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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Other cancers thought to be associated with this signaling pathway include breast, endometrial, gastric and pancreatic cancer, and lymphoblastic leukemia. Emerging preclinical evidence suggests that tumor growth occurring in mutation-driven and ligand over-expression models can be inhibited by blocking the key components of the signaling pathway, such as SMO. For basal cell carcinoma, which is associated with up-regulated Hedgehog signaling, two Hedgehog inhibitors, vismodegib (ErivedgeTM) and sonidegib (OdomzoTM), which work by targeting SMO (Smoothened) have been approved by the FDA for the treatment of basal cell carcinoma. A third approved agent of this class, glasdegib (DaurismoTM), works by the same mechanism but is approved for use in the newly diagnosed hematological cancer, acute myeloid leukemia (AML). These three agents are described below, along with the experimental agents TAK-441 and BMS-833923 which work through the same mechanism but did not reach the approval stage. Finally, it is interesting to note that the antifungal agent itraconazole (SporanoxTM and OrungalTM) has been shown to have Hedgehog pathway inhibitory properties.
Exposure–response modeling of the effect of glasdegib on cardiac repolarization in patients with cancer
Published in Expert Review of Clinical Pharmacology, 2021
Luke K. Fostvedt, Naveed Shaik, Giovanni Martinelli, Andrew J. Wagner, Ana Ruiz-Garcia
Study B1371002 was an open-label, multicenter, phase 1 study of glasdegib administered orally to 23 adult patients with solid tumor malignancies. Four dose levels were evaluated in this study (80, 160, 320, and 640 mg QD). One treatment cycle was defined as 28 days. In Cycle 1 only, patients received glasdegib for 25 days followed by 3 days without treatment to characterize the glasdegib plasma elimination after steady-state dosing. In Cycle 2 and beyond, glasdegib was administered continuously once a day. Triplicate ECGs were scheduled for Days 1, 15, and 25 of Cycle 1; and Day 1 of each cycle thereafter. Triplicate ECG readings paired with a PK sample were collected at pre dose, and 2 hours post dose on Day 1 of each cycle, and on Cycle 1/Day 15. On Cycle 1/Day 25 PK-ECG pairs were collected at pre dose, and at 2, 6, and 24 hours following glasdegib dosing [9].
Identifying effective drug combinations for patients with acute myeloid leukemia
Published in Expert Review of Anticancer Therapy, 2020
Musa Yilmaz, Tapan Kadia, Farhad Ravandi
Aberrant hedgehog pathway signaling has been implicated in AML and is important for leukemia stem-cell expansion and survival [62,63]. Preclinical data suggest that inhibition of the hedgehog pathway significantly enhances the sensitivity to chemotherapy [64]. Glasdegib, an oral selective inhibitor of the hedgehog pathway, is approved by the FDA in combination with LDAC for the newly diagnosed patients with AML unfit for intensive chemotherapy. In a phase 1b/2 study, Cortes and colleagues randomized 88 and 44 patients with newly diagnosed AML (n = 116) or high-risk MDS (n = 16) to receive glasdegib plus LDAC or LDAC alone. The CR rates were higher in the combination arm (17% vs. 2%). With a median follow-up of 20 months, patients treated with LDAC and glasdegib achieved better median OS, 9 months vs. 5 months. The addition of glasdegib was associated with an increased incidence of gastrointestinal symptoms, muscle spasms, and fatigue. In an interim result of a phase 1b study, 30 patients with newly diagnosed AML (median age of 74 years old) were treated with azacitidine plus glasdegib. In this study with a short follow-up, investigators reported 27% CRc rate, and median OS was not reached (70% of the patients were alive at six months). Glasdegib and azacitidine combination is currently in phase 3 clinical development for AML therapy (NCT03416179).
Emerging pharmacotherapies for elderly acute myeloid leukemia patients
Published in Expert Review of Hematology, 2020
Xavier Thomas, Mohamed Elhamri, Maël Heiblig
For patients who are not considered candidates for intensive chemotherapy, low-intensity treatments should be considered. They should be used continuously until disease progression, to obtain the optimal clinical response. Among low-intensity treatments, HMAs, which demonstrated superiority over low-dose cytarabine in randomized trials, are now widely used and can be considered as the new standard therapy in patients unfit for intensive treatment [7,8]. Their median response duration is about 1 year. HMAs seem to alter the natural course of AML even in patients who do not achieve CR with hematologic improvement yielding to clinical benefit, that is a reduction in transfusion needs and improved quality of life. Several promising investigational agents are currently being evaluated in clinical trials in older patients with AML, either alone or better in combination with existing drugs. In this setting, venetoclax, a BCL2 inhibitor, has shown high response rates in older patients with relapsed or refractory disease and very high response rates in combination with low-dose cytarabine or HMAs [116,117,120]. Glasdegib, which can potentially target the leukemia stem cell, has also demonstrated promising results [133]. Treatment options for older patients may therefore change as soon as new drugs or strategies become available.