Phase 1b Dose Escalation Study of Erlotinib in Combination with Infusional 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Advanced Solid Tumors

Hanauske, Axel‐R.; Cassidy, Jim; Sastre, Javier; Bolling, Claus; Jones, Robert J.; Rakhit, Ashok; Fettner, Scott; Brennscheidt, U.; Feyereislova, A.; Dı́az-Rubio, Eduardo

doi:10.1158/1078-0432.ccr-06-1627

Cited by 22 publications

(7 citation statements)

References 45 publications

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“…The combination of FOLFOX and erlotinib was generally well tolerated with few grade 3–4 toxicities consistent with a previous phase I study that examined this combination (Hanauske et al , 2007). Not surprisingly, an acneiform rash was the most common toxicity attributed to the addition of erlotinib in this trial.…”

Section: Discussionsupporting

confidence: 84%

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction

et al. 2011

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Background:There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ. This study evaluates the efficacy and safety of mFOLFOX6 and erlotinib in patients with metastatic or advanced Eso/GEJ cancers.Methods:Patients with previously untreated advanced or metastatic Eso/GEJ adenocarcinoma are treated with oxaliplatin 85 mg m–2, 5-FU 400 mg m–2, LV 400 mg m–2 on day 1, 5-FU 2400 mg m–2 over 48 h and erlotinib 150 mg PO daily. Treatment was repeated every 14 days. The primary objective was response rate (RR), secondary objectives include toxicity, progression-free survival (PFS), overall survival (OS) and to correlate clinical outcome with expression patterns and molecular alterations in the epidermal growth factor receptor-dependent pathways.Results:A total of 33 patients were treated and evaluable: there were two complete responses, 15 partial responses for an objective RR of 51.5% (95% CI, 34.5–68.6%). Median PFS was 5.5 months (95% CI, 3.1–7.5 months) and median OS was 11.0 months (95% CI, 8.0–17.4 months). The most common grade 3–4 toxicities were: diarrhoea (24%), nausea/vomiting (11%), skin rash (8%) and peripheral neuropathy (8%). The frequency of alterations was KRAS mutations (8%), EGFR mutations (0%) and HER2 amplification (19%).Conclusion:In patients with Eso/GEJ adenocarcinoma, mFOLFOX6 and erlotinib is active, has an acceptable toxicity profile and FOLFOX±erlotinib could be considered for further development.

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Section: Discussionsupporting

confidence: 84%

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction

et al. 2011

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“…There was no difference in 5-FU pharmacokinetics. The lack of pharmacokinetic interactions between these agents was expected, given an absence of interactions in the Hanauske et al study and our previously published study of FOLFIRI/erlotinib 24,39…”

Section: Discussionmentioning

confidence: 73%

“…The second CAPOX/erlotinib study also had excessive gastrointestinal toxicity, but rather than lower the dose of erlotinib, the dose of capecitabine was lowered from the standard 2000 mg/m 2 /day down to 1500 mg/m 2 /day after the first 13 patients 16. A phase Ib study of FOLFOX4/erlotinib by Hanauske et al in patients with solid tumors (72% CRC) explored 3 6-patient cohorts, starting with a dose reduction of both erlotinib and FOLFOX4 39. However, 2 of 6 DLTs were seen at the 100-mg cohort (with full-dose FOLFOX-4) and at the 150 mg cohort (including grade 5 sepsis), which would typically trigger a de-escalation to the previous dose level in a phase I study.…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Oxaliplatin, Infusional 5-Fluorouracil, and Leucovorin (FOLFOX4) With Erlotinib and Bevacizumab in Colorectal Cancer

Messersmith

Jimeno

Jacene

et al. 2010

Clinical Colorectal Cancer

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Rationale-This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/ leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.Patients and Methods-Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.Results-Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.Conclusion-The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.

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“…33 33 In parallel, higher AGP concentration was associated with higher AUC, C max of erlotinib, 28,59,67,73 and OSI-420 59,71 (Table 5).…”

Section: Influence Of Covariatesmentioning

confidence: 86%

“…Only an increase of total bilirubin was associated with a decrease of CL/F, 17 although many other studies 17,18,20,33,67,71,73 did not report a correlation (Table 5).…”

Section: Influence Of Covariatesmentioning

confidence: 91%

Erlotinib

Petit-Jean

Buclin

Guidi

et al. 2015

Therapeutic Drug Monitoring

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Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

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Phase 1b Dose Escalation Study of Erlotinib in Combination with Infusional 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Advanced Solid Tumors

Cited by 22 publications

References 45 publications

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction

Phase I Trial of Oxaliplatin, Infusional 5-Fluorouracil, and Leucovorin (FOLFOX4) With Erlotinib and Bevacizumab in Colorectal Cancer

Erlotinib

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