A Pilot Trial of Gefitinib in Combination with Docetaxel in Patients with Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

Manegold, Christian; Gatzemeier, U.; Buchholz, Erika; Smith, Robert P.; Fandi, Abderrahim

doi:10.3816/clc.2005.n.013

Cited by 18 publications

(16 citation statements)

References 14 publications

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“…However, given its unique irreversible panerbB inhibitory mechanism of action, it is still possible that CI-1033 contributed to the relatively high incidence of febrile neutropenia via a pharmacodynamic interaction. The toxicity profile noted for the CI-1033/docetaxel combination over the four dosing levels was otherwise fairly comparable with reports of other erbB family receptor inhibitors when given in combination with docetaxel (38), with a predominance of skin, constitutional, and gastrointestinal toxicities. Skin rash has been a pharmacodynamic marker of tumor response in some studies of EGFR inhibitors (40,41).…”

Section: Discussionsupporting

confidence: 53%

“…Phase III trials of paclitaxel plus carboplatin in combination with gefitinib or erlotinib in previously treated NSCLC patients have reported neutropenia rates of 8% to 35% and febrile neutropenia rates of 0% to 4%, not significantly different from the chemotherapy-only study arms (36,37). In a study of gefitinib (250 or 500 mg daily) in combination with docetaxel in first-line or second-line NSCLC, no excessive hematologic toxicity was reported (38). However, in a nontaxane-based phase II trial of gefitinib with irinotecan, 5-fluorouracil, and leucovorin, 62% of patients had grade 3 and 4 neutropenia, a rate that was considered by the study investigators to be excessive.…”

Section: Discussionmentioning

confidence: 99%

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A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

Garland

Hidalgo

Mendelson

et al. 2006

Clinical Cancer Research

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Purpose: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4.We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose. )], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics. Conclusions: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.Aberrant signaling through the erbB family of receptors, which includes erbB-1 [epidermal growth factor receptor (EGFR)], erbB-2, erbB-3, and erbB-4, plays an important role in the development and progression of a wide range of cancers. The majority of solid tumors express one or more members of the erbB receptor family, especially EGFR and erbB-2 (1, 2); tumor types include breast, ovarian, prostate, gastric, head and neck carcinoma, non -small cell lung carcinoma (NSCLC), and glioblastoma (3 -10). Tumors that overexpress these receptors generally have a more aggressive phenotype and a worse clinical prognosis (11,12).CI-1033 (canertinib dihydrochloride; Fig. 1) is a 4-anilinoquinazoline derivative that acts as a highly selective, irreversible ATP binding site -directed inhibitor of erB-1, erB-2, and erB-4 tyrosine kinases with IC 50 values in the low nanomolar/liter concentrations (13). Treatment with CI-1033 completely inhibited EGFR autophosphorylation in A431 human epidermoid carcinoma and MDA-MB-468 human breast cancer cells. Concentration-dependent inhibition of in vitro clone formation has been seen for a wide array of human tumors, including breast, ovary, kidney, liver, pancreas, and prostate. Oral administration of CI-1033 to animals bearing human tumor xenografts delayed growth of H125 (NSCLC) and ref. 14). Moreover, long-term administration (daily gavage, days 1-5 for 10 weeks over a 12-week period) of CI-1033 to mice bearing A431 xenografts caused long-term tumor regression (>9 weeks) without emergence of a drug-resistant population of tumor cells (15). Preclinical studies support an oral continuous daily dosing schedule. The predominant dose-limiting toxicity (DLT) noted in animal toxicology studies is gastrointestinal (diarrhea,

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

Garland

Hidalgo

Mendelson

et al. 2006

Clinical Cancer Research

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“…Data represent GMR with 90 % confidence interval Fig. 3 Changes of a docetaxel AUC 0-24 , b docetaxel C max , c gefitinib AUC 0-24 , and d gefitinib C max administrated alone and in combination in individual patients AUC 0-24 and C max of docetaxel, respectively, in two of ten pharmacokinetically evaluable patients [32]. Although this report suggested a drug-drug interaction between docetaxel and gefitinib, the small number of patients and sparse PK sampling points were inconclusive.…”

Section: Discussionmentioning

confidence: 99%

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug–drug interaction

Motonaga

Yamamoto²,

Makino

et al. 2015

Cancer Chemother Pharmacol

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“…Combination therapy with gefitinib and docetaxel has also been investigated previously [13][14][15]. A pilot study assessed two doses of gefitinib (250 and 500 mg/day) combined with docetaxel (75 mg/m 2 ) in patients with locally advanced or metastatic NSCLC as first-and second-line therapy.…”

Section: Discussionmentioning

confidence: 99%

Phase II combination of gefitinib and docetaxel for advanced or metastatic non-small cell lung cancer: clinical results and biological monitoring

et al. 2006

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The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib and the cytotoxic agent docetaxel are both used for the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of gefitinib in combination with docetaxel within this disease setting, and to evaluate the predictive value of assessing pre-treatment levels of soluble serum EGFR and HER2. In this open-label, noncomparative, multicenter, phase II trial, patients with nonresectable advanced or metastatic NSCLC were treated with oral gefitinib (250 mg/day) in combination with docetaxel (75 mg/m 2 IV every 3 weeks). Forty-eight patients were enrolled: 30 had progressed during or after platinum-based chemotherapy (Group A) and 18 were unsuitable for platinum-based chemotherapy (Group B). Anti-tumor activity was seen with objective response rates of 23.3% (Group A) and 11.8% (Group B). The most frequent adverse events considered to be gefitinib-related were diarrhea (57.4%) and skin-related events (dry-skin: 31.9%; rash: 29.8%; pruritus: 12.8%), and those considered to be docetaxel-related were alopecia (21.3%), nausea (19.1%), and diarrhea (17.0%). The addition of gefitinib did not seem to affect the hematological toxicity seen with docetaxel. Serum biomarker investigations revealed that patients who responded had lower serum EGFR levels than non-responders, although this association was not significant (p=0.07). In conclusion, the combination of gefitinib with docetaxel was feasible, generally well tolerated, and has activity for the treatment of advanced NSCLC. Soluble serum EGFR (and HER2 levels) did not appear to be predictive for response. Although this study confirms that the combination of gefinitib and docetaxel appears promisingly effective and tolerable, it should not be recommended as a standard option for second-line therapy in non-small cell lung cancer until results from phase III trials showing a significant superiority over docetaxel alone are available.

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A Pilot Trial of Gefitinib in Combination with Docetaxel in Patients with Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

Cited by 18 publications

References 14 publications

A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug–drug interaction

Phase II combination of gefitinib and docetaxel for advanced or metastatic non-small cell lung cancer: clinical results and biological monitoring

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