TY - JOUR
T1 - A phase I study of HER1, HER2 dual kinase inhibitor lapatinib plus the proteasome inhibitor bortezomib in patients with advanced malignancies
AU - Lynce, Filipa
AU - Wang, Hongkun
AU - Petricoin, Emanuel F.
AU - Pohlmann, Paula R.
AU - Smaglo, Brandon
AU - Hwang, Jimmy
AU - He, Aiwu R.
AU - Subramaniam, Deepa S.
AU - Deeken, John
AU - Marshall, John
AU - Pishvaian, Michael J.
N1 - Funding Information:
The project was partially supported by the Ruesch Center for the Cure of Gastrointestinal Cancers and Award Number P30CA051008 from the National Cancer Institute. Further support came from Novartis, and bortezomib was supplied by Millenium, Inc.
Funding Information:
FL has received research grants from BMS, Pfizer, Genentech/Roche, Immunomedics, Calithera, Chugai, Regeneron, Tesaro and Inivata; has participated in advisory boards (non-paid) with BMS, Jounce and AstraZeneca and travel expenses from BMS, Genentech and Jounce. EFP has a leadership role in Ceres Nanosciences and Perthera; has stock and other ownership interests in Avant Diagnostics, Ceres Nanosicences and Perthera; has consulting or advisory roles with Avant Diagnostics, AZGen, Ceres Nanosciences and Perthera; has received research funding from Abbvie, Ceres Nanosciences, GSK and Symphogen; has intellectual property rights in NIH Patents Licensing Fee Distribution/Royalty and University assigned patent licensing fee/royalty; has received travel expenses by Ceres Nanoscience and Perthera. PRP has intellectual property rights (United States Patents no. 8,486,413; no. 8,501,417; 9,023,362 and 9,745,377: Immunological Compositions as Cancer Biomarkers and/or Therapeutics); has ownership interests in Immunonet BioSciences; has consulted for Heron, Personalized Cancer Therapy, PUMA, Pfizer, Oncoplex Dx, CARIS, Sirtex; has received financial support for educational programs (non-CME teaching) from ASCO, Dava Oncology, Roche; has received research grants to the institution from Immunonet BioSciences, Genentech/Roche, Pfizer, Cascadian therapeutics/Seattle Genetics, Fabre-Kramer, Advanced Cancer Therapeutics, Pieris. BS has received honoraria for speaking for TAIHO. DSS is an employee and has stock and other ownership interests in AZ; DSS was on speakers’ bureau for AZ and Genentech until June 2019. JD has received research grants from Merck, BMS and Loxo Oncology and has outside income/royalties from UpToDate. JM has been a speaker/consultant and received honoraria from Genentech, Amgen, Celgene, Taiho, Bayer, Merck, Caris and Indivumed. MP has been a speaker/consultant for AstraZeneca/MedImmune, Caris Life Sciences, Celgene, Merrimack, Perthera, RenovoRx and Sirtex Medical; has received travel, accommodations and expenses Support from AstraZeneca/MedImmune, Merck, Caris Life Sciences, Perthera and Sirtex Medical and has Stock interests in Perthera.
Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Purpose: This phase I trial evaluated the maximum tolerated dose, safety and preliminary efficacy of lapatinib, a HER1, HER2 dual kinase inhibitor plus bortezomib, a proteasome inhibitor, in adult patients with advanced malignancies. Methods: Patients were enrolled in a standard 3 + 3 design with lapatinib (L) 750, 1000, 1250 or 1500 mg daily, and bortezomib (B) 0.7, 1.0, 1.3 or 1.6 mg/m2 for 3 weeks with 1 week off. Dose-limiting toxicities (DLT) were assessed during the first 28 days Results: Fifteen patients received the combination of lapatinib and bortezomib in three different cohorts and ten were evaluable for DLT. There were no DLTs. Anorexia was the most common adverse event. Biomarker analysis showed upregulation of p27 expression with lapatinib and the combination. No tumor response was observed and thus the study was closed early. Conclusion: The combination of lapatinib and bortezomib was well tolerated but no complete or partial tumor responses were observed at the dose levels tested. ClinicalTrials.gov Identifier: NCT01497626.
AB - Purpose: This phase I trial evaluated the maximum tolerated dose, safety and preliminary efficacy of lapatinib, a HER1, HER2 dual kinase inhibitor plus bortezomib, a proteasome inhibitor, in adult patients with advanced malignancies. Methods: Patients were enrolled in a standard 3 + 3 design with lapatinib (L) 750, 1000, 1250 or 1500 mg daily, and bortezomib (B) 0.7, 1.0, 1.3 or 1.6 mg/m2 for 3 weeks with 1 week off. Dose-limiting toxicities (DLT) were assessed during the first 28 days Results: Fifteen patients received the combination of lapatinib and bortezomib in three different cohorts and ten were evaluable for DLT. There were no DLTs. Anorexia was the most common adverse event. Biomarker analysis showed upregulation of p27 expression with lapatinib and the combination. No tumor response was observed and thus the study was closed early. Conclusion: The combination of lapatinib and bortezomib was well tolerated but no complete or partial tumor responses were observed at the dose levels tested. ClinicalTrials.gov Identifier: NCT01497626.
KW - Bortezomib
KW - EGFR
KW - HER2
KW - Lapatinib
KW - Phase I
KW - Proteasome inhibitor
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U2 - 10.1007/s00280-019-03947-7
DO - 10.1007/s00280-019-03947-7
M3 - Article
C2 - 31538230
AN - SCOPUS:85073487456
VL - 84
SP - 1145
EP - 1151
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 5
ER -