Cancer Chemotherapy and Pharmacology (2018) 81:597–607
Phase 1 summary of plasma concentration–QTc analysis
for idasanutlin, an MDM2 antagonist, in patients with advanced solid
tumors and AML
· Lin‑Chi Chen
· Cristiano Ferlini
· Jianguo Zhi
Received: 24 December 2017 / Accepted: 26 January 2018 / Published online: 1 February 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Purpose Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-
genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT
(QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.
Method Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin
(RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from base-
line (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed eﬀect model.
Categorical analysis was also performed.
Results A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma
concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at
concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical
analysis did not detect a potential signal of QT prolongation.
Conclusion The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted
concentration range currently in consideration for clinical development.
Keywords Idasanutlin · MDM2 antagonist · QT interval · Concentration–QTcF
The tumor suppressor protein 53 (p53) is a powerful growth
suppressive and pro-apoptotic protein that plays a central
role in protection from tumor development and is frequently
inactivated in human cancer. Some tumors overproduce the
negative p53 regulator, murine double minute 2 (MDM2),
to disable its function. Therefore, blocking the p53–MDM2
interaction is expected to overcome the oncogenic conse-
quences of MDM2 overproduction and to restore p53 func-
tion. Treatment of cancer cells expressing functional p53
with small molecule MDM2 antagonists resulted in the con-
current transcriptional activation of p53 downstream genes,
cell-cycle arrest, and apoptosis .
Idasanutlin (RO5503781, RG3788) is a potent and selec-
tive MDM2 antagonist of the p53–MDM2 interaction .
Following phase 1 studies in patients with solid tumors 
and AML , it is currently in phase 3 development for
relapsed/refractory AML (NCT02545283).
In nonclinical studies, there was no human ether-à-go-go
(hERG) signal in vitro (an IC
> 1.8 µM), but was of lim-
ited value due to insolubility of idasanutlin . Although
the human C
at doses exceeding the MTD was 15 times
higher than IC
, the protein-free plasma concentration of
idasanutlin required to induce the same inhibition in vivo
would be 100 or more times greater than the concentration
required in vitro with the IC
when considering protein
binding (99.99%). There were no eﬀects on QTc in the piv-
otal monkey study at idasanutlin doses that exceeded the
maximum tolerated dose (MTD) .
Three Phase I studies in patients with solid tumors [3,
7] and in patients with acute myeloid leukemia (AML) 
are completed and summarized in Table 1. Pharmacoki-
netic properties [3, 4, 7, 8] are well characterized by low
* Jianguo Zhi
Roche Innovation Center of New York, New York,
NY 10016, USA