Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53
Open accessPublished version of a preprint
Abstract
Purpose: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. Patients and Methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. Results: Seventy-one patients were enrolled: 41 in arm A (0.16–4.4 mg/kg) and 30 in arm B (0.32–2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. Conclusions: ALRN-6924 was well tolerated and demonstrated antitumor activity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ALRN-6924 has exhibited strong targeting activity in vitro ACUTE MYELOGENOUS LEUKEMIA cell lines and primary cells, induced apoptotic cell death in TCL cell lines, and significantly reduced tumor burden.
“The drug has exhibited strong targeting activity in vitro ACUTE MYELOGENOUS LEUKEMIA cell lines and primary cells, induced apoptotic cell death in TCL cell lines, and significantly reduced tumor burden.397,398”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [398]
ALRN-6924 has been shown to promote the recruitment of tumor-infiltrating immune cells, especially CD8+ killer T cells, and increase tumor-suppressing M1 macrophages.
“It has also been shown to promote the recruitment of tumor-infiltrating immune cells, especially CD8+ killer T cells, and increase tumor-suppressing M1 macrophages.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [398]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · see citing works
Tissue-based map of the human proteome
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015) · Science · doi:10.1126/science.1260419 · Cited by 15,286 · see citing works
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
Cheson, B. D., Fisher, R. I., Barrington, S. F., Cavalli, F., Schwartz, L. H., Zucca, E., & Lister, T. A. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.54.8800 · Cited by 5,715 · see citing works
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Mutations in the p53 gene occur in diverse human tumour types
Nigro, J. M., Baker, S. J., Preisinger, A. C., Jessup, J. M., Hosteller, R., Cleary, K. R., Signer, S. H., Davidson, N. E., Baylin, S., Devilee, P., et al. (1989) · Nature · doi:10.1038/342705a0 · Cited by 2,730 · see citing works
Appio, L., Landoni, C., Latargia, M. L., Bertolli, V. G., Chiarucci, M., Crovetti, G., Vassenna, E., Serio, G., & Bregni, M. (2017) · Chemotherapy · doi:10.1159/000458147 · Cited by 2,327 · see citing works
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · see citing works
The landscape of genomic alterations across childhood cancers
ICGC PedBrain-Seq Project, Gröbner, S. N., ICGC MMML-Seq Project, Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., Johann, P. D., Balasubramanian, G. P., et al. (2018) · Nature · doi:10.1038/nature25480 · Cited by 1,572 · see citing works
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · see citing works
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · cited 1× · see citing works
“To subvert this antitumor functionality, cancer cells neutralize p53 by deletion, mutation, degradation, or sequestration (2, 3).”
BackgroundSchafmeister, C. E., Po, J., & Verdine, G. L. (2000) · Journal of the American Chemical Society · doi:10.1021/ja000563a · Cited by 1,037 · see citing works
Chang, Y. S., Graves, B. J., Guerlavais, V., Tovar, C., Packman, K. E., To, K.-H., Olson, K. A., Kesavan, K. P., Gangurde, P., Mukherjee, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303002110 · Cited by 666 · see citing works
Self-citationMDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide
Bernal, F., Tyler, A. F., Korsmeyer, S. J., Walensky, L. D., & Verdine, G. L. (2007) · Journal of the American Chemical Society · doi:10.1021/ja0693587 · Cited by 559 · see citing works
Stapled Peptides for Intracellular Drug Targets
Verdine, G. L., & Hilinski, G. J. (2012) · Methods in Enzymology · doi:10.1016/b978-0-12-396962-0.00001-x · Cited by 433 · see citing works
MDM2 inhibition: an important step forward in cancer therapy
Konopleva, M. Y., Martinelli, G., Daver, N. G., Papayannidis, C., Wei, A. H., Higgins, B., Ott, M., Mascarenhas, J. O., & Andreeff, M. (2020) · Leukemia · doi:10.1038/s41375-020-0949-z · Cited by 376 · see citing works
HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2030930100 · Cited by 361 · see citing works
Results of the Phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia
Andreeff, M., Kelly, K. R., Yee, K., Assouline, S., Strair, R., Popplewell, L., Bowen, D., Martinelli, G., Drummond, M. W., Vyas, P., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0481 · Cited by 352 · see citing works
Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas
Vakiani, E., Janakiraman, M., Shen, R., Sinha, R., Zeng, Z., Shia, J., Cercek, A., Kemeny, N. E., D'Angelica, M. I., Viale, A. J., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.38.2994 · Cited by 282 · see citing works
Tisato, V., Voltan, R., Gonelli, A., Secchiero, P., & Zauli, G. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0500-5 · Cited by 255 · see citing works
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Carvajal, L. A., Neriah, D. B., Senecal, A., Benard, L., Thiruthuvanathan, V., Yatsenko, T., Narayanagari, S.-R., Wheat, J. C., Todorova, T. I., Mitchell, K., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao3003 · Cited by 249 · see citing works
