ASH Clinical News Focus on Myeloid Malignancies | Page 20

MEETING NEWS
Early-Phase Trials of HDM201 Show Promise in Leukemias
The HDM2 inhibitor HDM201 induced remissions in patients
with leukemia or solid tumors in two ongoing clinical trials
presented at the 2017 AACR Annual Meeting. HDM201, an
oral agent that inhibits degradation of TP53 by preventing
HDM2 from binding to it and may therefore enhance tumor
cell apoptosis, has shown clinical activity as a single agent
in various in vitro and in vivo tumor models of TP53 wild-
type cancers. The current studies attempted to determine
the optimal dose and schedule of HDM201 in patients with
advanced TP53 wild-type acute leukemia or solid tumors.
HDM201 in Acute Leukemia
Eytan Stein, MD, from Memorial Sloan Kettering Cancer
Center, and colleagues evaluated HDM201 in a multicenter,
open-label, dose-finding, phase I study that enrolled 37
patients: 35 with TP53 wild-type relapsed/refractory acute my-
eloid leukemia (AML) and two with TP53 wild-type relapsed/
refractory acute lymphocytic leukemia. 1
HDM201 was administered orally in four treatment regi-
mens: Two high-dose intermittent regimens (Reg 1) and two
low-dose extended regimens (Reg 2):
• Reg 1A: HDM201 400 mg administered on day 1 of a
3-week cycle (n=16)
• Reg 1B: HDM201 150 mg administered on days 1 and 8 of
a 4-week cycle (n=6)
• Reg 2A: HDM201 45 mg administered once daily for the
first 2 weeks of a 4-week cycle (n=7)
• Reg 2C: HDM201 45 mg administered once daily for the
first week of a 4-week cycle (n-8)
At data cutoff, three patients were still receiving treatment:
Two in Reg 1B and one in Reg 2C.
The most common grade 3/4 treatment-related adverse
events (AEs; occurring in ≥25% of patients) were cytopenias
and tumor lysis syndrome ( TABLE 1 ). Overall, six dose-limiting
toxicities were observed:
TABLE 1. Most Common Grade 3/4 Adverse Events
Reg 1A Reg 1B Reg 2A Reg 2C
Thrombocytopenia 50% 50% 29% 50%
Tumor lysis syndrome 44% 0% 14% 13%
Neutropenia 38% 17% 0% 25%
Anemia 25% 33% 29% 38%
Febrile neutropenia 25% 33% 29% 38%
Leukopenia 0% 0% 14% 25%
Reg = regimen
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Focus on Myeloid Malignancies
• Reg 1A: grade 4 hypophosphatemia (n=2), grade 3
infection (n=1), grade 3 chronic graft-versus-host disease
(n=1), grade 3 stomatitis (n=1), and grade 4 subarachnoid
hemorrhage (n=1)
• Reg 1B: grade 4 acute kidney injury (n=1)
• Reg 2C: tumor lysis syndrome (n=1)
Preliminary efficacy analysis showed an overall response rate
of 20.6 percent (95% CI 8.7-37.9) in 34 evaluable patients with
AML, including three complete responses (2 in Reg 1A and 1
in Reg 2C).
“Across all regimens, the AEs reported were overall ex-
pected and manageable, with no dose-limiting gastrointestinal
toxicities,” Dr. Stein and researchers concluded. “Preliminary
anti-leukemic activity is promising in these patients and war-
rants further study of this agent in AML.” Based on the safety
profile and preliminary efficacy analysis, the recommended
dose for expansion is 45 mg daily for the first week of a four-
week cycle, as in Reg 2C. Doses for the other regimens are still
being determined.
HDM201 in Solid Tumors
Next, in a multicenter, open-label, phase I trial conducted by
David M. Hyman, MD, and colleagues, HDM201 treatment
was evaluated in patients with advanced TP53 wild-type solid
tumors who had progressed on standard therapy. 2 Dr. Hyman
reported data from 85 patients enrolled in the ongoing trial as
of September 19, 2016, who received HDM201 in the following
regimens:
• Reg 1A: administered on day 1 of a 3-week cycle (n=26)
• Reg 1B: administered on days 1 and 8 of a 4-week cycle
(n=20)
• Reg 2A: administered every day for the first 2 weeks of a
4-week cycle (n=20)
• Reg 2C: administered every day for the first week of a
4-week cycle (n=19)
After a median duration of exposure of 8.5 weeks (range =
2-86 weeks), one patient in Reg 1A and one patient in Reg 1B
achieved a partial response. Stable disease was achieved in 34
percent of patients (n=29): Eight in Reg 1A, seven in Reg 1B,
seven in Reg 2A, and seven in Reg 2C. The authors also found
“the average plasma concentration per cycle reached with Reg
1A/Reg 1B was closer to the predicted preclinical target effica-
cious levels required for tumor regression, compared with Reg
2A/Reg 2C.”
The most common grade 3/4 treatment-related AEs