Escalating weekly doses of cetuximab and correlation with skin toxicity: A phase I study

Cheryl Ho, Randeep Sangha, Laurel A Beckett, Michael Tanaka, Derick H Lau, Daniel B Eisen, Rachel A. Burich, Paul A Luciw, Imran Khan, Philip Mack, David R Gandara, Angela M. Davies

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m2 intravenously (IV) followed by a weekly maintenance dose of 250 mg/m2. It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods: Four dose levels were tested: Cetuximab 400 mg/m2 IV loading dose and 250, 300, 350, 400 mg/m2 weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. Results: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m2). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m2) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. Conclusions: Cetuximab administered at 400 mg/m2 IV as a loading dose with weekly maintenance dose of 400 mg/m2 is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.

Original languageEnglish (US)
Pages (from-to)680-687
Number of pages8
JournalInvestigational New Drugs
Volume29
Issue number4
DOIs
StatePublished - Aug 2011

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Exanthema
Skin
Acne Vulgaris
Epidermal Growth Factor Receptor
Neoplasms
Lymphopenia
Maximum Tolerated Dose
Cholangiocarcinoma
Cetuximab
Dermatology
Esophagus
Fatigue
Prostate
Pancreas
Urinary Bladder
Breast
Neck
Head
Monoclonal Antibodies
Maintenance

Keywords

  • Acne lesion counting
  • Acneiform rash
  • Cetuximab
  • Global acne grading scale
  • Solid tumors

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Escalating weekly doses of cetuximab and correlation with skin toxicity : A phase I study. / Ho, Cheryl; Sangha, Randeep; Beckett, Laurel A; Tanaka, Michael; Lau, Derick H; Eisen, Daniel B; Burich, Rachel A.; Luciw, Paul A; Khan, Imran; Mack, Philip; Gandara, David R; Davies, Angela M.

In: Investigational New Drugs, Vol. 29, No. 4, 08.2011, p. 680-687.

Research output: Contribution to journalArticle

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abstract = "Background: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m2 intravenously (IV) followed by a weekly maintenance dose of 250 mg/m2. It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods: Four dose levels were tested: Cetuximab 400 mg/m2 IV loading dose and 250, 300, 350, 400 mg/m2 weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. Results: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m2). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m2) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. Conclusions: Cetuximab administered at 400 mg/m2 IV as a loading dose with weekly maintenance dose of 400 mg/m2 is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.",
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author = "Cheryl Ho and Randeep Sangha and Beckett, {Laurel A} and Michael Tanaka and Lau, {Derick H} and Eisen, {Daniel B} and Burich, {Rachel A.} and Luciw, {Paul A} and Imran Khan and Philip Mack and Gandara, {David R} and Davies, {Angela M.}",
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T1 - Escalating weekly doses of cetuximab and correlation with skin toxicity

T2 - A phase I study

AU - Ho, Cheryl

AU - Sangha, Randeep

AU - Beckett, Laurel A

AU - Tanaka, Michael

AU - Lau, Derick H

AU - Eisen, Daniel B

AU - Burich, Rachel A.

AU - Luciw, Paul A

AU - Khan, Imran

AU - Mack, Philip

AU - Gandara, David R

AU - Davies, Angela M.

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N2 - Background: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m2 intravenously (IV) followed by a weekly maintenance dose of 250 mg/m2. It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods: Four dose levels were tested: Cetuximab 400 mg/m2 IV loading dose and 250, 300, 350, 400 mg/m2 weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. Results: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m2). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m2) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. Conclusions: Cetuximab administered at 400 mg/m2 IV as a loading dose with weekly maintenance dose of 400 mg/m2 is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.

AB - Background: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m2 intravenously (IV) followed by a weekly maintenance dose of 250 mg/m2. It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods: Four dose levels were tested: Cetuximab 400 mg/m2 IV loading dose and 250, 300, 350, 400 mg/m2 weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. Results: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m2). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m2) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. Conclusions: Cetuximab administered at 400 mg/m2 IV as a loading dose with weekly maintenance dose of 400 mg/m2 is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.

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