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Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D).Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting.Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294–303. ©2018 AACR.

Additional Methods: MTD determination; Biomarker analyzed Supplementary Table S1. Patient disposition by treatment group Supplementary Table S2. Treatment-related AEs reported in >10% of patients in arm A Supplementary Table S3. Treatment-related AEs reported in in {greater than or equal to}2 patients in arm B Supplementary Table S4. Treatment-related AEs reported in >20% of patients in arm C Supplementary Table S5 Median treatment duration and dose reductions/delays by treatment group Supplementary Table S6. Treatment discontinuations by treatment group Supplementary Table S7. Glasdegib pharmacokinetic parameters at the RP2D Supplementary Table S8. Best overall response in patients with AML by treatment arm Supplementary Table S9. Selected baseline characteristics including gene mutations and response to treatment Supplementary Figure S1. Potential associations of MMP-3 and SDF-1 with response in patients administered glasdegib plus cytarabine/daunorubicin

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038., Open Access funding enabled and organized by Projekt DEAL. This study was funded by Pfizer.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038., Open Access funding enabled and organized by Projekt DEAL. This study was funded by Pfizer.

Background The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015). Methods This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR. Results In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41–0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively. Conclusions Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR. Trial registration ClinicalTrials.gov NCT01546038 (March 7, 2012)

Additional file 4: Fig S4. Blood count recovery in patients who did not achieve CR. Percentage of patients with a. ANC b. hemoglobin c. platelets recovery during cycles one to ten. One threshold measurement was required; all patients were included regardless of their BL levels but each cycle only included remaining patients at risk in that cycle. Analysis set, N = number of patients with ANC results in the cycle; patients, n = number of patients meeting recovery criteria in the cycle. Abbreviations: ANC, absolute neutrophil count; BL, baseline; CR, complete remission; LDAC, low-dose cytarabine.

Additional file 5: Table S1. Patient disposition

Additional file 1: Fig. S1. Duration of treatment with best overall response. a For patients receiving glasdegib + LDAC. b For patients receiving LDAC alone. Abbreviations: CR, complete remission; CRi, CR with incomplete hematologic response; EOT, end of treatment; LDAC, low-dose cytarabine; MR, minor response; PR, partial response; SD, stable disease

Additional file 6: Table S2. Treatment-emergent all-causality adverse events* occurring during first 90 days and after 90 days of therapy

Additional file 3: Fig. S3. Kaplan–Meier plots of OS with censoring for systemic follow-up therapies. a In patients who achieved CR. b In patients who did not achieve CR. Abbreviations: CI, confidence interval; CR, complete remission; LDAC, low-dose cytarabine; N/E, not evaluable; OS, overall survival

Additional file 2: Fig. S2. Kaplan–Meier plots of OS. a In patients who achieved CR or CRi. b In patients who did not achieve CR or CRi. Abbreviations: CI, confidence interval; CR, complete remission; CRi, CR with incomplete hematologic response; LDAC, low-dose cytarabine; OS, overall survival

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open‐label, phase 2 study ({"type":"clinical-trial","attrs":{"text":"NCT01546038","term_id":"NCT01546038"}}NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28‐day cycles from day −3, with intravenous cytarabine 100 mg/m2 on days 1‐7 and daunorubicin 60 mg/m2 on days 1‐3. Patients in remission then received consolidation therapy (2‐4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27‐75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7‐54.1) achieved investigator‐reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9‐48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4‐19.3) months, with 12‐month survival probability 66.6% (80% CI 58.5‐73.4). The most common treatment‐related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high‐risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

