Therapy Detail
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| Therapy Name | Tipifarnib |
| Synonyms | |
| Therapy Description |
Zarnestra (tipifarnib) is a farnesyltransferase inhibitor, which alters post-translational modification and activation of Ras proteins, and may result in decreased tumor cell proliferation and reduced tumor growth (PMID: 11196150, PMID: 25323927, PMID: 32557577). |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| Tipifarnib | Zarnestra|R115777 | Farnesyltransferase Inhibitor 3 | Zarnestra (tipifarnib) is a farnesyltransferase inhibitor, which alters post-translational modification and activation of Ras proteins, and may result in decreased tumor cell proliferation and reduced tumor growth (PMID: 11196150, PMID: 25323927, PMID: 32557577). |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| HRAS V29Cfs*19 | bladder urothelial carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, a patient with bladder urothelial carcinoma harboring HRAS V29Cfs*19 achieved a partial response (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS Q61L | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a head and neck squamous cell carcinoma cell line xenograft model harboring HRAS Q61L was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth and vessel formation, increased apoptotic activity, and decreased cell proliferation (PMID: 32727882). | 32727882 |
| HRAS G12S | renal pelvis transitional cell carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, a patient with renal pelvis transitional cell carcinoma harboring HRAS G12S achieved a partial response (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS mutant | salivary gland cancer | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 8% (1/12) in patients with recurrent or metastatic salivary gland cancer harboring HRAS mutations, with a median progression-free survival of 7 months (J Clin Oncol 38: 2020 (suppl; abstr 6504); NCT02383927). | detail... |
| HRAS G12C | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a head and neck squamous cell carcinoma cell line xenograft model harboring HRAS G12C was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth and vessel formation, increased apoptotic activity, and decreased cell proliferation (PMID: 32727882). | 32727882 |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 55% (11/20) in patients with head and neck squamous cell carcinoma harboring HRAS missense mutations at a variant allele frequency over 20%, with nine patients achieved stable disease and a median progression-free survival of 5.6 months (PMID: 33750196; NCT02383927). | 33750196 |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, head and neck squamous cell carcinoma cell lines harboring an HRAS mutation were sensitive to treatment with Zarnestra (tipifarnib), demonstrating reduced cell growth and decreased phosphorylation of Erk and Mek, and inhibition of spheroid viability in culture (PMID: 32727882). | 32727882 |
| HRAS G12V | head and neck squamous cell carcinoma | sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, Zarnestra (tipifarnib) treatment led to decreased cell viability and inhibition of clonogenic and anchorage-independent growth in a head and neck squamous cell carcinoma cell line harboring HRAS G12V in culture (PMID: 35247914). | 35247914 |
| HRAS act mut | salivary gland carcinoma | sensitive | Tipifarnib | Clinical Study | Actionable | In a clinical study, Zarnestra (tipifarnib) treatment resulted in an overall response rate of 8% (n=13) with one ongoing partial response with a duration of 14 months and stable disease as the best response in 58% (7/12) of evaluable patients with HRAS-mutant metastatic salivary gland carcinoma, and a median overall survival of 18 months, and a median progression-free survival of 7 months (PMID: 32557577). | 32557577 |
| HRAS K117N | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS K117N was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS Q61R | bladder urothelial carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, 2 patients with bladder urothelial carcinoma harbored HRAS Q61R achieved partial responses (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS G13R | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS G13R was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS G13R | renal pelvis transitional cell carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, a patient with renal pelvis transitional cell carcinoma harboring HRAS G13R achieved a partial response (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS G12D | head and neck squamous cell carcinoma | sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, Zarnestra (tipifarnib) treatment led to decreased cell viability and inhibition of clonogenic and anchorage-independent growth in head and neck squamous cell carcinoma cell lines harboring HRAS G12D in culture (PMID: 35247914). | 35247914 |
| HRAS over exp | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, Zarnestra (tipifarnib) treatment resulted in tumor regression in patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma overexpressing wild-type Hras (J Clin Oncol 38: 2020 (suppl; abstr e15658)). | detail... |
| HRAS act mut | transitional cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated safety and preliminary efficacy in patients with metastatic urothelial carcinoma harboring HRAS mutations (n=14) or STK11:rs2075606, 3 of 4 patients achieved progression-free survival at 6 months harbored HRAS activating mutations, and no response was observed in HRAS wild-type patients (J Clin Oncol 38: 2020 (suppl; abstr 5086); NCT02535650). | detail... |
| HRAS mutant | transitional cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS missense (Q61R, G12S, G13R) or frameshift (V29Cfs*19) mutations, progression-free survival was significantly improved in patients harboring HRAS mutations (5.1 vs 0.8 months, HR=0.262) compared to wild-type patients (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS A146T | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS A146T was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS G12S | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS G12S was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS G13R PTEN inact mut | Advanced Solid Tumor | predicted - sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, cultured cells expressing HRAS G13R and PTEN inactivating mutations in the context of an HRAS, NRAS, and KRAS knockout were resistant to treatment with Zarnestra (tipifarnib) (Cancer Res 2022;82(12_Suppl):Abstract nr 1181). | detail... |
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| Clinical Trial | Phase | Therapies | Title | Recruitment Status | Covered Countries | Other Countries |
|---|---|---|---|---|---|---|
| NCT02779777 | Phase II | Tipifarnib | Tipifarnib in Subjects With Transfusion-dependent, Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes | Terminated | USA | 0 |
| NCT02807272 | Phase II | Tipifarnib | Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML) | Completed | USA | 0 |
| NCT00006199 | Phase I | Tipifarnib Topotecan | Study of the Farnesyl Transferase Inhibitor, R115777, in Combination With Topotecan (NYU 99-32) | Unknown status | USA | 0 |
| NCT02383927 | Phase II | Tipifarnib | Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations | Completed | USA | ITA | FRA | ESP | DEU | BEL | 4 |
| NCT03496766 | Phase II | Tipifarnib | Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS | Active, not recruiting | ESP | 0 |
| NCT04284774 | Phase II | Tipifarnib | Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial | Recruiting | USA | 1 |
| NCT03719690 | Phase II | Tipifarnib | Safety and Efficacy of Tipifarnib in Head and Neck Cancer With HRAS Mutations and Impact of HRAS on Response to Therapy (AIM-HN/SEQ-HN) | Active, not recruiting | USA | ITA | ESP | DEU | BEL | AUT | 10 |
| NCT02464228 | Phase II | Tipifarnib | Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma | Completed | USA | ESP | 1 |
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