3691 - Trial in Progress: CTEP 10492, A Phase 1/1b Study of the AKT Inhibitor Ipatasertib with Chemoradiation for Locally Advanced Head and Neck Squamous Cell Carcinoma

M. D. Mattes¹, H. Willers², Y. Lin³, L. A. Gharzai⁴, E. Alesi⁵, C. E. Lominska⁶, S. Kim⁷, M. Haigentz³, V. Kaur⁸, S. Arnold⁹, T. Synold¹⁰, J. S. Gutkind¹¹, L. Wirth², A. Hanker¹², R. Said¹³, L. L. Siu¹⁴, and S. K. Jabbour¹⁵; ¹Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, ²Massachusetts General Hospital, Boston, MA, ³Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, ⁴Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, ⁵VCU Massey Cancer Center, Richmond, VA, ⁶Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, ⁷, Rutgers University, New Brunswick, NJ, ⁸University of Virginia, Charlottesville, VA, ⁹University of Kentucky, Albert B. Chandler Hospital, 800 Rose street, Lexington, KY, ¹⁰City of Hope Cancer Center, Duarte, CA, ¹¹University of California San Francisco, San Francisco, CA, ¹²University of Texas Southwestern, Dallas, TX, ¹³National Cancer Institute, Bethesda, MD, ¹⁴Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, ¹⁵Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, New Brunswick, NJ

Purpose/Objective(s): Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with definitive chemoradiation therapy (CRT). However, locoregional recurrence rates of approximately 50% may occur in high risk patients. As such, there is an unmet need for up-front treatment intensification in this patient population. Preclinical evidence suggests that both radiation therapy (RT) and cisplatin activate the PI3K/AKT pathway, leading to treatment resistance through multiple processes, including increased DNA repair, decreased apoptosis, and modulation of the tumor microenvironment by promoting angiogenesis, immune escape and hypoxia. Furthermore, AKT inhibitors have been shown to sensitize a subset of HNSCC models to RT and platinum chemotherapy in vitro and in vivo. However, radiosensitization using a specific AKT inhibitor has not yet been studied in humans. This phase I study will be the first to establish safety and preliminary efficacy of ipatasertib combined with standard of care definitive CRT for HNSCC. Materials/

Methods: The primary objective of this study is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of ipatasertib in combination with definitive CRT in locally advanced HNSCC based on dose-limiting toxicities (DLTs). Secondary objectives include assessment of acute and late toxicities, long term swallowing function, and a preliminary assessment of efficacy. Eligible subjects must have pathologically confirmed, previously untreated, non-metastatic HNSCC that is either human papilloma virus (HPV)-negative clinical stage III-IVB, or HPV-positive clinical stage III. The study schema includes dose escalation and expansion cohorts. All subjects will receive RT for a standard 70 Gy in 7-week course, with concurrent weekly cisplatin. Two 28-day cycles of orally administered ipatasertib will be given concurrently with CRT. The four dose levels of ipatasertib range from 100-400 mg daily. Dose escalation of ipatasertib will follow a Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design, with DLT window extending from the start of CRT, through 28 days after completion of RT. The expansion cohort will enroll an additional 10 subjects at the RP2D, and incorporate pharmacodynamic biopsies for each subject to evaluate whether the addition of ipatasertib to CRT will result in increased gamma-H2AX, consistent with radiosensitization, and also decreased pS6 and pPRAS40 to evaluate AKT pathway inhibition. Additional correlative studies include assessment of the pharmacokinetic profile of ipatasertib with CRT, as well as correlation of efficacy with tumor genotype (such as alterations in PIK3CA, PTEN, and/or AKT1), based on whole exome sequencing of pre-treatment biopsy specimens.
Results: n/a
Conclusion: Enrollment is currently at dose level 2 in the escalation phase, and is expected to complete accrual in 2025. The clinicaltrials.gov registry number is NCT05172245.