Erlotinib and vinorelbine in advanced malignant solid tumors: a phase I study

Davies, Angela M.; Ho, Cheryl; Hesketh, Paul J.; Beckett, Laurel A.; Lara, Primo N.; Lau, Derick H; Gandara, David R.

doi:10.1007/s10637-007-9045-8

Cited by 6 publications

(8 citation statements)

References 16 publications

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“…Previous trials performed by our group and others have also showed apparent sensitization of the myeloid compartment by toceranib as evidenced by enhanced myelosuppression noted when toceranib is used in combination with CCNU and vinblastine . In human clinical trials, similar findings have been observed with the combination of cytotoxic agents and RTKIs including gefitinib/gemcitabine, gefitinib/vinorelbine, erlotinib/vinorelbine and vinca alkaloids/EGFR inhibitor combination protocols . One suggested mechanism for this increased haematologic toxicity is that the RTKIs, DOX and vinca alkaloids are all metabolized by CYP3A4 enzymes, resulting in prolonged systemic exposure to the active metabolites due to saturation of hepatic metabolism when these agents are combined .…”

Section: Discussionsupporting

confidence: 75%

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Pellin

Wouda

Robinson

et al. 2016

Vet Comparative Oncology

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Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single-agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose-finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg by mouth every other day (PO EOD) while escalating DOX dosage. The dose-limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m of DOX q 21 days given concurrently with toceranib 2.75 mg kg PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti-tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long-term AE profiles.

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Section: Discussionsupporting

confidence: 75%

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Pellin

Wouda

Robinson

et al. 2016

Vet Comparative Oncology

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“…Neutropenia was the main cause limiting delivery of treatment and requiring dose delays. These results are similar to those reported by Davies et al [11] in a phase I study of erlotinib and vinorelbine in advanced malignant solid tumours and by Scagliotti et al [12] when combining gefitinib with vinorelbine in a phase II study. Nevertheless, it can be noticed that neutropenia did not translate to a high incidence of severe toxicities, as only 2 patients experienced febrile neutropenia, and one patient experienced neutropenic infection.…”

Section: Discussionsupporting

confidence: 92%

Phase I dose-escalation study of oral vinflunine in combination with erlotinib in pre-treated and unselected EGFR patients with locally advanced or metastatic non-small-cell lung cancer

Krzakowski¹,

Bennouna

Dansin

et al. 2013

Cancer Chemother Pharmacol

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BackgroundErlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug–drug interaction was also investigated. Patients and methodsPatients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg.ResultsThirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease.ConclusionThe recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.

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Section: Discussionmentioning

confidence: 99%

“…The combination of erlotinib and vinorelbine administered intravenously in the conventional manner has previously been investigated in another phase I study by Davies et al [ 21 ]. They reported an MTD of vinorelbine 25 mg/m 2 administered intravenously on Days 1 and 8 with erlotinib 100 mg/day every 21 days [ 21 ]. In contrast to the low incidence of haematological toxicities observed in the CSV group in our study, the investigators noted a high incidence of grade 3/4 neutropenia (50%) and febrile neutropenia (25%), which occurred in patients receiving intravenous vinorelbine 25 mg/m 2 with erlotinib 150 mg.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, both vinorelbine and erlotinib are substrates of CYP3A4. Although erlotinib does not commonly cause haematological toxicities, it is possible that erlotinib at a higher dose of 150 mg may elevate the systemic exposure of vinorelbine as compared to erlotinib at lower dose of 100 mg, which may explain the high incidence of haematological toxicities in the study by Davies et al [ 21 ]. Unfortunately, since only 1 patient in the CSV group receiving 80 mg/m 2 vinorelbine and 150 mg erlotinib was recruited and none of the patients in the MSV group received 150 mg erlotinib, this could not be supported by the pharmacokinetics findings of this study.…”

Section: Discussionmentioning

confidence: 99%

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Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

et al. 2016

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PurposeThis study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC).MethodsThis was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily.ResultsThe maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group.ConclusionsCombination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups.Trial RegistrationClinicalTrials.gov NCT00702182

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Erlotinib and vinorelbine in advanced malignant solid tumors: a phase I study

Cited by 6 publications

References 16 publications

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Phase I dose-escalation study of oral vinflunine in combination with erlotinib in pre-treated and unselected EGFR patients with locally advanced or metastatic non-small-cell lung cancer

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

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