TY - JOUR
T1 - ANG1005, a Brain-Penetrating Peptide–Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases
AU - Kumthekar, Priya
AU - Tang, Shou Ching
AU - Brenner, Andrew J.
AU - Kesari, Santosh
AU - Piccioni, David E.
AU - Anders, Carey
AU - Carrillo, Jose
AU - Chalasani, Pavani
AU - Kabos, Peter
AU - Puhalla, Shannon
AU - Tkaczuk, Katherine
AU - Garcia, Agustin A.
AU - Ahluwalia, Manmeet S.
AU - Wefel, Jeffrey S.
AU - Lakhani, Nehal
AU - Ibrahim, Nuhad
N1 - Funding Information:
P. Kumthekar holds ownership interest (including patents) in Angiochem, and is an advisory board member/unpaid consultant for Elevate Bio. D.E. Piccioni is an employee/paid consultant for Tocagen. C.K. Anders is an employee/paid consultant for Genentech, Eisai, IPSEN, Seattle Genetics, and PUMA, reports receiving commercial research grants from PUMA, Lilly, Merck, Seattle Genetics, Nektar, and G1-Therapeutics, and is an advisory board member/unpaid consultant for Merck, Novartis, Merrimack, Lilly, Nektar, and Seattle Genetics, and reports receiving other remuneration from UpToDate and Jones and Bartlett. P. Chalasani is an advisory board member/unpaid consultant for Bayer, Amgen, Novartis, Heron Therapeutics, Nanostring Technologies, Eisai, and Asthenex. P. Kabos reports receiving commercial research grants (all to University of Colorado) from Pfizer, Radius Health, Eli Lilly, Angiochem, and Genentech. S.L. Puhalla is an employee/paid consultant for Abbvie, Medimmune, Celldex, Puma, Pfizer, AstraZeneca, Eisai, and Nanostring, reports receiving commercial research grants from AstraZeneca, Pfizer, and reports receiving other commercial research support from Abbvie and Lilly. M.S. Ahluwalia is an employee/paid consultant for Abbvie, AstraZeneca, BMS, Bayer, Kadmon, Karyopharm, Forma Therapeutics, VBI Vaccines, Flatrion, Varian Medical Systems, Tocagen, CBT Pharmaceuticals, and Monteris, reports receiving commercial research grants from AstraZeneca, Abbvie, Novocure, Novartis, Pharmacyclics, Incyte, BMS, Bayer, Merck, and Inspire, and holds ownership interest (including patents) in Mimivax and Doctible. J.S. Wefel is an employee/paid consultant for Angiochem, AbbVie, Bayer, Blueprint Medicines, Juno, Novocure, and Vanquish Oncology. N. Lakhani is an employee/paid consultant for Inovent Biologics. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This research was sponsored by Angiochem, Inc. We thank all patients and families for participating in this study and staff at member institutions for their assistance. We thank Christine Pan and the CPAN, Inc. team for their contribution with statistical analysis. We thank Serge Rivest and Paul Prefontaine from Laval University for their research on the mechanism of ANG1005 and their assistance with the respective section of the manuscript. We thank Vihra Iordanova, Rosemary Mazanet MD, PhD, Betty Lawrence, and Lisa Nezvitsky from Angiochem Inc. team for their assistance in the manuscript preparation.
Funding Information:
This research was sponsored by Angiochem, Inc. We thank all patients and families for participating in this study and staff at member institutions for their assistance. We thank Christine Pan and the CPAN, Inc. team for their contribution with statistical analysis. We thank Serge Rivest and Paul Préfontaine from Laval University for their research on the mechanism of ANG1005 and their assistance with
Publisher Copyright:
2020 American Association for Cancer Research.
PY - 2020/6/15
Y1 - 2020/6/15
N2 - Purpose: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood–brain and blood–cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. Patients and Methods: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted (n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). Results: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4–9.4). Conclusions: Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis (n = 28).
AB - Purpose: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood–brain and blood–cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. Patients and Methods: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted (n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). Results: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4–9.4). Conclusions: Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis (n = 28).
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U2 - 10.1158/1078-0432.CCR-19-3258
DO - 10.1158/1078-0432.CCR-19-3258
M3 - Article
C2 - 31969331
AN - SCOPUS:85084236118
VL - 26
SP - 2789
EP - 2799
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 12
ER -