Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: Results of a phase I/II trial

Randeep Sangha, Angela M. Davies, Primo N Lara, Philip Mack, Laurel A Beckett, Paul J. Hesketh, Derick H Lau, Tianhong Li, Natasha Perkins, David R Gandara

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. Methods: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. Results: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2%, and the disease control rate was 64.1%. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≤3 toxicities were neutropenia (36%) and diarrhea (18%). Conclusions: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.

Original languageEnglish (US)
Pages (from-to)2112-2119
Number of pages8
JournalJournal of Thoracic Oncology
Volume6
Issue number12
DOIs
StatePublished - Dec 2011

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docetaxel
Appointments and Schedules
Maximum Tolerated Dose
Non-Small Cell Lung Carcinoma
Drug Therapy
Febrile Neutropenia
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Diarrhea
Mucositis
Erlotinib Hydrochloride
Exanthema
Neutropenia
Disease-Free Survival

Keywords

  • Docetaxel
  • Erlotinib
  • Non-small cell lung cancer
  • Pharmacodynamic separation
  • Phase II

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation : Results of a phase I/II trial. / Sangha, Randeep; Davies, Angela M.; Lara, Primo N; Mack, Philip; Beckett, Laurel A; Hesketh, Paul J.; Lau, Derick H; Li, Tianhong; Perkins, Natasha; Gandara, David R.

In: Journal of Thoracic Oncology, Vol. 6, No. 12, 12.2011, p. 2112-2119.

Research output: Contribution to journalArticle

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abstract = "Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. Methods: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. Results: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2{\%}, and the disease control rate was 64.1{\%}. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≤3 toxicities were neutropenia (36{\%}) and diarrhea (18{\%}). Conclusions: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.",
keywords = "Docetaxel, Erlotinib, Non-small cell lung cancer, Pharmacodynamic separation, Phase II",
author = "Randeep Sangha and Davies, {Angela M.} and Lara, {Primo N} and Philip Mack and Beckett, {Laurel A} and Hesketh, {Paul J.} and Lau, {Derick H} and Tianhong Li and Natasha Perkins and Gandara, {David R}",
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T2 - Results of a phase I/II trial

AU - Sangha, Randeep

AU - Davies, Angela M.

AU - Lara, Primo N

AU - Mack, Philip

AU - Beckett, Laurel A

AU - Hesketh, Paul J.

AU - Lau, Derick H

AU - Li, Tianhong

AU - Perkins, Natasha

AU - Gandara, David R

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N2 - Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. Methods: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. Results: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2%, and the disease control rate was 64.1%. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≤3 toxicities were neutropenia (36%) and diarrhea (18%). Conclusions: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.

AB - Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. Methods: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. Results: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2%, and the disease control rate was 64.1%. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≤3 toxicities were neutropenia (36%) and diarrhea (18%). Conclusions: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.

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KW - Erlotinib

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