A Study of AL58805 in Advanced, Metastatic GYN, STS or Breast Cancers

Summary

This phase 1b/2a study evaluates AL58805, an oral investigational drug that blocks PI3K and mTOR signaling, in combination with one of three anticancer treatments: AL8326 (veonetinib), eribulin, or fulvestrant. Adults with recurrent, advanced, or metastatic endometrial cancer, cervical cancer, soft tissue sarcoma, or breast cancer may be eligible after at least one prior standard treatment has failed or could not be tolerated and no effective standard treatment option remains. In phase 1b, small groups of participants will receive different doses of AL58805 with a fixed dose of the partner treatment to identify a recommended combination dose based on dose-limiting side effects. In phase 2a, disease-specific groups will receive the selected combination dose to estimate the objective response rate and further evaluate duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and exploratory tumor biomarkers. Protocol treatment may continue for up to 12 months, with continued treatment beyond 12 months possible for participants who remain clinically benefiting and receive investigator and sponsor approval.

Timeline

Start

2026-09-01

Primary completion

2030-09-01

Completion

2031-09-01

Publications

• Background Wen W, Marcinkowski E, Luyimbazi D, Luu T, Xing Q, Yan J, Wang Y, Wu J, Guo Y, Tully D, Han ES, Yost SE, Yuan Y, Yim JH. Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer. Cells. 2019 Aug 30;8(9):1010. doi: 10.3390/cells8091010.
• Background Gris-Oliver A, Ibrahim YH, Rivas MA, Garcia-Garcia C, Sanchez-Guixe M, Ruiz-Pace F, Viaplana C, Perez-Garcia JM, Llombart-Cussac A, Grueso J, Pares M, Guzman M, Rodriguez O, Anton P, Cozar P, Calvo MT, Bruna A, Arribas J, Caldas C, Dienstmann R, Nuciforo P, Oliveira M, Cortes J, Serra V. PI3K activation promotes resistance to eribulin in HER2-negative breast cancer. Br J Cancer. 2021 Apr;124(9):1581-1591. doi: 10.1038/s41416-021-01293-1. Epub 2021 Mar 15.
• Background Lan C, Shen J, Wang Y, Li J, Liu Z, He M, Cao X, Ling J, Huang J, Zheng M, Zou G, Yan H, Liu Q, Yang F, Wei W, Deng Y, Xiong Y, Huang X. Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial. J Clin Oncol. 2020 Dec 1;38(34):4095-4106. doi: 10.1200/JCO.20.01920. Epub 2020 Oct 14.
• Background Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. doi: 10.1200/JCO.18.01265. Epub 2019 Apr 3.
• Background Tinker AV, Ellard S, Welch S, Moens F, Allo G, Tsao MS, Squire J, Tu D, Eisenhauer EA, MacKay H. Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol. 2013 Aug;130(2):269-74. doi: 10.1016/j.ygyno.2013.05.008. Epub 2013 May 11.
• Background Zhang L, Wu J, Ling MT, Zhao L, Zhao KN. The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. Mol Cancer. 2015 Apr 17;14:87. doi: 10.1186/s12943-015-0361-x.
• Background Tewari KS. Cervical Cancer. N Engl J Med. 2025 Jan 2;392(1):56-71. doi: 10.1056/NEJMra2404457. No abstract available.
• Background Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yanez E, Gumus M, Olivera Hurtado de Mendoza M, Samouelian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. doi: 10.1200/JCO.23.00914. Epub 2023 Nov 1.
• Background Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yanez E, Gumus M, Olivera Hurtado de Mendoza M, Samouelian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. doi: 10.1056/NEJMoa2112435. Epub 2021 Sep 18.
• Background Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-1482. doi: 10.1016/S1470-2045(15)00290-9. Epub 2015 Oct 22.
• Background Matsuki M, Adachi Y, Ozawa Y, Kimura T, Hoshi T, Okamoto K, Tohyama O, Mitsuhashi K, Yamaguchi A, Matsui J, Funahashi Y. Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci. 2017 Apr;108(4):763-771. doi: 10.1111/cas.13169. Epub 2017 Apr 20.
• Background Vergote I, Powell MA, Teneriello MG, Miller DS, Garcia AA, Mikheeva ON, Bidzinski M, Cebotaru CL, Dutcus CE, Ren M, Kadowaki T, Funahashi Y, Penson RT. Second-line lenvatinib in patients with recurrent endometrial cancer. Gynecol Oncol. 2020 Mar;156(3):575-582. doi: 10.1016/j.ygyno.2019.12.039. Epub 2020 Jan 17.
• Background Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, Romeo M, Bratos R, Brose MS, DiSimone C, Messing M, Stepan DE, Dutcus CE, Wu J, Schmidt EV, Orlowski R, Sachdev P, Shumaker R, Casado Herraez A. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol. 2020 Sep 10;38(26):2981-2992. doi: 10.1200/JCO.19.02627. Epub 2020 Mar 13.
• Background Makker V, Colombo N, Casado Herraez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D; Study 309-KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. doi: 10.1056/NEJMoa2108330. Epub 2022 Jan 19.
• Background Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C, Nicoletti R, Winckler W, Grewal R, Hanna M, Wyhs N, Ziaugra L, Richter DJ, Trovik J, Engelsen IB, Stefansson IM, Fennell T, Cibulskis K, Zody MC, Akslen LA, Gabriel S, Wong KK, Sellers WR, Meyerson M, Greulich H. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8713-7. doi: 10.1073/pnas.0803379105. Epub 2008 Jun 13.
• Background Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, Matsangou M, Costa R, Carneiro B, Villaflor VM, Cristofanilli M, Giles FJ. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget. 2017 Feb 28;8(9):16052-16074. doi: 10.18632/oncotarget.14109.
• Background Starks DC, Rojas-Espaillat L, Meissner T, Williams CB. Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors. Gynecol Oncol. 2022 Sep;166(3):403-409. doi: 10.1016/j.ygyno.2022.07.005. Epub 2022 Jul 15.
• Background Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 2012 Nov 1;18(21):5856-64. doi: 10.1158/1078-0432.CCR-12-0662. Epub 2012 Oct 18.
• Background Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, Lu Y, Stemke-Hale K, Dyer MD, Zhang F, Ju Z, Cantley LC, Scherer SE, Liang H, Lu KH, Broaddus RR, Mills GB. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011 Jul;1(2):170-85. doi: 10.1158/2159-8290.CD-11-0039. Epub 2011 Jun 7.
• Background How JA, Jazaeri AA, Westin SN, Lawson BC, Klopp AH, Soliman PT, Lu KH. Translating biological insights into improved management of endometrial cancer. Nat Rev Clin Oncol. 2024 Nov;21(11):781-800. doi: 10.1038/s41571-024-00934-7. Epub 2024 Aug 28.
• Background Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4.
• Background Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16.

Drugs

Indications