glasdegib and Myelodysplastic-Syndromes

Glasdegib (DAURISMO™) is an oral inhibitor of the Hedgehog signalling pathway, the activation of which is associated with a number of malignancies. It has been developed by Pfizer and was approved in November 2018 in the USA for use in combination with low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukaemia (AML) in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. Glasdegib is the first Hedgehog pathway inhibitor to be approved for AML in the USA. It received orphan designation for the treatment of AML in the USA in June 2017 and in the EU in October 2017, and for the treatment of myelodysplastic syndrome (MDS) in the USA in October 2017. It is also undergoing clinical development for use in select haematological and other malignancies, including MDS, in various countries worldwide. This article summarizes the milestones in the development of glasdegib leading to its use in combination with low-dose cytarabine for the treatment of newly-diagnosed AML in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Drug Approval; Europe; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenylurea Compounds; Signal Transduction; United States

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

Topics: Adult; Azacitidine; Benzimidazoles; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenylurea Compounds; Risk Assessment; Treatment Outcome

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.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Benzimidazoles; Cytarabine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Phenylurea Compounds; Prognosis; Survival Rate

Hypomethylating agent (HMA) failure myelodysplastic syndrome (MDS) patients have poor outcomes and urgent need for novel therapies. Hedgehog pathway signaling upregulation plays a central role in myeloid neoplasm pathogenesis and leukemia stem cell survival. We evaluated the efficacy and safety of the smoothened inhibitor glasdegib in HMA-failure MDS (n = 35, median age 73 years). According to the International Prognostic Scoring System and the MD Anderson Global Risk Model, 54% and 77% had higher risk disease, respectively. Overall response was 6% (n = 2), and best response was marrow complete remission with hematologic improvement in both patients. Median OS and median follow-up were 10.4 and 42.8 months, respectively. Drug response/stable disease (SD) resulted in better OS than treatment failure (20.6 [95% CI, 10.4-] vs 3.9 months [95% CI, 0.7-9.1]; P< .0001). Response/SD was confirmed to be an independent covariate for improved OS (P <  .0001). Grade 3 or higher infections occurred in 11% of patients (n = 4); non-hematologic toxicities were rare. Early mortality (< 30 days) occurred in 11% of patients (n = 4). Glasdegib was well tolerated among HMA-failure MDS patients, although single-agent activity was limited. SD or better resulted in notably superior OS. These results support further investigation of glasdegib, potentially in novel drug combinations, in MDS patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Benzimidazoles; Biomarkers, Tumor; Cohort Studies; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Phenylurea Compounds; Prognosis; Salvage Therapy; Survival Rate

Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies.. We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758.. Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily.. Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis.. Pfizer.

Topics: Administration, Oral; Benzimidazoles; Half-Life; Humans; Italy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Maximum Tolerated Dose; Myelodysplastic Syndromes; Phenylurea Compounds; Primary Myelofibrosis; Treatment Outcome; United States

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Compassionate Use Trials; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Phenylurea Compounds

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Clinical Trials, Phase II as Topic; Cytarabine; Drug Approval; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenylurea Compounds; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration