Intermittent erlotinib in combination with pemetrexed: Phase I schedules designed to achieve pharmacodynamic separation

Angela M. Davies, Cheryl Ho, Laurel A Beckett, Derick H Lau, Sidney A Scudder, Primo N Lara, Natasha Perkins, David R Gandara

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40 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). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. Methods: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m2 intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. Results: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status ≥90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. Conclusions: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m 2 and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m 2 and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

Original languageEnglish (US)
Pages (from-to)862-868
Number of pages7
JournalJournal of Thoracic Oncology
Volume4
Issue number7
DOIs
StatePublished - Jul 2009

Fingerprint

Pemetrexed
Appointments and Schedules
Arm
Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Drug Therapy
Protein-Tyrosine Kinases
Erlotinib Hydrochloride
Karnofsky Performance Status
Maximum Tolerated Dose
Infection
Exanthema
Neutropenia

Keywords

  • Erlotinib
  • Intermittent dosing
  • Non-small cell lung cancer
  • Pemetrexed
  • Pharmacodynamic separation

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

@article{701265268f3b4d41ba4c1a371edf0b06,
title = "Intermittent erlotinib in combination with pemetrexed: Phase I schedules designed to achieve pharmacodynamic separation",
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). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. Methods: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m2 intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. Results: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status ≥90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55{\%} in arm A and 90{\%} in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. Conclusions: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m 2 and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m 2 and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.",
keywords = "Erlotinib, Intermittent dosing, Non-small cell lung cancer, Pemetrexed, Pharmacodynamic separation",
author = "Davies, {Angela M.} and Cheryl Ho and Beckett, {Laurel A} and Lau, {Derick H} and Scudder, {Sidney A} and Lara, {Primo N} and Natasha Perkins and Gandara, {David R}",
year = "2009",
month = "7",
doi = "10.1097/JTO.0b013e3181a94b08",
language = "English (US)",
volume = "4",
pages = "862--868",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
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TY - JOUR

T1 - Intermittent erlotinib in combination with pemetrexed

T2 - Phase I schedules designed to achieve pharmacodynamic separation

AU - Davies, Angela M.

AU - Ho, Cheryl

AU - Beckett, Laurel A

AU - Lau, Derick H

AU - Scudder, Sidney A

AU - Lara, Primo N

AU - Perkins, Natasha

AU - Gandara, David R

PY - 2009/7

Y1 - 2009/7

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). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. Methods: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m2 intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. Results: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status ≥90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. Conclusions: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m 2 and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m 2 and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

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). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. Methods: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m2 intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. Results: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status ≥90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. Conclusions: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m 2 and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m 2 and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

KW - Erlotinib

KW - Intermittent dosing

KW - Non-small cell lung cancer

KW - Pemetrexed

KW - Pharmacodynamic separation

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