Context The BRIGHT AML 1003 randomized phase 2 study ( NCT01546038 ) compared glasdegib (GLAS) plus LDAC vs LDAC-alone in patients with newly diagnosed AML or high-risk MDS who were ineligible for intensive chemotherapy. Addition of GLAS to LDAC approximately doubled overall survival (OS) without significant worsening of myelosuppression-related complications ostensibly by targeting leukemic stem cells dependent on the hedgehog pathway, which is not involved in normal adult hematopoiesis. Objective Evaluate potential association of outcomes with early blood count recovery. Design Patients were randomized 2:1 to open-label GLAS+LDAC or LDAC-alone (first patient visit Jan-2014), and continued treatment to a maximum of 4 years (final data cutoff April 2019). Setting Multicenter (European and North American centers). Patients This analysis included patients with AML (78 GLAS+LDAC; 38 LDAC-alone). Interventions Glasdegib 100 mg QD; LDAC 20 mg BID × 10 days q28 days. Main outcome measures The study primary endpoint was OS (previously published: Cortes et al., 2019, HR 0.51; p=0.0004). This post hoc analysis compared outcomes with GLAS+LDAC vs LDAC-alone in subgroups according to cell counts at cycle 2 day 1 (C2D1), using thresholds for absolute neutrophil count (ANC) ≥ 1000 or 500/μL, hemoglobin ≥ 10 or 9 g/dL, and platelets ≥ 100,000 or 50,000/μL. Results Among all patients regardless of baseline ANC, hemoglobin or platelets, achievement of thresholds at C2D1 was associated with improved OS with GLAS+LDAC (all comparisons p Conclusions In these patients, improved OS was associated with various blood count thresholds after 1 cycle of GLAS+LDAC vs LDAC-alone. In patients with baseline measurements below threshold, recovery of hemoglobin and platelet thresholds was associated with improved OS. Platelet recovery correlated with response in the GLAS+LDAC group. These exploratory results are consistent with the hematopoiesis-sparing mechanism of GLAS, and merit further evaluation. Study sponsor Pfizer.

Context In newly diagnosed AML or high-risk MDS, the randomized phase 2 BRIGHT AML 1003 ( NCT01546038 ) primary analysis showed superior overall survival (OS) for glasdegib (GLAS) + low-dose cytarabine (LDAC) vs LDAC-alone. After the primary cutoff, the trial continued to predefined completion 4 years from randomization of all patients. Objective To assess outcomes at study completion (data cutoff April 2019). Design Beginning January 2014, patients with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to open-label GLAS+LDAC or LDAC-alone. Setting Multicenter study at centers in Europe and North America. Patients For the randomized groups (88 GLAS+LDAC vs 44 LDAC-alone), median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; 4/88 vs 1/44 completed ≥4 years' follow-up, and median follow-up was >45 months for both groups. Interventions Glasdegib 100-mg QD; LDAC 20-mg BID×10 days q28 days. Main outcome measures The prespecified primary endpoint was OS (Jan 2017 cutoff: HR 0.51; 80%CI 0.39-0.67 p=0.0004). We compared OS, complete remission (CR), and safety at the final data cutoff. Results Consistent with the primary findings, GLAS+LDAC prolonged OS vs LDAC-alone in the overall ITT population (median OS 8.8 [95%CI 5.0-11.7] vs 4.9 months [2.9-6.5] HR 0.53 [95%CI 0.35-0.80] p=0.001). Results were consistent in patients with AML (HR 0.53 [95%CI 0.35-0.80] p=0.001). Similarly, OS results were consistent for subgroups by cytogenetic risk, patient characteristics, and de novo/secondary AML. GLAS+LDAC induced higher CR rates in the ITT population (16/88 vs 1/44; RR 8.12, 95%CI 1.05-62.78, p=0.010) and across subgroups. Notably, fewer patients discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC-alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%), and alopecia (10.7%), with only 1 patient discontinuing due to dysgeusia. Conclusions This BRIGHT AML 1003 analysis showed primary results were maintained after >20 months' additional follow-up. Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC-alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Study sponsor Pfizer.

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D).Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting.Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294–303. ©2018 AACR.

