A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies

Awada, Ahmad; Zhang, Steven; Gil, Thierry; Valeriola, Dominique de; Lalami, Yassine; Porre, Peter De; Piccart‐Gebhart, Martine

doi:10.1185/030079907x178810

Cited by 9 publications

(3 citation statements)

References 28 publications

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“…As a matter of fact, farnesyl transferase inhibitors, which antagonize the RAS‐dependent signaling, have shown to be active in cetuximab‐resistant HNSCC in the preclinical setting . Moreover, the combination of docetaxel and the farnesyl transferase inhibitor tipifarnib, has been already tested in a phase I clinical study with promising results …”

Section: Introductionmentioning

confidence: 99%

Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications

Perri¹,

et al. 2015

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Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)-related tumors has shown a significant increase, and HPV-related tumors show distinctive features if compared with the HPV-negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance. Preclinical and clinical evidence highlighted that 3 main pathways, including the epidermal growth factor receptor (EGFR), the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and the p53 signaling cascades, play a crucial role in radioresistance development. A future approach may consist in the association of radiotherapy (RT) and selective inhibition of the key pathways involved in radioresistance. Phase I, II, and III clinical trials are currently testing these novel treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications

Perri¹,

et al. 2015

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“…The cells that co-inhibited with KO-2806 and adagrasib showed reduced ERK phosphorylation and mTOR signaling. Although tipifarnib has shown an unfavorable toxicity profile, especially regarding bone marrow suppression when combined with cytotoxic chemotherapy, it was better tolerated as a monotherapy, though its efficacy was more limited ( 88 , 89 ). Since KRAS G12C inhibitors are not very myelosuppressive, combining KRAS G12C and FTase inhibitors might have reasonable safety and efficacy.…”

Section: Discussionmentioning

confidence: 99%

KRAS G12C inhibitor combination therapies: current evidence and challenge

Miyashita,

Kato,

Hong

2024

Front. Oncol.

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Although KRAS G12C inhibitors have proven that KRAS is a “druggable” target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

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“…Topotecan administration followed by docetaxel also results in a decreased clearance of the latter, but in this case, the order of administration is important [38]. More recently, the absence of clinically relevant PK interactions was shown for docetaxel and lapatinib [80], bortezomib [81,82], ispinesib [83], erlotinib [84], the combination erlotinib/capecitabine [85], vinorelbine [86,87], pertuzumab [88], tipifarnib [89], granisetron [90] or celecoxib [91]. The combination of docetaxel and paclitaxel only changes the docetaxel PK parameters: increase in docetaxel clearance when the administration order is changed from paclitaxel/docetaxel into docetaxel/paclitaxel [29].…”

Section: Sources Of Variabilitymentioning

confidence: 99%

Level of evidence for therapeutic drug monitoring of taxanes

Schieveen

Royer

Therapeutics³

2010

Fundamental &Amp; Clinical Pharmacology

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Taxanes are anticancer drugs on the market for more than 10 years that are thought to be interesting for therapeutic drug monitoring (TDM): high inter- and intra-patient variability, relationship between exposure and efficacy and especially toxicity. Nevertheless, the paclitaxel and docetaxel characteristics result in different conclusions for these two molecules with respect to their TDM. For paclitaxel, the nonlinear pharmacokinetics makes that the parameter which seems the more reliable to toxicity or outcome is the time during which the plasma concentration exceeds 0.05 μm. Concentration controlled studies using Bayesian adaptation showed that the TDM of paclitaxel is feasible in routine. However, this target needs to be prospectively validated with new weekly schedules of administration, leading to a balance between 'recommended' and 'potentially useful'. For docetaxel, the 3-weekly administration, which is the more effective scheme, is also the more toxic. However, neutropenia can be individually modeled and efficiently predicted without using plasma drug concentrations. The docetaxel TDM using this docetaxel-related neutropenia modeling however needs to be prospectively validated in routine. The level of evidence of TDM thus 'needs to be assessed'.

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A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies

Cited by 9 publications

References 28 publications

Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications

Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications

KRAS G12C inhibitor combination therapies: current evidence and challenge

Level of evidence for therapeutic drug monitoring of taxanes

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