p53 is one of the most frequently inactivated proteins in human cancer, either through direct mutation of the TP53 gene or via suppressive mechanisms such as overexpression of HDM2. NVP-CGM097 is a potent and specific inhibitor of the HDM2/p53 interaction and has been shown to restore p53 function in preclinical models.
This is a multi-center, open-label Phase 1, first in human study, enrolling patients (pts) with p53WT solid tumors. The primary objective is to determine the maximum tolerated dose (MTD); secondary objectives are to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity. NVP-CGM097 was administered orally, initially in a continuous regimen three times weekly (3QW) in a 28-day cycle, and subsequently on an alternative regimen of 3QW in a two weeks on/ one week off 21-day cycle. Dosing started at 10 mg 3QW and escalation was guided by a Bayesian logistic regression model to determine the MTD. Peripheral blood was collected for PK at multiple time points during the first 24 hours and after multiple dosing, and plasma GDF-15 levels were assessed at pre- and post-treatment on day 1.
48 pts received at least one dose of NVP-CGM097. Post cycle 1 adverse event data suggested that the continuous regimen (31 pts, dose range 10-400 mg, 2 pts ongoing) was not tolerated due to delayed grade 3/4 thrombocytopenia and/or neutropenia. The switch to the pre-defined alternative dosing regimen allowed escalation to higher doses (17 pts, dose range 300-700 mg, 5 pts ongoing). Best overall responses were: 1 partial response (melanoma) 2.1%; 21 stable diseases (SD), 43.8%. Pts achieving SD had median duration of exposure of 24.14 weeks (wks) (range: 7.7-86.7 wks, ongoing pts censored at data cutoff date). 12 pts (25%) had duration of exposure of more than 24 wks. p53 pathway activation by NVP-CGM097 was demonstrated in pts by induction of its downstream target GDF-15 in serum and plasma.
NVP-CGM097 single agent shows clinical activity (disease control) in pts with solid tumors as demonstrated for pts who remained on study more than 24 wks. 7 pts (14.6%) are still on treatment and dose escalation is ongoing.
Clinical trial identification
NCT01760525 First received January 2, 2013
Legal entity responsible for the study
Novartis Pharma AG
Novartis Pharma AG
S. Bauer: Research support: Novartis, Blueprint Medicines, Ariad Consultant: GSK, Novartis, Pfizer, Bayer, Fresenius, Lilly, Blueprint Medicines Honoraria (CME): Pharmamar, GSK, Pfizer, Bayer Travel support: Pharmamar, Bayer. G. Demetri: The following interactions with NOVARTIS are noted as study sponsor: 1. Consultant, consulting fees, 2. Patent on imatinib licensed to Novartis from Dana-Farber 3. Research support to Dana-Farber for clinical trial. S. Jeay: I am an employee and stockholder of Novartis A.G. R. Dummer: Research funding from Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline (GSK) and has a consultant or advisory board relationship with Novartis, MSD, BMS, Roche, GlaxoSmithKline, Amgen outside the submitted work. N. Guerreiro, E. Halilovic: Novartis employee and stock owner. D.S. Tan: Consulting or advisory fees from Novartis, Bayer, Boehringer Ingelheim and Eisai; honoraria from Novartis and Pfizer; research funding from Novartis, Bayer and GSK; and expense reimbursements from Novartis and MERCK, outside the submitted work. A. Kumar, C. Meille, L. Van Bree: Novartis employee. J.U. Wuerthner: Employee of Novartis and has stock ownership of Novartis. P. Cassier: Received honoraria and research funding from Novartis, Roche, BluePrint and Amgen, as well as research funding from Eli Lilly, Celgene, AstraZeneca, GlaxoSmithKline, Merck Sharp Dohme, Merck Serono.