Self-citationStapled Peptides with Improved Potency and Specificity That Activate p53
Brown, C. J., Quah, S. T., Jong, J., Goh, A. M., Chiam, P. C., Khoo, K. H., Choong, M. L., Lee, M. A., Yurlova, L., Zolghadr, K., et al. (2012) · ACS Chemical Biology · doi:10.1021/cb3005148 · Cited by 206 · see citing works
Activation of p53 by MDM2 Antagonists Can Protect Proliferating Cells from Mitotic Inhibitors
Carvajal, D. M., Tovar, C., Yang, H. S., Vu, B. T., Heimbrook, D. C., & Vassilev, L. T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3576 · Cited by 202 · see citing works
Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3
Patton, J. T., Mayo, L. D., Singhi, A. D., Gudkov, A. V., Stark, G. R., & Jackson, M. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3832 · Cited by 189 · see citing works
Ishiguro, N., Maeda, K., Kishimoto, W., Saito, A., Harada, A., Ebner, T., Roth, W., Igarashi, T., & Sugiyama, Y. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.009175 · Cited by 178 · see citing works
Weiss, J. M., Csőszi, T., Maglakelidze, M., Hoyer, R. J., Beck, J. T., Gómez, M. D., Łowczak, A., Aljumaily, R. M., Lima, C. M. R., Boccia, R. V., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz278 · Cited by 169 · see citing works
Choong, M. L., Yang, H. C., Lee, M. A., & Lane, D. P. (2009) · Cell Cycle · doi:10.4161/cc.8.17.9503 · Cited by 141 · see citing works
Okamoto, T., Zobel, K., Fedorova, A., Quan, C., Yang, H., Fairbrother, W. J., Huang, D. C. S., Smith, B. J., Deshayes, K., & Czabotar, P. E. (2013) · ACS Chemical Biology · doi:10.1021/cb3005403 · Cited by 136 · see citing works
de Jonge, M. J. A., de Weger, V. A., Dickson, M. A., Langenberg, M. H. G., Cesne, A. L., Wagner, A. J., Hsu, K., Zheng, W., Macé, S., Tuffal, G., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.02.005 · Cited by 130 · see citing works
Gluck, W. L., Gounder, M. M., Frank, R., Eskens, F., Blay, J. Y., Cassier, P. A., Soria, J.-C., Chawla, S., de Weger, V., Wagner, A. J., et al. (2020) · Investigational New Drugs · doi:10.1007/s10637-019-00840-1 · Cited by 127 · see citing works
Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors
Wagner, A. J., Banerji, U., Mahipal, A., Somaiah, N., Hirsch, H., Fancourt, C., Johnson-Levonas, A. O., Lam, R., Meister, A. K., Russo, G., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.70.7117 · Cited by 120 · see citing works
Self-citationTargetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
Ng, S. Y., Yoshida, N., Christie, A. L., Ghandi, M., Dharia, N. V., Dempster, J. M., Murakami, M. A., Shigemori, K., Morrow, S. N., Scoyk, A. V., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04356-9 · Cited by 114 · see citing works
Self-citationActivation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis
Iancu-Rubin, C., Mosoyan, G., Glenn, K., Gordon, R. E., Nichols, G. L., & Hoffman, R. (2014) · Experimental Hematology · doi:10.1016/j.exphem.2013.11.012 · Cited by 90 · see citing works
Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies
Kato, S., Ross, J. S., Gay, L. M., Dayyani, F., Roszik, J., Subbiah, V., & Kurzrock, R. (2018) · JCO Precision Oncology · doi:10.1200/po.17.00235 · Cited by 77 · see citing works
Siu, L. L., Italiano, A., Miller, W. H., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.2535 · Cited by 67 · see citing works
Lenos, K., Grawenda, A. M., Lodder, K., Kuijjer, M. L., Teunisse, A. F. A. S., Repapi, E., Grochola, L. F., Bartel, F., Hogendoorn, P. C. W., Wuerl, P., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0215 · Cited by 65 · see citing works
Ravandi, F., Gojo, I., Patnaik, M. M., Minden, M. D., Kantarjian, H., Johnson-Levonas, A. O., Fancourt, C., Lam, R., Jones, M. B., Knox, C. D., et al. (2016) · Leukemia Research · doi:10.1016/j.leukres.2016.07.004 · Cited by 57 · see citing works
P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis
Mahfoudhi, E., Lordier, L., Marty, C., Pan, J., Roy, A., Roy, L., Rameau, P., Abbes, S., Debili, N., Raslova, H., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7881 · Cited by 53 · see citing works
Bauer, T. M., Gounder, M. M., Weise, A. M., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.36.15_suppl.11514 · Cited by 44 · see citing works
Self-citationDegree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma
Bill, K. L. J., Seligson, N. D., Hays, J. L., Awasthi, A., Demoret, B., Stets, C. W., Duggan, M. C., Bupathi, M., Brock, G. N., Millis, S. Z., et al. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0047 · Cited by 42 · see citing works
Bardot, B., Bouarich-Bourimi, R., Leemput, J., Lejour, V., Hamon, A., Plancke, L., Jochemsen, A. G., Simeonova, I., Fang, M., & Toledo, F. (2014) · Oncogene · doi:10.1038/onc.2014.230 · Cited by 41 · see citing works
Dobbelstein, M., & Levine, A. J. (2020) · Cancer Science · doi:10.1111/cas.14433 · Cited by 38 · see citing works
Hata, A. N., Rowley, S. C., Archibald, H. L., Gomez‐Caraballo, M., Siddiqui, F. M., Ji, F., Jung, J., Light, M. E., Lee, J. S., Debüssche, L., et al. (2017) · Oncogene · doi:10.1038/onc.2017.258 · Cited by 34 · see citing works
What does a modified-Fibonacci dose-escalation actually correspond to?
