Table of Contents As filed with the Securities and Exchange Commission on August 12, 2025. Registration No. 333- UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Form S-1 REGISTRATION STATEMENT Under The Securities Act of 1933 PLUS THERAPEUTICS, INC. (Exact name of Registrant as specified in its charter) (State or other jurisdiction of incorporation or organization) Delaware 2834 33-0827593 (Primary Standard Industrial Classification Code Number) (I.R.S. Employer Identification Number ...

Core Insights - Plus Therapeutics, Inc. is set to launch its CNSide cerebrospinal fluid (CSF) assay platform and testing services in Texas by August 2025, focusing initially on NCI-Designated Cancer Centers and large private healthcare systems [2][9] - The CNSide assay is designed to diagnose and monitor leptomeningeal metastases (LM), a severe complication of advanced cancer, with a high sensitivity of 92% and specificity of 95% [6][7] - The company has conducted over 11,000 CNSide tests at more than 200 U.S. cancer institutions since 2020, demonstrating significant clinical utility and influencing treatment decisions in over 90% of cases [6][8] Company Overview - Plus Therapeutics, Inc. is a clinical-stage pharmaceutical company headquartered in Houston, Texas, focusing on developing targeted radiotherapeutics for difficult-to-treat CNS cancers [9] - CNSide Diagnostics, LLC, a wholly-owned subsidiary of Plus Therapeutics, develops proprietary laboratory tests to identify tumor cells that have metastasized to the CNS [8] - The CNSide CSF Assay Platform enables quantitative analysis and molecular characterization of tumor cells and circulating tumor DNA, improving patient management for those with LM [8] Market Context - Leptomeningeal metastases occur in approximately 5% of patients with metastatic cancer, with median survival typically ranging from 2 to 6 months, indicating a critical need for effective diagnostic tools and therapies [7] - The current standard of care, CSF cytology, has suboptimal sensitivity, leading to missed or delayed diagnoses, which CNSide aims to address with its advanced testing capabilities [6][5]

Core Insights - Plus Therapeutics, Inc. has received an advance payment of $1.6 million from the Cancer Prevention and Research Institute of Texas (CPRIT) as part of a $17.6 million grant for the development of targeted radiotherapeutics for leptomeningeal cancer [1][2] - The company expects to receive an additional $6 million in funding over the next 12 months, which will provide significant non-dilutive financing to support its clinical programs [2] - Plus Therapeutics is developing REYOBIQ™, a novel injectable radiotherapy aimed at treating CNS tumors, and is conducting clinical trials for recurrent glioblastoma, leptomeningeal metastases, and pediatric brain cancer [4][7] Funding and Financial Support - The funding from CPRIT, along with active grants from the NIH and DoD, reflects strong institutional support for Plus Therapeutics' clinical programs and enhances its capital position for long-term growth [2] - CPRIT is recognized as the second-largest public cancer research funder globally, with a mission to invest in cancer research and prevention initiatives in Texas [5] Clinical Development and Research - Leptomeningeal metastases (LM) occur in approximately 5% of patients with metastatic cancer, with limited effective treatment options available, highlighting the need for innovative therapies [3] - REYOBIQ is designed to deliver targeted high-dose radiation specifically to CNS tumors, potentially improving patient outcomes compared to existing therapies [4] - The CNSide diagnostic test is being developed to identify tumor cells that have metastasized to the central nervous system, which is crucial for managing patients with leptomeningeal metastases [6]

Core Insights - Plus Therapeutics is set to present the final results of its ReSPECT-LM clinical trial at the SNO/ASCO CNS Metastases Conference, highlighting the safety and efficacy of its treatment for leptomeningeal metastases [1][2] - The company will also host an educational symposium focusing on advancements in managing leptomeningeal metastases, featuring presentations from leading neuro-oncologists [3] Company Overview - Plus Therapeutics, Inc. is a clinical-stage pharmaceutical company based in Houston, Texas, specializing in targeted radiotherapeutics for central nervous system cancers [8] - The company is advancing a pipeline of product candidates, particularly in the areas of leptomeningeal metastases and recurrent glioblastoma, utilizing image-guided local beta radiation and targeted drug delivery [8] Product Information - REYOBIQ (rhenium Re186 obisbemeda) is a novel injectable radiotherapy developed by Plus Therapeutics, designed to deliver targeted high-dose radiation to CNS tumors [6] - REYOBIQ is currently being evaluated in clinical trials for recurrent glioblastoma, leptomeningeal metastases, and pediatric brain cancer, with significant funding support from various institutions [6] Industry Context - Leptomeningeal metastases are a severe complication of advanced cancer, occurring in approximately 5% of metastatic cancer patients, with limited effective treatment options available [5] - The median survival for patients with leptomeningeal metastases is typically between 2 to 6 months, underscoring the urgent need for novel therapies [5]

