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FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia Kelly J

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FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia Kelly J Published OnlineFirst May 7, 2019; DOI: 10.1158/1078-0432.CCR-19-0365 CCR Drug Updates Clinical Cancer Research FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia Kelly J. Norsworthy1, Kunthel By1, Sriram Subramaniam1, Luning Zhuang1, Pedro L. Del Valle1, Donna Przepiorka1, Yuan-Li Shen1, Christopher M. Sheth1, Chao Liu1, Ruby Leong1, Kirsten B. Goldberg2, Ann T. Farrell1, and Richard Pazdur2 Abstract On November 21, 2018, the FDA approved glasdegib 95% confidence interval, 0.30–0.71; one-sided stratified (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, log-rank P ¼ 0.0002). Median OS was 8.3 months with the in combination with low-dose cytarabine (LDAC) for treat- combination and 4.3 months with LDAC alone. Common ment of newly diagnosed acute myeloid leukemia (AML) in adverse reactions included cytopenias, fatigue, hemorrhage, adults 75 years or with comorbidities that preclude use of febrile neutropenia, musculoskeletal pain, nausea, edema, intensive induction chemotherapy. Evidence of clinical dyspnea, decreased appetite, dysgeusia, mucositis, constipa- benefit came from Study BRIGHT AML 1003, a randomized tion, and rash. The label includes a boxed warning for embryo- trial comparing glasdegibþLDAC with LDAC alone for treat- fetal toxicity and a warning for QT interval prolongation. There ment of newly diagnosed AML in 115 patients either 75 is a limitation of use for patients with moderate-to-severe years old or 55 years old with preexisting comorbidities. hepatic and severe renal impairment; trials studying glasdegib Efficacy was established by improved overall survival (OS) in these patient populations are required as a condition of this with the combination compared with LDAC alone (HR, 0.46; approval. Introduction mance status, preexisting severe organ comorbidity, infection resistant to therapy, and cognitive impairment (7). Acute myeloid leukemia (AML) occurs in patients of all ages but Recommended treatments for newly diagnosed AML in older is primarily a disease of older adults, with a median age at patients or those with severe comorbidities include hypomethy- diagnosis of 67 years (1). The current standard of care for patients lating agents (HMA), low-dose cytarabine (LDAC), gemtuzumab with newly diagnosed AML includes intensive induction chemo- ozogamicin (GO) for CD33-positive AML, venetoclax combina- therapy when treating with intent to cure. However, almost half of tions, or best supportive care (BSC; ref. 8). Off-label use of HMAs adults with newly diagnosed AML are not treated with intensive and LDAC results in complete remission (CR) rates of 8% to 20% induction chemotherapy (2–4), presumably due to perception and median overall survival (OS) of 3 to 10 months (9–11). that toxicity may outweigh potential benefit. In an epidemiologic Venetoclax combinations and GO monotherapy are approved for study, high early mortality was noted for patients 75 years with this population. For GO, the CR rate was 15%, and median OS newly diagnosed AML, independent of treatment (5). The prog- was 4.9 months (12). For venetoclax in combination with aza- nostic values of several comorbidity indices have been evaluated citidine, decitabine, or LDAC, the CR rates were 37%, 54%, and with inconsistent results (6). Although some variation may exist at 21%, respectively (13). Only LDAC and GO have demonstrated a the individual patient level regarding the ability to tolerate inten- survival benefit compared with hydroxyurea or BSC, respective- sive chemotherapy, a formal consensus process among leukemia ly (9, 12). Despite emerging nonintensive AML treatment options, experts identified parameters that would preclude use of intensive there is still a clear need for alternatives for patients who cannot induction chemotherapy, including age > 75 years, poor perfor- tolerate intensive chemotherapy. Glasdegib, also known as PF-04449913, is a small-molecule 1Center for Drug Evaluation and Research, U.S. Food and Drug Administration, inhibitor of Smoothened, a key protein in the Hedgehog (Hh) Silver Spring, Maryland. 