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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tipifarnib appears to be relatively free of severe toxicities, and doses of up to 1,300 mg twice a day have been given to patients in Phase I clinical trials without any significant adverse effects other than a dose-limiting reversible myelosuppression.
Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The systemic inflammatory disease that characterizes mevalonic aciduria has been related to the secretion of caspase-1-dependent IL-1β, and this has been related to a shortage of geranylgeranylpyrophosphate (GGPP). This has led to the use of farnesyltransferase inhibitors tipifarnib and lonafarnib, which had been developed as cancer chemotherapeutic agents [31, 32]. Success in treating murine monocytic cell lines in vitro was followed by their use in monocytes from two patients. Lipopolysaccharide induced secretion of IL-1β was significantly reduced. The mechanism was thought to involve recovery of GGPP flux. Allogeneic bone marrow transplantation has been reported [31] in a three-year-old who had sustained remission from febrile attacks and inflammation. Cord blood stem cell transplantation in a two-year-old yielded sustained remission from Febrile attacks and inflammation [33], and neurologic and psychomotor development were normal after years at the time of report.
Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Several studies have aimed to define the activity of FTIs in MDS. Kurzrock and colleagues have completed phase I and II clinical trials of tipifarnib (50–52). In the original phase I study, tipifarnib was administered twice daily, in a three-weeks-on/one-week-off schedule. DLTs occurred at 900 mg BID with fatigue and confusion (52). Responses were noted in 6 of 20 patients (30%), including two PRs and one CR. As reported in the phase I trial for acute leukemias (46), responses were seen across all dosing cohorts, including the very lowest. In the phase II trial, where tipifarnib was administered at 600 mg BID for four weeks out of every six, significant treatment-related toxicity consisting of fatigue, myelosuppression, neurotoxicity, and rash necessitated dose reduction or discontinuation of in over 40% of patients (51). Clinical responses (CR + PR) occurred in only a minority of patients (11%), due at least in part to the high rate of drug discontinuation.
An update on treatment of higher risk myelodysplastic syndromes
Published in Expert Review of Hematology, 2019
Farnesylation is another posttranslational modification by which a cysteine residue in the C-terminal region of some proteins is modified with an isoprenoid lipid – the 15-carbon farnesyl group – and the exposed carboxyl group is methylated: This reaction is catalyzed by the enzyme protein farnesyltransferase. This process seems to be critical to proto-oncogene Ras maturation into its biologically active form [78]. This observation has led to the development of farnesyltransferase inhibitors, such as tipifarnib [79]. A phase II multicenter trial evaluated single-agent tipifarnib in 82 higher risk MDS patients [80]: 32% responded, 15% achieved CR with a median duration of 11.5 months, and 7 patients (8.5%) were still alive more than 3 years after treatment onset. Thus, responses to tipifarnib are durable. Since then, Patnaik et al (ASH 2017, Abstract 2963) reported favorable results from an open-label phase 2 study of tipifarnib in CMML. However, combination with AZA has not been yet evaluated.
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
Tipifarnib inhibits farnesyltransferase and blocks the post-translational isoprenylation of RAS leading to dysfunctional RAS proteins [91]. Given that loss of neurofibromin leads to activated RAS, inhibition of RAS farnesylation was hypothesized to inhibit PN growth. A pediatric phase I trial of tipifarnib for children with refractory solid tumors or NF1-related inoperable PN enrolled 40 patients assessable for toxicity, 17 of which were NF1 patients. In the NF1 population, 13 were treated on a 21-day schedule at one of the four dose levels and 4 patients were treated on the continuous schedule at the dose identified MTD on the 21-day schedule. The MTD was found to be 200 mg/m2 administered twice daily for 21 consecutive days followed by a 7-day break and dose-limiting toxicities included myelosuppression, rash and gastrointestinal disturbance. No objective responses were observed in this trial [92]. A subsequent phase II randomized, flexible crossover, double-blinded, placebo-controlled study of tipifarnib evaluated TTP in 60 children and young adults (median age 8.5 years, range 3–21.5 years) with unresectable, progressive PNs with the potential to cause significant morbidity and showed only a non-significant increase in TTP with tipifarnib versus placebo. The toxicities related to tipifarnib were the same as seen in the phase I study (NCT00021541) [93]. Of note, other studies showed that tipifarnib is only able to inhibit the HRAS isoform. Unlike HRAS, KRAS and NRAS can undergo alternative prenylation in the presence of a farnesyltransferase inhibitor. Therefore, this may partially explain why tipifarnib was ineffective in clinical trials [94].
Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma
Published in Expert Opinion on Pharmacotherapy, 2021
Anna Wolska-Washer, Piotr Smolewski, Tadeusz Robak
Tipifarnib (R115777, Zarnestra, Johnson & Johnson Pharmaceutical Research and Development, Kura Oncology) is an oral inhibitor of farnesyltransferase, an enzyme that facilitates the attachment of farnesyl groups required for trafficking of signaling molecules to the inner part of the cell membrane [84]. Tipifarnib inhibits the production of CXCL12 chemokine essential for T lymphocyte homing to the lymph nodes and the bone marrow. High CXCL12 expression is a negative prognostic factor for AITL and other PTCLs [85]. Preliminary data from a phase 2 study recorded three PRs and three patients with stable disease (SD) among 18 patients with relapsed/refractory PTCL [86]. The most common high-grade AEs were neutropenia (61%), anemia (39%), and thrombocytopenia (39%), mainly due to myelosuppression. The best responses were observed in patients with a high expression of CXCL12, which is a chemokine essential for homing of the stem cells to the bone marrow and lymphoid organs. The amended study by the same team revealed another two patients with SD, and a similar pattern of AEs [87]. Patients carrying variants of the KIR3DL2 responded better to tipifarnib, compared to their responses to conventional chemotherapy. Tipifarnib is currently being investigated in a phase 2 clinical trial in 65 relapsed/refractory patients with PTCL (ClinicalTrials.gov Identifier NCT02464228). The preliminary results of the study in 20 AITL patients demonstrated ORR of 50% with five CRs and five PRs [87]. Patients with high CXCL12 expression or KIR3DL2 variants were more sensitive to tipifarnib. The latter finding emphasizes the need for mutational analysis to allow personalized treatment of patients.