Core Insights - Plus Therapeutics, Inc. is focused on developing targeted radiotherapeutics for central nervous system (CNS) cancers, with a particular emphasis on leptomeningeal metastases (LM) and recurrent glioblastoma (GBM) [5] - The company's subsidiary, CNSide Diagnostics, will present its CNSide Cerebrospinal Fluid (CSF) Assay Platform at the SNO/ASCO CNS Metastases Conference, showcasing its clinical utility in managing patients at risk for CNS metastases [1][2] Company Overview - Plus Therapeutics is a clinical-stage pharmaceutical company headquartered in Houston, Texas, developing advanced platform technologies for CNS cancers [5] - CNSide Diagnostics specializes in proprietary laboratory-developed tests to identify tumor cells that have metastasized to the CNS, enhancing patient management for those with leptomeningeal metastases [3] Industry Context - Leptomeningeal metastases occur in approximately 5% of patients with metastatic cancer, with breast cancer, lung cancer, and melanoma being the most common sources [4] - Median survival for patients with LM is typically between 2 to 6 months, indicating a significant need for novel therapeutic options [4]

Core Insights - Plus Therapeutics, Inc. is advancing its ReSPECT-LM dose optimization trial for REYOBIQ, targeting leptomeningeal metastases (LM) with initial patient treatments underway [1][2] - The trial aims to identify optimal dosing regimens to maximize efficacy and safety, building on positive results from a previous Phase 1 study [3][4] - The company anticipates rapid enrollment due to the lack of FDA-approved therapies for LM and expects to complete Cohort 1 by the end of the year [2][4] Company Overview - Plus Therapeutics is a clinical-stage pharmaceutical company focused on developing targeted radiotherapeutics for central nervous system cancers [11] - The company’s lead product, REYOBIQ, is designed to deliver high-dose radiation directly to CNS tumors, potentially improving patient outcomes compared to existing therapies [8][11] - The ReSPECT-LM trial is supported by a $17.6 million grant from the Cancer Prevention & Research Institute of Texas (CPRIT), a significant funding source for cancer research [6][9] Clinical Trial Details - The ReSPECT-LM trial's primary objectives include determining the safety and tolerability of multiple REYOBIQ doses and identifying the maximum tolerated dose and minimum effective dose [3] - The previous Phase 1 trial demonstrated that a single dose of REYOBIQ could deliver an average absorbed dose of over 250 Gy, with significant tumor reduction observed in patients [4] - Data from the completed Phase 1 study will be presented at the upcoming SNO/ASCO CNS Metastases Conference in August 2025 [5] Industry Context - Leptomeningeal metastases occur in approximately 5% of patients with metastatic cancer, with limited treatment options available, highlighting the need for innovative therapies [7] - REYOBIQ is being evaluated for multiple indications, including recurrent glioblastoma and pediatric brain cancer, indicating a broad potential application in CNS oncology [8][9]

Core Viewpoint - Plus Therapeutics has initiated the ReSPECT-LM dose optimization trial for REYOBIQ™ to determine the optimal dosing schedule for treating leptomeningeal metastases, building on previous trial results and supported by a $17.6 million grant from CPRIT [1][7]. Trial Design and Objectives - The trial aims to optimize treatment dosing for maximum efficacy and safety, focusing on the safety and tolerability of multiple REYOBIQ doses administered via intraventricular catheter [2]. - Primary objectives include identifying the maximum tolerated dose and minimum effective dose for patients with LM from any primary solid tumor cancer [2]. Enrollment and Study Details - The trial will enroll up to 24 patients, evaluating REYOBIQ at a recommended Phase 2 dose of 44.1 mCi across three dosing intervals [4]. - Key cohorts include dosing intervals of 56 days, 28 days, and 14 days, with up to six patients per cohort [4]. Efficacy and Safety Data - Previous trials showed a clinical benefit rate of 76%, with 29% of patients achieving partial responses and 47% maintaining stable disease [5]. - No dose-limiting toxicities were observed in the first four cohorts, although one Grade 4 DLT occurred in each of Cohorts 5 and 6 [5]. Future Plans - The company plans to present data from the completed single-dose escalation trial at the SNO/ASCO CNS Metastases Conference in August 2025 and will request an End of Phase 1 Type B meeting with the FDA [6]. About Leptomeningeal Metastases - Leptomeningeal metastases occur in approximately 5% of patients with metastatic cancer, with median survival typically ranging from 2 to 6 months, highlighting the urgent need for effective treatment options [8]. About REYOBIQ™ - REYOBIQ™ is a novel injectable radiotherapy designed for targeted high-dose radiation in CNS tumors, with potential advantages over currently approved therapies [9]. Company Overview - Plus Therapeutics is a clinical-stage pharmaceutical company focused on developing targeted radiotherapeutics for challenging CNS cancers, with a pipeline that includes treatments for leptomeningeal metastases, recurrent glioblastoma, and pediatric brain cancer [10].

