New trial model could slash cancer drug development time and costs

Abstract Background Many promising agents or combination regimens relevant to solid malignancies lack sufficient clinical information for use in the curative setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I PRE-ISPY trial was created. Methods The PRE-ISPY trial was envisioned as part of the growing I-SPY network of trials, leveraging its efficiencies in streamlined regulatory pathways and trial design processes, including contracting, activation, enrollment, data gathering and analysis. The goals of designing the PRE-ISPY trial were to support investigators and industry partners in meeting safety and preliminary efficacy qualifications for phase II/III studies and gathering translational data to identify the optimal clinical development setting in a timely fashion. The primary aims of the trial are to assess drug toxicity/safety, to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D), to evaluate preliminary treatment efficacy via Overall Response Rate and Clinical Benefit Rate; and biospecimen acquisition, while gaining experience with the drug/regimen in patients with advanced/recurrent solid malignancies. Arms are independent and may have additional specific aims. Sample size depends on the arm design, number of dose-finding cohorts, and number of expansion cohorts. The minimum sample size for an arm is 15 patients, with no maximum. Study arms include dose finding (Part 1) and dose expansion (Part 2) components. Part 1 is optional if MTD and RP2D have already been established. Each study arm may have specific criteria for transitioning from Part 1 to Part 2. Pre-specified exploratory and qualifying transcriptomic, proteomic and phosphoprotein biomarkers will be analyzed. Results The study is sponsored by Quantum Leap Healthcare Collaborative (QLHC). PRE-ISPY uses a master protocol to evaluate multiple regimens in parallel, enabling seamless addition, modification and removal of study arms. New regimens are introduced through appendices in subsequent amendments. A centralized regulatory process accelerates the activation process. Centralized systems handle cost analysis, budgeting, industry contract management, electronic case report forms and electronic data capture systems creation, and data management. Drug and lab kit shipments are coordinated via a unified logistics system. Research specimen collection utilizes a centralized biobanking infrastructure to ensure consistency in sample handling and storage. General eligibility includes adults with advanced/metastatic or recurrent solid tumors, adequate performance status, and organ function. Arm-specific criteria detail additional requirements for tumor histology, treatment history, and organ function. Graduation of a PRE-ISPY regimen to I-SPY2 (neoadjuvant breast cancer trial) or K-SPY (colorectal trial) is not mandatory. The PRE-ISPY trial opened for enrollment on 2/1/2023. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group and K-SPY consortium. The current arms under study are PRE1 ALX-148/T-DXd; PRE2 tucatinib/zanidatamab; and PRE3 vidutolimod/cemiplimab. As of July 2025, eight main sites and two satellite sites are activated, with fourteen additional site activations planned from Q3 2025 to Q1 2026. All sites are academic centers affiliated with NCI-Designated Comprehensive Cancer Centers. An estimated 18 weeks are required from concept arm development to study arm activation; final protocol version to study arm activation requires 6 weeks. Conclusion The PRE-ISPY phase I/Ib trial has been successfully implemented nationally as part of the Consortium of I-SPY trials. