Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

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.Peer reviewe

Correction to: Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

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.Peer reviewe

Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

AML-140: Effect of Early Blood Counts on Response and Overall Survival Following Glasdegib Plus LDAC in Newly Diagnosed AML: BRIGHT AML 1003 Post Hoc Analysis

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. Evaluate potential association of outcomes with early blood count recovery. 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). Multicenter (European and North American centers). This analysis included patients with AML (78 GLAS+LDAC; 38 LDAC-alone). Glasdegib 100 mg QD; LDAC 20 mg BID × 10 days q28 days. 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. 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 < 0.01). Notably, in patients who did not meet thresholds at C2D1, OS benefit with GLAS+LDAC was also observed (all p ≤ 0.05). Patients with baseline anemia or thrombocytopenia also had improved OS associated with C2D1 recovery of hemoglobin or platelets (all p < 0.05). Response (CR/CRi/PR) to GLAS+LDAC correlated with achieving platelet thresholds at C2D1, including recovery in patients with baseline thrombocytopenia (p < 0.0001). 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. Pfizer

Clinical Benefit of Glasdegib in Combination with Azacitidine or Low-Dose Cytarabine in Patients with Acute Myeloid Leukemia

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

A Phase 1b Study of Glasdegib in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

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

Glasdegib in Addition to Intensive or Non-Intensive Chemotherapy in Patients with Acute Myeloid Leukemia: Safety Analysis of Glasdegib 'On Target' Adverse Events

Abstract 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