post- Of note, given that the approval of ivosidenib was based on marketing requirement. evaluation of a single-arm trial, it is not clear how the efficacy of ivosidenib compares to other treatment options for patients with R/R IDH1-mutated AML. The endpoints on Study Disclosure of Potential Conflicts of Interest AG120-C-001 indicated a transfusion benefit to patients, but it is No potential conflicts of interest were disclosed.

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Disclaimer S.E. Dorff, D. Przepiorka, Y.-L. Shen, R. Charlab, G.M. Williams, A.T. Farrell, The Editor handling the peer review and decision-making process for this R. Pazdur article has no relevant employment associations to disclose. Writing, review, and/or revision of the manuscript: K.J. Norsworthy, L. Luo, V. Hsu, R. Gudi, S.E. Dorff, D. Przepiorka, A. Deisseroth, Y.-L. Shen, C.M. Sheth, R. Charlab, G.M. Williams, K.B. Goldberg, A.T. Farrell, R. Pazdur Authors' Contributions Administrative, technical, or material support (i.e., reporting or organizing Conception and design: K.J. Norsworthy, D. Przepiorka, R. Pazdur data, constructing databases): K.J. Norsworthy, V. Hsu, D. Przepiorka, Development of methodology: K.J. Norsworthy, D. Przepiorka, R. Pazdur K.B. Goldberg, A.T. Farrell, R. Pazdur Acquisition of data (provided animals, acquired and managed patients, Study supervision: R. Pazdur provided facilities, etc.): R. Pazdur Analysis and interpretation of data (e.g., statistical analysis, Received November 16, 2018; revised December 21, 2018; accepted January biostatistics, computational analysis): K.J. Norsworthy, L. Luo, V. Hsu, 23, 2019; published ﬁrst January 28, 2019.

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FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation

Kelly J. Norsworthy, Lola Luo, Vicky Hsu, et al.

Clin Cancer Res Published OnlineFirst January 28, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-18-3749

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