Introduction: Glasdegib, an oral inhibitor of the Hedgehog (Hh) signaling pathway, is approved in the USA in combination with low-dose cytarabine (LDAC) to treat patients (pts) with newly diagnosed acute myeloid leukemia (AML) unable to receive intensive chemotherapy due to comorbidities or age (≥75 years). In a randomized trial, this combination significantly improved overall survival (OS) vs LDAC alone (Cortes et al. 2019). Here we report the efficacy and safety of glasdegib combined with azacitidine (AZA) in pts with higher-risk myelodysplastic syndromes (MDS), AML, and chronic myelomonocytic leukemia (CMML) similarly ineligible for intensive chemotherapy. Methods: This open-label, multicenter, phase 1b trial (BRIGHT MDS & AML 1012; NCT02367456) enrolled pts with newly diagnosed higher-risk MDS, AML, and CMML (Start date, April 2015; estimated study completion date, January 2021). Pts received oral glasdegib (100 mg once daily) continuously in combination with AZA (75 mg/m2/day) on Days 1-7 of a 28-day cycle. Treatment was continued until disease progression, unacceptable toxicity, death, or pt refusal. The primary endpoint was complete remission (CR) using European LeukemiaNet (ELN) for AML/MDS International Working Group criteria per investigator assessment. Efficacy outcomes are reported as of June 17, 2019; all other outcomes are reported as of April 19, 2019. Results: Sixty pts (AML, n=30; MDS, n=30) were enrolled and received treatment with glasdegib + AZA. Among pts with AML, the median age was 74.0 years (range, 56-87), 40% were female; 7%, 30% and 57% of pts had a favorable, intermediate and adverse ELN genetic risk category, respectively. Median treatment duration was 19.2 weeks (range, 1.1-47.4); median follow-up was 7.8 (95% CI, 5.9-9.6) months. At the time of data cut-off, 43% of pts were still receiving glasdegib and/or AZA. The most frequent (>30% of pts) all-causality treatment-emergent adverse-events (TEAEs) of all grades were nausea (60%), decreased appetite (53%), constipation (50%), vomiting (43%), diarrhea (43%), and pyrexia (33%). The most frequent (>10% of pts) serious TEAEs were febrile neutropenia (20%) and pyrexia (13%). The 30-day mortality rate was 10%. Two of 23 pts (8.7%) had Cycle 2 delay due to adverse events (AEs). Eight (27%) pts achieved CR/CR with partial hematologic recovery/CR with incomplete hematologic recovery; 6 (20%) achieved CR. Median time to CR was 5.5 months (range, 3.1-6.0). Median OS was not evaluable (NE [95% CI, NE-NE]) and the 6-month survival probability was 70.0% (95% CI, 50.3-83.1%). Response and survival by risk category are shown in the Table. Of the 30 pts with MDS (including 3 with CMML), the median age was 72 years (range, 55-89) and 20% were female; 15, 52, and 33% of pts had an intermediate, high, and very high Revised International Prognostic Scoring System risk, respectively. Median treatment duration was 19.6 weeks (range, 1.6-50.6); median follow-up was 6.9 months (95% CI, 6.5-10.9). At the time of data cut-off, 40% of pts were still receiving glasdegib and/or AZA. The most frequent (>30% of