A phase i trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

Laura Q.M. Chow, Derek I. Jonker, Grace K. Dy, Garth Nicholas, Catherine Fortin, Daniel Patricia, Alex Adjei, Chandra P. Belani, Ashok Gupta, Jong Soon Park, Steven Zhang, Eric I. Sbar, Scott A. Laurie

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Experimental design: Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). Results: The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. Conclusions: The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

Original languageEnglish (US)
Pages (from-to)1273-1285
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number5
DOIs
StatePublished - May 1 2013
Externally publishedYes

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Pharmacodynamics
Pharmacokinetics
Carboplatin
Paclitaxel
Safety
Maximum Tolerated Dose
Tumors
Neoplasms
Vascular Endothelial Growth Factor Receptor
Diarrhea
Dehydration
Design of experiments
Toxicity
Cells
Fatigue of materials
BMS-690514
Febrile Neutropenia
Anorexia
Exanthema
Neutropenia

Keywords

  • BMS-690514
  • EGFR
  • Intercalated therapy
  • Paclitaxel/carboplatin
  • Phase I
  • Solid malignancies
  • Tyrosine kinase inhibitor
  • VEGFR

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase i trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies. / Chow, Laura Q.M.; Jonker, Derek I.; Dy, Grace K.; Nicholas, Garth; Fortin, Catherine; Patricia, Daniel; Adjei, Alex; Belani, Chandra P.; Gupta, Ashok; Park, Jong Soon; Zhang, Steven; Sbar, Eric I.; Laurie, Scott A.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 5, 01.05.2013, p. 1273-1285.

Research output: Contribution to journalArticle

Chow, Laura Q.M. ; Jonker, Derek I. ; Dy, Grace K. ; Nicholas, Garth ; Fortin, Catherine ; Patricia, Daniel ; Adjei, Alex ; Belani, Chandra P. ; Gupta, Ashok ; Park, Jong Soon ; Zhang, Steven ; Sbar, Eric I. ; Laurie, Scott A. / A phase i trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 5. pp. 1273-1285.
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abstract = "Purpose: A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Experimental design: Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). Results: The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 {\%}), acneiform rash (60 {\%}), fatigue (43 {\%}), nausea (30 {\%}), and anorexia (30 {\%}). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. Conclusions: The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.",
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AU - Chow, Laura Q.M.

AU - Jonker, Derek I.

AU - Dy, Grace K.

AU - Nicholas, Garth

AU - Fortin, Catherine

AU - Patricia, Daniel

AU - Adjei, Alex

AU - Belani, Chandra P.

AU - Gupta, Ashok

AU - Park, Jong Soon

AU - Zhang, Steven

AU - Sbar, Eric I.

AU - Laurie, Scott A.

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N2 - Purpose: A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Experimental design: Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). Results: The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. Conclusions: The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

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KW - EGFR

KW - Intercalated therapy

KW - Paclitaxel/carboplatin

KW - Phase I

KW - Solid malignancies

KW - Tyrosine kinase inhibitor

KW - VEGFR

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