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Journal of Clinical Oncology : Official... Jun 2021Mutations in the (m) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a...
PURPOSE
Mutations in the (m) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts function. We evaluated the efficacy of tipifarnib in patients with R/M m HNSCC.
METHODS
We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m variant allele frequency (VAF) data, enrollment was limited to those with a m VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.
RESULTS
Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).
CONCLUSION
Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with mutations for whom limited therapeutic options exist (NCT02383927).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation, Missense; Proto-Oncogene Mas; Proto-Oncogene Proteins p21(ras); Quinolones; Squamous Cell Carcinoma of Head and Neck; Young Adult
PubMed: 33750196
DOI: 10.1200/JCO.20.02903 -
Current Opinion in Investigational... Feb 2002Janssen is developing tipifarnib (formerly known as R-1 15777), an inhibitor of RAS farnesylation, for the potential treatment of neoplasia [287030], [289610]. Janssen... (Review)
Review
Janssen is developing tipifarnib (formerly known as R-1 15777), an inhibitor of RAS farnesylation, for the potential treatment of neoplasia [287030], [289610]. Janssen commenced clinical trials in the US, in conjunction with the National Cancer Institute, in April 1997 [287030], [289610], and by May 1999, phase II trials in patients with advanced non-small cell lung cancer were being planned [325960]. By February 2001, phase III trials for the potential treatment of pancreatic cancer and leukemia had been initiated [399065], and by June 2001, it was in phase II trials for RAS-dependent solid tumors [412618]. In November 2001, Credit Lyonnais Securities predicted NDAfilings in 2002 and 2003 for pancreatic cancer and other cancers, respectively, and projected US introductions for these indications in 2004 and 2005, respectively [436939].
Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Ataxia; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drugs, Investigational; Farnesyltranstransferase; Humans; Neoplasms; Quinolones; Structure-Activity Relationship; Thrombocytopenia; Treatment Outcome
PubMed: 12020065
DOI: No ID Found -
Cancer Research Oct 2023Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18...
UNLABELLED
Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.
SIGNIFICANCE
The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Neoplasm Recurrence, Local; TOR Serine-Threonine Kinases; Head and Neck Neoplasms; Class I Phosphatidylinositol 3-Kinases; Biomarkers; Proto-Oncogene Proteins p21(ras)
PubMed: 37339176
DOI: 10.1158/0008-5472.CAN-23-0282 -
Expert Review of Anticancer Therapy Mar 2006Tipifarnib is an oral nonpeptidomimetic farnesyl transferase inhibitor developed to inhibit a variety of farnesylated targets potentially relevant to the therapy of... (Review)
Review
Tipifarnib is an oral nonpeptidomimetic farnesyl transferase inhibitor developed to inhibit a variety of farnesylated targets potentially relevant to the therapy of various malignancies. The agent has, thus far, been tested in a wide array of both solid tumors and myeloid malignancies. Phase I trials have demonstrated that tipifarnib is best given in a twice-daily fashion in doses of 600-1200 mg/day to avoid significant neuropathy, fatigue and myelosuppression. Subsequent trials demonstrated that pauses in therapy (with staccato dosing schedules) seem to increase tolerability without a clear decrease in efficacy. Phase II and III trials of tipifarnib as monotherapy for breast, colorectal, lung (both non-small cell and small cell), brain, pancreatic and urothelial cancers have all been disappointing. Combination trials of tipifarnib with cytotoxic, hormonal or biological therapies are ongoing. Tipifarnib has displayed the most interesting activity in the myeloid malignancies of myelodysplastic syndrome, myelofibrosis with myeloid metaplasia and elderly/high-risk acute myeloid leukemia. Overall clinical response rates of approximately 20-30% have been reported in myelodysplastic syndrome and acute myeloid leukemia patients who have few alternative therapeutic options. US FDA approval for tipifarnib awaits results of subsequent Phase III trials of the agent in elderly acute leukemia.
Topics: Clinical Trials as Topic; Drug Administration Schedule; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Quinolones; Treatment Outcome
PubMed: 16503848
DOI: 10.1586/14737140.6.3.313 -
Cancer Sep 2020To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant... (Clinical Trial)
Clinical Trial
BACKGROUND
To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC.
METHODS
The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.
RESULTS
A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.
