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Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Multiple small molecule FLT3 inhibitors and other tyrosine kinase inhibitors (TKIs) have been in clinical trials for over a decade but none have been licensed for AML so far. In addition to the recently licensed FLT3ITD inhibitor, midostaurin, there are three multitargeted TKIs, sorafenib, sunitinib and ponatinib, which are licensed for a variety of other haematological malignancies and have demonstrated in vitro activity against FLT3. Sorafenib has been used ‘off-label’ and reported to accord remissions in relapsed FLT3ITD AML. Several clinical trials are currently on-going, with phase II results of quizartinib (AC220) as a monotherapy, being perhaps the most impressive with remission rates in relapsed AML approaching 51%. The drug appears to work rapidly, with little systemic toxicity and in this study, has allowed 35% of patients to undergo an allograft. Other candidate drugs include estaurtinib, pexidartinib (PLX3397) and crenolanib, which have demonstrated activity in patients with FLT3TKD mutations; gilternib (ASP-2215) has shown activity in both FLT3ITD and FLT3TKD. TKIs of other pathologically activated kinases such as KIT and JAK2 have met less success.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The clinical outcomes of patients with relapsed and primary refractory disease and those with therapy-related myeloid neoplasms (t-MNs), a distinct WHO 2016 category, remain very poor with median OS of 3 to 7 months and no approved standard of care.25 The treatment of these patients requires a carefully balanced assessment of treatment benefit versus treatment complications, and clinical trials should be considered whenever possible. The demonstration of a synergistic effect of venetoclax in combination with HMA or low-dose cytarabine led to this combination being approved by the FDA for untreated older AML patients not suitable for intensive chemotherapy, and there have been numerous clinical single-arm studies assessing the combination in the relapsed/refractory setting. In addition, targeted immunotherapy approaches combined with a backbone of venetoclax and HMAs represent a novel approach. As an illustration, tagraxofusp, a novel, rationally designed CD123-targeted immunotherapy, is being tested in combination with venetoclax and HMAs in untreated older AML patients and relapsed/refractory patients with high CD123 expression. Tagraxofusp was licensed in 2018 for pediatric and adult patients with BPDCN.26 The investigational therapeutic armamentarium of AML in general continues to be driven largely by targeted agents and immunotherapy. Additionally, the lessons learned from the mechanism of resistance against these agents is paving the way for the next-generation drugs. For example, following the licensing of midostaurin and gilteritinib for FLT3ITD AML, the rational development of the next generation of FLT3 inhibitors is in progress, with drugs such as quizartinib (licensed in Japan), estaurtinib, pexidartinib, and crenolanib. Also, following the approval of the IDH1 and IDH2 inhibitors ivosidenib and enasidebib, respectively, new drugs are being developed to target the recurrent mutations in isocitrate dehydrogenase (IDH) enzymes. A principal challenge in assessing many of these agents is the actual design of a clinical trial, where the objective is to find treatments that make a clinical difference in addition to survival benefits. Moreover, in AML trials, the impact of a post-remission strategy is important and can easily negate any potential improvements achieved with a newer induction regimen.27
Tenosynovial giant cell tumors (TGCT): molecular biology, drug targets and non-surgical pharmacological approaches
Published in Expert Opinion on Therapeutic Targets, 2022
Geert Spierenburg, Lizz van der Heijden, Kirsten van Langevelde, Karoly Szuhai, Judith V.G.M. Bovée, Michiel A.J. van de Sande, Hans Gelderblom
Pexidartinib is a novel TGCT targeting drug, the first drug approved by the US Food and Drug Administration (FDA)[84]. It was derived from other TKIs, and showed more potential in blocking CSF1R dependent cells and limited cross-reactivity with other kinases. Besides strong selective activity against CSF1R, it also inhibits KIT and fmls-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)[85]. In a phase I study by Tap et al., 41 patients were enrolled in various dose-escalation cohorts. 27% had at least one drug-related adverse event of grade 3 or higher, including anemia, increase in aspartate aminotransferase level (AST), and decrease in lymphocytes. The maximum tolerated dose was set at 1000 mg per day taken orally. In the phase II extension study, 23 patients with D-TGCT were enrolled. Frequently experienced AEs were hair color change, fatigue, nausea, dysgeusia, and periorbital edema. Eight patients had grade 3 or higher AEs, including elevated levels of liver enzymes. Two patients discontinued treatment because of AEs. Disease control was observed in 19 (83%) patients, of which 12 had a partial response. Only one patient with metastatic TGCT had disease progression after a stable period of eight months.
Plexiform neurofibroma: shedding light on the investigational agents in clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Simge Acar, Amy E. Armstrong, Angela C. Hirbe
Pexidartinib is an oral agent that inhibits protein tyrosine kinases including regulators of tumor microenvironment CSF-1 R and KIT [79]. CSF-1 R signaling is important for the mobilization and proliferation of M2 macrophages and monocytes [80]. Monocytes and monocyte-derived cells expressing high levels of CSF-1 R enhance cancer cell survival [81] and inhibiting CSF-1/CSF-1 R signaling may favor M1 macrophages that enhance host defense by inducing anti-tumor T cells and phagocytosis of tumor cells [82]. NF1 related PN express high numbers of tumor associated macrophages, therefore pexidartinib may have a role in reducing tumor progression [59]. No dose limiting toxicity was observed in a phase I study with 12 patients on pexidartinib therapy for leukemia and solid tumors including PN. Non-dose limiting toxicities were headache, serum amylase or CPK elevation, and proteinuria [83]. A mixed phase I/II study is currently evaluating the safest pexidartinib dose and treatment response in leukemia and solid tumors. The phase II portion does include PN (NCT02390752) [84].
Protein kinase inhibitors for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Vincent Chau, Ravi A. Madan, Jeanny B. Aragon-Ching
Clinical trial evidence supporting the potential effectiveness of pexidartinib (PLX3397) is circumstantial thus far. In a phase Ib trial, pexidartinib plus paclitaxel were given to patients with advanced solid tumors (though prostate cancer patients were not formally included), and was shown to be well-tolerated [17]. Another phase I study showed that pexidartinib was well tolerated in Asian patients with advanced solid tumors, but again, prostate cancer patients were not included [18]. In addition, a monoclonal antibody against CSF1 receptor (LY3022855) was well tolerated and produced increased levels of CSF1 and decreased levels of proinflammatory monocytes CD14DIMCD16BRIGHT in patients with mCRPC [19]. Unfortunately, a phase II trial of pexidartinib in mCRPC was terminated early due to not meeting its enrollment timeline [20]. Results are being awaited for a completed, phase I, dose-escalation trial, in which patients with non-metastatic, intermediate or high-risk prostate cancer who are candidates for radiation therapy, were treated with pexidartinib, radiation therapy, and ADT [21]. Therefore, it is currently unclear whether pexidartinib is effective for treatment of mCRPC.