pts) all-causality TEAEs were nausea (67%), constipation (47%), diarrhea (40%), muscle spasms (40%), neutrophil count decreased (40%), anemia (37%), dysgeusia (37%), platelet count decreased (33%) and vomiting (33%). The most frequently (>10% of pts) reported serious TEAEs were febrile neutropenia (17%) and sepsis (17%). The 30-day mortality rate was 3%. Three of 26 pts (11.5%) had Cycle 2 delay due to AEs. Eleven (37%) pts achieved CR/marrow CR/partial remission; 5 (17%) achieved CR. Median time to CR was 5.6 months (range, 3.7-6.4). Median (95% CI) OS was NE months (7.2-NE) and the 6-month survival probability was 78.9% (95% CI, 58.9-89.9%). Response and survival by diagnosis and by risk category are shown in the Table. Conclusions: The addition of glasdegib to AZA for pts with newly diagnosed higher-risk MDS, AML, or CMML ineligible for intensive chemotherapy showed promising rates of CR and OS. Glasdegib + AZA was generally well tolerated, with a safety profile consistent with toxicities of AZA monotherapy and other marketed inhibitors of the Hh signaling pathway. Glasdegib is currently in phase 3 clinical development for AML therapy in combination with AZA (NCT03416179). Further studies of glasdegib + AZA in pts with MDS are warranted. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Schuster:Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Astellas: Speakers Bureau; Celgene: Speakers Bureau; Genentech: Speakers Bureau; Actinium: Research Funding. Krauter:Pfizer: Honoraria. Maertens:Astellas Pharma: Other: Personal fees and non-financial support; Pfizer: Other: Grant and personal fees; F2G: Other: Personal fees and non-financial support; Gilead Sciences: Other: Grants, personal fees and non-financial support; Merck: Other: Personal fees and non-financial support; Cidara: Other: Personal fees and non-financial support; Amplyx: Other: Personal fees and non-financial support. Gyan:Pfizer: Honoraria. Kovacsovics:Abbvie: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Jazz: Consultancy. Verma:BMS: Research Funding; Janssen: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Vyas:Abbvie: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Pfizer: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Astellas: Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Ma:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. Kudla:Pfizer: Employment, Equity Ownership. Chan:Pfizer Inc: Employment, Equity Ownership. Zeidan:Agios: Honoraria; Ariad: Honoraria; Cardinal Health: Honoraria; Novartis: Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; ADC Therapeutics: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Glasdegib is approved in the US in combination with low-dose cytarabine for treatment of newly diagnosed AML in patients not suitable for intensive chemotherapy due to comorbidities or age (75 years or older). Here we report data from a phase 1b trial where glasdegib was combined with azacitidine in patients with higher-risk myelodysplastic syndromes, AML, and chronic myelomonocytic leukemia similarly ineligible for intensive chemotherapy.