Core Insights - Plus Therapeutics is set to launch its CNSide CSF Assay Platform in the U.S. market in the second half of 2025, targeting a significant unmet need in CNS cancer diagnostics with a market opportunity exceeding $6 billion [1][2][4] Company Overview - Plus Therapeutics, Inc. is a clinical-stage pharmaceutical company focused on developing targeted radiotherapeutics for central nervous system (CNS) cancers [14] - The company has invested over $300 million in the CNSide technology, which aims to address the clinical need for better diagnostic tools in CNS cancer [3] Product Details - The CNSide CSF Assay Platform is designed for patients suspected of having CNS cancer metastases, with the first test, CNSide CSF Tumor Cell Enumeration (TCE), expected to be commercialized soon [2][4] - The platform has demonstrated high sensitivity (92%) and specificity (95%) in diagnosing CNS metastases, influencing treatment decisions in 90% of cases [5] Market Opportunity - CNS metastases affect approximately 30% of adult cancer patients, and the current standard of care for diagnosis is outdated, leading to missed or delayed diagnoses [4] - The CNSide platform is positioned to provide superior clinical utility compared to the current standard of care, which has been validated through real-world use and peer-reviewed publications [5] Commercial Strategy - Plus Therapeutics has established a scalable testing laboratory in Houston, TX, and is executing a commercial market access strategy that includes state licensure and reimbursement codes [6][7] - The company anticipates launching the CNSide platform in Texas first, followed by expansion into additional states [6] Financial Outlook - The revenue contributions from the CNSide subsidiary are expected to become meaningful to Plus Therapeutics' operations in fiscal year 2026 [9]

Core Insights - Plus Therapeutics, Inc. is set to provide a business update on June 26, 2025, before the market opens, followed by a conference call and webcast at 9:00 a.m. ET [1] Company Overview - Plus Therapeutics is a clinical-stage pharmaceutical company based in Houston, Texas, focused on developing targeted radiotherapeutics for challenging central nervous system cancers [4] - The company aims to enhance clinical outcomes through a combination of image-guided local beta radiation and targeted drug delivery approaches [4] - Plus Therapeutics has a pipeline of product candidates, with lead programs targeting leptomeningeal metastases and recurrent glioblastoma [4] - The company has established a supply chain through strategic partnerships to support the development, manufacturing, and potential commercialization of its products [4]

Core Insights - Plus Therapeutics has received FDA clearance for its Investigational New Drug application for REYOBIQ, aimed at treating pediatric patients with high-grade glioma and ependymoma [2][5] - The Phase 1/2a trial, named ReSPECT-PBC, is supported by a $3 million grant from the U.S. Department of Defense and will focus on determining the maximum tolerated dose and safety of REYOBIQ in children aged 6 to 21 [1][4][7] Company Overview - Plus Therapeutics is a clinical-stage pharmaceutical company based in Houston, Texas, specializing in targeted radiotherapeutics for central nervous system cancers [9] - The company is advancing a pipeline that includes treatments for recurrent glioblastoma, leptomeningeal metastases, and pediatric brain cancer [9] Trial Design and Objectives - The ReSPECT-PBC trial is a two-part, single-arm study designed to assess the safety and tolerability of REYOBIQ, with a focus on pediatric patients with rare and aggressive brain tumors [4][7] - The trial will enroll approximately 56 patients, with 24 in Phase 1a for dose escalation and 32 in Phase 2a to assess efficacy [7] Treatment Potential - REYOBIQ is designed to deliver high doses of beta radiation directly to brain tumors while minimizing damage to surrounding healthy tissue, potentially improving outcomes for patients with limited treatment options [5][8] - The targeted delivery method via convection enhanced delivery (CED) aims to bypass the blood-brain barrier, which is a significant challenge in treating CNS tumors [4][5]