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 myeloid leukemia (AML) and two with TP53 wild-type relapsed/refractory acute lymphocytic leukemia.1
HDM201 was administered orally in four treatment regimens: 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:

  • 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 expected and manageable, with no dose-limiting gastrointestinal toxicities,” Dr. Stein and researchers concluded. “Preliminary anti-leukemic activity is promising in these patients and warrants 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 efficacious levels required for tumor regression, compared with Reg 2A/Reg 2C.”

The most common grade 3/4 treatment-related AEs were neutropenia, thrombocytopenia, and anemia (TABLE 2). Nausea was the most common treatment-related AE (Reg 1A = 62%; Reg 1B = 60%; Reg 2A = 40%; Reg 2C = 42%), and neutropenia and thrombocytopenia were dose-limiting in four patients.

Again, the authors concluded that “HDM201 demonstrated a manageable safety profile and clinical activity in a heavily pretreated population.” A planned dose-expansion study will use Reg 1B because patients treated under this dosing schedule had the lowest incidence of grade 3/4 thrombocytopenia while achieving therapeutically relevant exposures.
There are limitations to both studies, including the small patient populations and the high rates of thrombocytopenia. In future studies, Dr. Hyman and researchers noted, HDM201 will be combined with eltrombopag to try to mitigate thrombocytopenia.


References

  1. Hyman D, Chatterjee M, de Vos F, et al. CT150 – Optimizing the therapeutic index of HDM2 inhibition: Results from a dose- and regimen-finding Phase I study of NVP-HDM201 in pts with TP53 wt advanced tumors. Presentation #12356. Presented at the American Association for Cancer Research 2017 Annual Meeting, April 4, 2017; Washington, DC.
  2. Stein E, Chromik J, DeAngelo D, et al. CT152 – Phase I dose- and regimen-finding study of NVP-HDM201 in pts with advanced TP53 wt acute leukemias. Presentation #12358. Presented at the American Association for Cancer Research 2017 Annual Meeting, April 4, 2017; Washington, DC.

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

 

TABLE 2. Most Common Grade 3/4 Adverse Events

Reg 1A Reg 1B Reg 2A Reg 2C
Neutropenia 23% 25% 15% 5%
Thrombocytopenia 23% 10% 20% 11%
Anemia 12% 0% 20% 16%
Reg = regimen

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