PRIMROSE: A modular phase 1/2a study of AZD3470, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP deficient advanced solid tumors.

person Alexander I. Spira NEXT Oncology Virginia, Fairfax, VA info_outline Alexander I. Spira, James Lau, Maureen M. Hattersley, Boaz E. Aronson, Jane Peters, Yee Soo-Hoo, Aarti Sawant, Joanna Loizou, Claire Smith, Emma Dean, Sophie Postel-Vinay, Benjamin J. Solomon

Authors person Alexander I. Spira NEXT Oncology Virginia, Fairfax, VA info_outline Alexander I. Spira, James Lau, Maureen M. Hattersley, Boaz E. Aronson, Jane Peters, Yee Soo-Hoo, Aarti Sawant, Joanna Loizou, Claire Smith, Emma Dean, Sophie Postel-Vinay, Benjamin J. Solomon Organizations NEXT Oncology Virginia, Fairfax, VA, AstraZeneca, Gaithersburg, MD, AstraZeneca, Waltham, MA, AstraZeneca, New York, NY, AstraZeneca, Cambridge, United Kingdom, AstraZeneca, R&D Oncology, Cambridge, United Kingdom, ERC Chromatin Remodeling, DNA Repair and Epigenetics Laboratory, INSERM U981, and Drug Development Department (DITEP), Institut Gustav Roussy, Villejuif, France, Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia Abstract Disclosures Research Funding AstraZeneca Background: Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine substrates, regulating multiple cell processes. Deletion of the methylthioadenosine phosphorylase gene MTAP in tumor cells results in accumulation of the metabolite methylthioadenosine (MTA), a partial inhibitor of PRMT5, potentially rendering tumor cells susceptible to further PRMT5 targeting. Clinical activity of first-generation, non-selective PRMT5 inhibitors (PRMT5i) is limited by bone marrow toxicity due to lack of selectivity between normal cells and MTAP-deficient tumor cells. Second-generation PRMT5i, including AZD3470, should selectively target MTAP-deficient tumor cells whilst sparing normal cells. AZD3470 preferentially binds PRMT5 in the presence of MTA in MTAP-deficient tumor cells, inhibiting PRMT5 methylation activity, and is less effective in MTAP-proficient cells. PRIMROSE (NCT06130553) is a first-in-human, Phase 1/2a, open-label, multicenter study of AZD3470 as monotherapy and in combination with anti-cancer agents in patients with MTAP-deficient advanced / metastatic solid tumors. Methods: Eligible patients are aged ≥18 years with MTAP-deficient advanced or refractory solid tumors, ≥1 prior line of treatment in the recurrent / metastatic setting, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0/1, adequate organ and bone marrow function, and no prior treatment with PRMT5i. Module 1 will evaluate AZD3470 monotherapy. Part A (dose escalation) will enroll up to ~54 patients and follow a modified toxicity probability interval-2 (mTPI-2) design with once-daily dosing in 21-day cycles. Treatment will be given until progression or discontinuation criteria are met. Part B (dose optimization and expansion) will expand specific patient populations and / or tumor types, with up to ~30 patients per cohort; dosing will be based on safety and tolerability data from Part A. Further modules for combination treatments may be added based on emerging supportive data. The primary objectives are to assess safety and tolerability, including dose-limiting toxicities, and to determine the recommended phase 2 dose of AZD3470. The secondary objective is evaluation of efficacy, including objective response rate, duration of response, disease control rate, change in tumor size, progression-free survival, and overall survival. An additional secondary objective in Module 1 is to assess pharmacokinetics. The study is planned to take place in ~20 centers across eight countries. The study was opened to enrollment in December 2023. Clinical trial information: NCT06130553.

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