Introduction: Attempts to improve on the 20% complete remission (CR) rate and 10.4 month median overall survival (OS) in the frontline treatment (1L) of older unfit patients (pts) with acute myeloid leukemia (AML) using azacitidine (AZA) combination therapy have been met with cytopenic complications that may result in cycle (Cyc) 2 dose delays as frequently as 33% of the time. Glasdegib in combination with low-dose cytarabine (LDAC) showed superior overall survival vs LDAC alone in the BRIGHT AML 1003 trial that included pts with newly diagnosed AML who were ineligible for intensive chemotherapy (IC). The combination did not appear to increase cytopenias, bleeding, or infection. We analyzed the safety profile of glasdegib in combination with AZA or LDAC in 1L AML, focusing on cytopenias, infections, and dose delays. Methods: BRIGHT MDS & AML 1012 (NCT02367456) is an ongoing single-arm study in which untreated pts with myelodysplastic syndromes (MDS) or AML who were ineligible for IC received glasdegib (100 mg once daily [QD]) + AZA (75 mg/m2/day) on Days 1-7 every 28 days until disease progression, unacceptable toxicity, death, or pt refusal. Efficacy outcomes are reported as of Jun 17, 2019; all others as of Apr 19, 2019. BRIGHT AML 1003 (NCT01546038) is a completed study in which untreated pts with MDS or AML who were ineligible for IC were randomized to receive glasdegib (100 mg QD) + LDAC (20 mg twice daily on Days 1-10 every 28 days) or LDAC alone. Outcomes reported as of Oct 11, 2018. To minimize bias due to imbalances in survival between the 1003 study arms, safety outcomes within the first 90 days for the AML cohorts of each study are presented here. Results: Thirty pts with AML received treatment with glasdegib + AZA (Table 1). Median treatment duration was 5 Cyc (range, 1-11); median follow-up time was 7.8 months (95% CI, 5.9-9.6). CR was achieved by 6 pts (20.0%) receiving glasdegib + AZA. Two additional pts achieved CR with incomplete hematologic recovery (CRi) and discontinued treatment to prepare for transplant. Six-month survival probability was 70.0% (95% CI, 50.3-83.1), with 19 pts still in survival follow-up. Pts (N=116) were assigned to treatment with glasdegib + LDAC (n=78) or LDAC alone (n=38 [Table 1]); median treatment duration (range) was 3 Cyc (1-44) for glasdegib + LDAC and 2 Cyc (1-9) for LDAC alone; median follow-up time (95% CI) was 43.4 (39.7-49.1) and 42.0 (CI not evaluable) months, respectively. As previously reported, glasdegib + LDAC significantly improved OS vs LDAC alone (hazard ratio, 0.495 [95% CI, 0.325-0.752]; P=0.0004). The incidence of select treatment-emergent adverse events (TEAEs) and serious TEAEs associated with cytopenias, bleeding, and infection did not appear worse with glasdegib + AZA or glasdegib + LDAC than with LDAC alone, with some AEs even occurring less frequently (Table 1). Dose delays due to AEs were required in Cyc 2 by 8.7% (n=2/23, glasdegib + AZA), 6.7% (n=4/60, glasdegib + LDAC), and 4.2% (n=1/24, LDAC alone) of pts. Recovery of absolute neutrophil count, hemoglobin, and platelets at 2 cell-count thresholds was seen as early as Cyc 1 in approximately half of the evaluable pts (Table 2). Gastrointestinal toxicities, including nausea and vomiting, were frequent in pts receiving glasdegib + AZA (60.0 and 40.0%, respectively) and glasdegib + LDAC (29.3 and 20.0%, respectively). Glasdegib treatment was associated with AEs thought to be linked to inhibition of the Hedgehog pathway in normal tissue (muscle spasms, dysgeusia, alopecia [Table 1]). Conclusions: The addition of glasdegib to AZA does not appear to increase hematologic toxicities or cytopenic complications substantially, in contrast to the increased toxicity typically observed with combinational therapy. In the context of different baseline characteristics of the populations studied with AZA alone in 1L AML (Dombret, et al. Blood 2016), glasdegib + AZA did not substantially increase AEs related to cytopenias like infections, especially given the low rates of Cyc 2 delays due to AEs. These results are consistent with the lack of substantially increased toxicities with glasdegib + LDAC vs LDAC alone. In light of the survival benefit observed with glasdegib + LDAC vs LDAC alone, the addition of glasdegib to AZA may improve clinical outcomes without substantially increasing toxicities. A randomized phase 3 trial looking at the addition of glasdegib to AZA (vs AZA alone) in 1L AML (NCT03416179) is ongoing. Disclosures Zeidan: Astellas: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding. Schuster:Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Astellas: Speakers Bureau; Celgene: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Actinium: Research Funding. Krauter:Pfizer: Honoraria. Maertens:Pfizer: Other: Grant and personal fees; Astellas Pharma: Other: Personal fees and non-financial support; Gilead Sciences: Other: Grants, personal fees and non-financial support; Merck: Other: Personal fees and non-financial support; F2G: Other: Personal fees and non-financial support; Cidara: Other: Personal fees and non-financial support; Amplyx: Other: Personal fees and non-financial support. Gyan:Pfizer: Honoraria. Menne:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Ma:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. Kudla:Pfizer: Employment, Equity Ownership. Chan:Pfizer Inc: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Glasdegib is approved in the US in combination with low-dose cytarabine for treatment of newly diagnosed AML in patients not suitable for intensive chemotherapy due to comorbidities or age (75 years or older). Here we report data from a phase 1b trial where glasdegib was combined with azacitidine in patients with AML similarly ineligible for intensive chemotherapy.

