A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel
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PHASE I STUDIES
A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer Sagar Sardesai 1 & Mohamed Badawi 2 & Ewa Mrozek 3 & Evan Morgan 1 & Mitch Phelps 2 & Julie Stephens 3 & Lai Wei 4 & Mahmoud Kassem 1 & Yonghua Ling 2 & Maryam Lustberg 1 & Daniel Stover 1 & Nicole Williams 1 & Rachel Layman 5 & Raquel Reinbolt 1 & Jeffrey VanDeusen 1 & Mathew Cherian 1 & Michael Grever 6 & William Carson 7 & Bhuvaneswari Ramaswamy 1 & Robert Wesolowski 1,8 Received: 12 December 2019 / Accepted: 10 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IVand RO4929097 10 mg daily given orally (PO) on days 1–3, 8–10 and 15–17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2–3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR. Keywords Neoadjuvant . Chemotherapy . Breast cancer . Gamma secretase . Notch pathway . Phase I clinical trial . Pharmacokinetics
Introduction Triple negative breast cancer (TNBC) is defined by the lack of estrogen receptor, progesterone receptor and human epidermal
Sagar Sardesai and Mohamed Badawi contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00895-5) contains supplementary material, which is available to authorized users. * Robert Wesolowski [email protected] Extended author information available on the last page of the article
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