2Oncology Center of Excellence, U.S. Food and Drug signaling pathway (14). In vitro, glasdegib inhibited Hh signaling Administration, Silver Spring, Maryland. with an IC50 of 5.2 nmol/L in a cell-based reporter gene assay. Note: Supplementary data for this article are available at Clinical Cancer Activation of the Hh pathway has been implicated in hematologic Research Online (http://clincancerres.aacrjournals.org/). malignancies. In a murine xenotransplant model of human AML, glasdegib was synergistic with low doses of cytarabine in inhibit- This is a U.S. Government work. There are no restrictions on its use. þ þ ing tumor growth and limiting the percentage of CD45 /CD33 Corresponding Author: Kelly J. Norsworthy, U.S. Food and Drug Administration, blasts in the marrow (14). Silver Spring, MD 20993. Phone: 301-348-1937; Fax: 301-796-9909; E-mail: Kelly. [email protected] Herein, we provide a summary of FDA's review of the marketing application that led to approval of glasdegibþLDAC for treatment Clin Cancer Res 2019;XX:XX–XX of adults with newly diagnosed AML who are 75 years old or doi: 10.1158/1078-0432.CCR-19-0365 who have comorbidities that preclude use of intensive induction Ó2019 American Association for Cancer Research. chemotherapy. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst May 7, 2019; DOI: 10.1158/1078-0432.CCR-19-0365 Norsworthy et al. Clinical Pharmacology The primary efficacy endpoint was OS. The study was designed Dose selection assuming a median OS for LDAC of 5 months. A sample size of The pharmacodynamic effects observed in patients included 132 subjects (92 OS events) was calculated to demonstrate an HR inhibition of GLI1 expression. The first-in-human study in of 0.625 with 80% power at a one-sided alpha of 0.1. CR rate was a patients with hematologic malignancies (NCT00953758) identi- secondary endpoint. Response was assessed with bone marrow fied the MTD of glasdegib as 400 mg once daily. Inhibition of and peripheral blood assessments on cycle 3 day 1 and every third GLI1 expression was >90% at 100 mg and 80% at 50 mg. cycle thereafter, within 14 days of initial hematologic recovery in Thus, 100 mg was chosen as a safe and biologically effective dose the peripheral blood (ANC > 1 Gi/L and platelets 100 Gi/L), and to evaluate in Study BRIGHT AML 1003, allowing for increased at end of treatment. glasdegib exposures when patients required coadministration of A total of 132 patients were randomized, 88 to glasdegibþ strong CYP3A inhibitors. LDAC (78 AML, 10 HR-MDS) and 44 to LDAC (38 AML, 6 HR- MDS). In the analysis of the primary endpoint in the intent-to- Pharmacokinetics treat (ITT) population (n ¼ 132), OS was superior on the glasde- Glasdegib exhibited a dose proportional increase in exposure gibþLDAC arm compared with the LDAC arm [HR, 0.51; 95% from 5 to 600 mg once daily. Steady-state plasma levels were confidence interval (CI), 0.34–0.77: one-sided P value 0.0004 reached by 8 days of daily dosing with median accumulation ratio stratified log-rank test]. Based on the small number of patients of 1.2 to 2.5. Following 100 mg daily oral administration, with MDS accrued, it was concluded there were insufficient data to glasdegib median time to peak plasma concentrations at establish efficacy for MDS. For further evaluations, the efficacy steady-state ranged from 1.3 to 1.8 hours. There was no notable population was limited to 115 patients with confirmed AML. food effect on exposure, supporting the recommendation to administer glasdegib with or without food. The mean elimination Demographics and disposition of the patients with AML half-life (ÆSD) following glasdegib 100 mg once daily was 17.4 The demographics of the efficacy population are shown (3.7) hours. in Table 1. In addition, 41 (36%) had pulmonary disease on Population pharmacokinetics analysis showed that age, sex, medical history, but no grading was provided. Overall, 114 (99%) race, body weight, mild-to-moderate renal impairment (RI) fulfilled the minimal age or comorbidities criteria expected for the [creatinine clearance (CLcr) 30–89 mL/minute], or mild hepatic proposed indication (see discussion in Regulatory Insights), but impairment [HI; total bilirubin upper limit of normal (ULN) there were no patients at the extreme levels of the criteria (i.e. and AST > ULN, or total bilirubin 1–1.5 Â ULN and any AST] had ECOG PS 3, creatinine clearance < 30 mL/minute, or total no clinically meaningful effects on the pharmacokinetics of bilirubin > 1.5 times the ULN at baseline). glasdegib. The effect of severe (CLcr 15–29 mL/minute) RI and At the time of the primary efficacy analysis, the median follow- moderate (total bilirubin 1.5–3 Â ULN and any AST) and severe up was approximately 20 months. Four patients on the glasde- (total bilirubin > 3 Â ULN and any AST) HI on the pharmaco- gibþLDAC arm remained on therapy versus none on the LDAC kinetics of glasdegib is unknown. alone arm. Reasons for treatment discontinuation included pri- mary disease (47% glasdegibþLDAC vs. 45% LDAC), adverse Drug interactions reactions (AR; 31% vs. 39%), physician/patient decision (6% vs. Glasdegib is metabolized primarily by CYP3A4, and thus, 5%), and global deterioration in health (4% vs. 5%). Median concomitant strong CYP3A4 inhibitors and inducers will increase and decrease glasdegib plasma concentrations, respectively.
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