Background: Novel agents are frequently added to standard acute myeloid leukemia (AML) treatment backbones yet it is unclear how much additional toxicity this introduces, with the potential for adverse events (AEs) to be caused by the backbone chemotherapy or the disease itself. Glasdegib (PF-04449913) is an investigational, oral small molecule inhibitor of the Hedgehog (Hh) pathway component Smoothened (SMO), currently in clinical development for AML treatment. In a Phase 2 randomized study, addition of glasdegib to low-dose cytarabine (LDAC) improved overall survival (OS) vs LDAC alone and combination therapy was generally well tolerated with minor differences in AE rates vs chemotherapy alone. Here, we analyzed specific 'on target' AEs consistent with inhibition of the SMO component of the Hh pathway to assess impact on overall toxicity. Methods: We pooled safety data from both portions of a Phase 1b + Phase 2 multicenter study (NCT01546038), including AML patients assigned to glasdegib 100 mg QD with LDAC (non-intensive treatment) or with cytarabine/daunorubicin on a 7+3 schedule (intensive treatment) (figure 1). We assessed 'on target' all-causality treatment-emergent AEs of muscle spasms, alopecia, and dysgeusia. We also compared AE onset in defined study time-periods (non-intensive: 0-6, 6-12, or >12 months; intensive: induction, consolidation, maintenance); defining long-term treatment as >12 months for non-intensive and maintenance for intensive. Results: Across studies, 93 patients were enrolled in the non-intensive group and 80 in the intensive group. Here, we focused on patients treated with glasdegib: 89 patients in the non-intensive group and 78 in the intensive group. Table 1 shows baseline characteristics; median treatment duration was 69 days (range 3-1280) and 51 days (10-539), respectively. Rates of treatment discontinuation due to all AEs (inclusive of 'on target' and others), deemed by the investigator to be related to study drug (glasdegib and/or backbone chemotherapy) were similar (non-intensive, 10 patients [11.2%]; intensive, 15 patients [19.2%]). Frequency of muscle spasms was similar for the 2 groups; observed in 19 of the non-intensive group (21.3%) and 18 (23.1%) of the intensive group (table 1), with few grade 3 events (non-intensive 4.5%; intensive 1.3%), and the number of patients who developed muscle spasms (nearly all grade 1) when exposed to long-term treatment was small (4 non-intensive patients; 7 intensive patients) with no cases of rhabdomyolysis. Alopecia was reported for 8 (9.0%) of the non-intensive group and 16 (20.5%) of the intensive group (table 1). Alopecia had earlier time to onset in the intensive arm than in the non-intensive arm (table 1), likely reflecting the concomitant chemotherapy. Alopecia was less frequent during glasdegib maintenance monotherapy (5.3%) in the intensive arm than when given with 7+3 (16.7%). Dysgeusia was similar for the 2 groups, observed in 22 of the non-intensive group (24.7%) and 24 (30.8%) of the intensive group (table 1). For both groups, dysgeusia had similar time to onset and was less common during long-term treatment. The number of patients having a dose modification as a consequence of class-related AEs was low (for non-intensive and intensive, respectively: dose reduction, 5.6% and 2.6%; temporary discontinuation, 4.5% and 2.6%; permanent discontinuation, 1.1% and 2.6%). Conclusions: Glasdegib 'on target' AEs of muscle spasms, alopecia, and dysgeusia were mainly of mild severity, had infrequent dose modifications or permanent discontinuations, and did not appear to impair tolerability of combination treatment. In comparison, muscle spasms and dysgeusia occurred in ≤5% for the LDAC alone arm, and no alopecia was reported. Although muscle spasms and dysgeusia occurred with similar frequency, dysgeusia occurred earlier, for a shorter duration, and was more persistent at the time of discontinuation compared with muscle spasms. Similar safety profiles were observed when combining glasdegib with LDAC or 7+3, suggesting that glasdegib in combination with standard chemotherapy has a manageable safety profile and thus can be an acceptable combination partner in the treatment of AML. Our results are consistent with previously reported safety outcomes for glasdegib as monotherapy in hematologic malignancies. Clinical trials of glasdegib in combination with other standard of care AML agents are ongoing. Disclosures Cortes: Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Candoni:Pfizer: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau. Leber:Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuko: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ma:Pfizer Inc: Employment, Equity Ownership. Gallo Stampino:Pfizer Inc: Employment, Equity Ownership. O'Connell:Pfizer Inc: Employment, Equity Ownership. Zeremski:Pfizer Inc: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.