Penel, N., & Kramar, A. (2012) · BMC Medical Research Methodology · doi:10.1186/1471-2288-12-103 · Cited by 31 · see citing works
Valianatos, G., Valčíková, B., Growková, K., Verlande, A., Mlčochová, J., Radová, L., Štětková, M., Vyhnakova, M., Slabý, O., & Uldrijan, S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185801 · Cited by 28 · see citing works
A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors.
Rasco, D. W., Lakhani, N. J., Li, Y., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.15_suppl.3126 · Cited by 27 · see citing works
Organization, expression, and localization of the murine mdmx gene and pseudogene
Parant, J. M., Reinke, V., Mims, B. H., & Lozano, G. (2001) · Gene · doi:10.1016/s0378-1119(01)00432-2 · Cited by 20 · see citing works
Stein, E., Chromik, J., DeAngelo, D. J., Chatterjee, M., Noppeney, R., Vos, F. D., Minami, H., Jeay, S., Meille, C., Halilovic, E., et al. (2017) · Cancer Research · doi:10.1158/1538-7445.am2017-ct152 · Cited by 11 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [32]Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, et al Phase 1/1b Study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (Pts). Blood 2014; 124: 116.
Cited by
Sorted by citations
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
MDM2 inhibition in the treatment of glioblastoma: From concept to clinical investigation
Pellot Ortiz, K. I., Rechberger, J. S., Nonnenbroich, L. F., Daniels, D. J., & Sarkaria, J. N. (2023) · Biomedicines · doi:10.3390/biomedicines11071879 · Cited by 30 · see citing works
Bird, G. H., Patten, J. J., Zavadoski, W., Barucci, N., Godes, M., Moyer, B. M., Owen, C. D., DaSilva-Jardine, P., Neuberg, D. S., Bowen, R. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44361-1 · Cited by 22 · see citing works
- Authors
- Saleh, M. N., Patel, M. R., Bauer, T. M., Goel, S., Falchook, G. S., Shapiro, G. I., Chung, K. Y., Infante, J. R., Conry, R. M., Rabinowits, G., Hong, D. S., Wang, J. S., Steidl, U., Naik, G., Guerlavais, V., Vukovic, V., Annis, D. A., Aivado, M., & Meric-Bernstam, F.
- Affiliations
- University of Alabama at Birmingham (US)
- 2Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.
- Sarah Cannon (US)
- Albert Einstein College of Medicine (US)
- HealthONE (US)
- Dana-Farber Cancer Institute (US)
- Prisma Health (US)
- 8The Kirkland Clinic at Acton Road, Birmingham, Alabama.
- The University of Texas MD Anderson Cancer Center (US)
- 10Aileron Therapeutics, Inc., Watertown, Massachusetts.
- 9The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Corresponding author
- Saleh, Mansoor N.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-07-22
- Volume
- 27
- Issue
- 19
- Pages
- 5236-5247
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC9401461
- OpenAlex
- W3184405846
- Cited by
- 159
- References
- 51
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 35 · 2023: 40 · 2022: 24 · 2021: 3
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-01-15)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Texas MD Anderson Cancer Center
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- MDM2 inhibitors, p53 reactivation, solid tumors, lymphoma, dose escalation, pharmacokinetics, p53 activation, dose-limiting toxicity, anticancer activity
- MeSH terms
- Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Fatigue, Humans, Lymphoma, Neoplasms, Tumor Suppressor Protein p53, Maximum Tolerated Dose, Mice, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