CONCLUSIONS
Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Progression-Free Survival; Proto-Oncogene Proteins p21(ras); Quinolones; Salivary Gland Neoplasms; Treatment Outcome
PubMed: 32557577
DOI: 10.1002/cncr.33036 -
Cancer Research Aug 2018Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this...
Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers ( ) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective , whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a nonsense mutation and an activating mutation in at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance This study demonstrates the feasibility of targeting Ras membrane association in cancers and predicts combination therapies that confer additional benefit. Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. .
Topics: Animals; Benzimidazoles; Carcinogenesis; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Humans; Mice; Mutation; Neurofibromin 1; Proto-Oncogene Proteins p21(ras); Quinolones; Thyroid Neoplasms; Xenograft Model Antitumor Assays
PubMed: 29760048
DOI: 10.1158/0008-5472.CAN-17-1925 -
Molecular Cancer Therapeutics Sep 2020Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling...
Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of -mutant and wild-type head and neck squamous cell carcinoma (HNSCC) xenograft models. Tipifarnib treatment displaced both mutant and wild-type HRAS from membranes but only inhibited proliferation, survival, and spheroid formation of -mutant cells. , tipifarnib treatment induced tumor stasis or regression in all six -mutant xenografts tested but displayed no activity in six wild-type patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, induction of apoptosis, and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FTase inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDXs. These preclinical findings support that represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring mutations.
Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Head and Neck Neoplasms; Humans; MAP Kinase Signaling System; Male; Mice; Mutation; Precision Medicine; Prenylation; Proto-Oncogene Proteins p21(ras); Quinolones; Sequence Analysis, RNA; Squamous Cell Carcinoma of Head and Neck
PubMed: 32727882
DOI: 10.1158/1535-7163.MCT-19-0958 -
Cardiovascular Research Mar 2017RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated...
AIMS
RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect.
METHODS AND RESULTS
The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins.
CONCLUSIONS
Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
Topics: Animals; Antihypertensive Agents; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Hypertension, Pulmonary; Hypoxia; Male; Mice, Inbred C57BL; Phenotype; Protein Prenylation; Proteomics; Pulmonary Artery; Quinolones; Time Factors; Transfection; Vasoconstriction; Vasodilation; rhoB GTP-Binding Protein
PubMed: 28395021
DOI: 10.1093/cvr/cvw258 -
Oral Oncology Nov 2021To test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts...
OBJECTIVE
To test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts for the majority of HNSCC.
MATERIALS AND METHODS
Cell growth, apoptosis and signaling changes in HNSCC cells following tipifarnib exposure in vitro were assessed by SRB, colony formation assay, annexin V staining and Western blot, respectively. A patient-derived xenograft (PDX) animal model was adopted to evaluate the efficacy of tipifarnib in vivo with and without cetuximab.
RESULTS
Treatment of wild-type H-Ras HNSCC cell lines in vitro with tipifarnib reduced cell growth and increased levels of defarnesylated H-Ras in a dose-dependent manner. In a PDX mouse model, treatment with single-agent tipifarnib led to only near-significant growth inhibition. The addition of cetuximab resulted in increased anti-proliferative effect both in culture and in PDX models, which was also mirrored by Western blot and apoptosis assay results.
CONCLUSION
Tipifarnib has only a moderate ability to slow tumor growth as a single agent in HNSCC with wild type H-Ras, despite specifically inhibiting the farnesyltransferase upon which the function of H-Ras depends. The combination of cetuximab and tipifarnib appears to enhance the anti-proliferative effect of single-agent tipifarnib and marginally enhance that of single agent cetuximab. These findings deserve further evaluation.
Topics: Animals; Cell Line, Tumor; Cetuximab; Drug Resistance, Neoplasm; Head and Neck Neoplasms; Humans; Mice; Quinolones; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays
PubMed: 34700281
DOI: 10.1016/j.oraloncology.2021.105546 -
Leukemia Research Dec 2021Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of... (Randomized Controlled Trial)
Randomized Controlled Trial
Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.
PURPOSE
Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse.
PATIENTS AND METHODS
Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients.
RESULTS
One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001).
CONCLUSION
This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.
Topics: Antineoplastic Agents; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Quinolones; Salvage Therapy; Survival Rate
PubMed: 34773794
DOI: 10.1016/j.leukres.2021.106736