California-based Rain Therapeutics, a late-stage company developing precision oncology therapeutics, has signed a clinical supply agreement with Roche for the supply of the anti-Programmed Death Ligand-1 (PD-L1) antibody atezolizumab (Tecentriq®; Genentech/Roche).

Under the terms of the agreement, Rain Therapeutics is the sponsor of anticipated clinical trials designed to evaluate  a combination treatment of atezolizumab with milademetan (Rain-32), an oral mouse double minute 2 (MDM2) inhibitor. Roche will supply atezolizumab.

The combination strategy of milademetan and atezolizumab is especially developed to evaluate the opportunity for MDM2-checkpoint inhibition in genetically selected patient populations.

Research has shows that targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. [1]

Treatment challenges
In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. [2]

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Milademetan is a small molecule, oral inhibitor of MDM2 and is being developed in patients with MDM2-dependent cancers.

Historically, MDM2 inhibition has presented major treatment challenges due to dose-limiting, on-target hematologic toxicities.

However, scientists at Rain Therapeutics believe an MDM2-targeted therapy should include certain pharmacological characteristics related to potency, pharmacokinetics and drug accumulation to allow for the design of an optimized dosing schedule. Such an optimized dosing schedule is intended to improve peak drug exposure leading to apoptosis and cell cycle arrest during the dosing period, while permitting hematopoietic precursor cell recovery during the dosing break, thereby minimizing hematologic toxicity.

A previous phase I study conducted in Japan demonstrated that milademetan was well tolerated and showed modest antitumor activity in patients with solid tumors. In this study, designed to establish dose-limiting toxicities, safety, tolerability, maximum tolerated dose, and pharmacokinetics, 18 participating patients diagnosed with solid tumors who relapsed after or were refractory to standard therapy, patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28-day cycle.

The investigators of this study noted that the most frequent treatment-emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Furthermore, dose-limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120-mg cohort. The plasma concentrations of milademetan increased in a dose-dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Overall, the study showed that milademetan was well tolerated and showed modest antitumor activity. [3]

Based on these results, the investigators determined that the recommended phase II study dose should be considered to be 90 mg in the once-daily 21/28-day schedule.

Trial design
An initial Phase 1 clinical trial is planned to evaluate the safety, tolerability and efficacy of milademetan in combination with atezolizumab in patients with loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and wildtype p53 advanced solid tumors. CDKN2A encodes for the tumor suppressor p14ARF, an inhibitor of MDM2, and the loss of CDKN2A may lead to MDM2-dependent cancers.

Rain Therapeutics anticipates the start of the Phase 1 clinical trial in the second half of 2022. Subsequent Phase 2 clinical trials evaluating the combination of milademetan and atezolizumab may span various additional tumor types.

“We are excited to evaluate the combination of MDM2 inhibition and cancer immunotherapy with milademetan and atezolizumab, and believe it presents a strong mechanistic rationale,” said Avanish Vellanki, co-founder and chief executive officer of Rain.

“We believe the therapeutic index afforded by milademetan will enable synergistic combination with PD-L1 checkpoint inhibition and are excited about the potential for favorable results from the Phase 1 study to support moving into subsequent studies across various MDM2-dependent cancers.”

Highlights of prescribing information
Atezolizumab (Tecentriq®; Genentech/Roche)(Prescribing Information)

[1] Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, Ott M, Mascarenhas J, Andreeff M. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874. doi: 10.1038/s41375-020-0949-z. Epub 2020 Jul 10. PMID: 32651541.
[2] Liao G, Yang D, Ma L, Li W, Hu L, Zeng L, Wu P, Duan L, Liu Z. The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy. Eur J Med Chem. 2018 Nov 5;159:1-9. doi: 10.1016/j.ejmech.2018.09.044. Epub 2018 Sep 18. PMID: 30253242.
[3] Takahashi S, Fujiwara Y, Nakano K, Shimizu T, Tomomatsu J, Koyama T, Ogura M, Tachibana M, Kakurai Y, Yamashita T, Sakajiri S, Yamamoto N. Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study. Cancer Sci. 2021 Jun;112(6):2361-2370. doi: 10.1111/cas.14875. Epub 2021 May 2. PMID: 33686772; PMCID: PMC8177775.

Featured Image by Drew Hays on Unsplash. Used with permission.

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