Results of the Phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia
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Abstract
PURPOSE: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. EXPERIMENTAL DESIGN: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. RESULTS: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. CONCLUSIONS: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.
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Initial clinical trials showed therapeutic responses in relapsed leukemia and liposarcoma, but also indicated that molecular profiling could be essential for identifying responders versus nonresponders.
“Initial clinical trials have yielded evidence of therapeutic responses in relapsed leukemia3 and liposarcoma, but indicate that molecular profiling could be essential in identifying responders versus nonresponders. 28”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [3]
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- Authors
- Andreeff, M., Kelly, K. R., Yee, K., Assouline, S., Strair, R., Popplewell, L., Bowen, D., Martinelli, G., Drummond, M. W., Vyas, P., Kirschbaum, M., Iyer, S. P., Ruvolo, V., González, G. M. N., Huang, X., Chen, G., Graves, B., Blotner, S., Bridge, P., Jukofsky, L., Middleton, S., Reckner, M., Rueger, R., Zhi, J., Nichols, G., & Kojima, K.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Princess Margaret Cancer Centre (CA)
- McGill University (CA)
- Rutgers, The State University of New Jersey (US)
- City Of Hope National Medical Center (US)
- 7St. James's Institute of Oncology, Leeds, United Kingdom.
- University of Bologna (IT)
- Beatson West of Scotland Cancer Centre (GB)
- University of Oxford (GB)
- 1The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 11Roche Innovation Center New York, New York.
- Forma Therapeutics (United States) (US)
- 13Roche Innovative Center Penzberg, Penzberg, Germany.
- Corresponding author
- Andreeff, Michael
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-02-14
- Volume
- 22
- Issue
- 4
- Pages
- 868-876
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4809642
- OpenAlex
- W2182708897
- Cited by
- 352
- References
- 35
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 39 · 2023: 35 · 2022: 30 · 2021: 36 · 2020: 39 · 2019: 37 · 2018: 25 · 2017: 35 · 2016: 24 · 2015: 2 · 2014: 1
- FWCI
- 12.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Hoffmann-La Roche, Inc. NIH (P01 CA49639 and CA16672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- RG7112, MDM2 inhibitors, p53 stabilization, acute myeloid leukemia, chronic lymphocytic leukemia, relapsed/refractory leukemia, TP53 mutation, pharmacokinetics, dose-limiting toxicity, p53 target genes, hematologic malignancies
- MeSH terms
- Antineoplastic Agents, DNA Mutational Analysis, Drug Administration Schedule, Humans, Leukemia, Lymphoid, Gene Expression, Tumor Suppressor Protein p53, Apoptosis, Maximum Tolerated Dose, Imidazolines, Proto-Oncogene Proteins c-mdm2
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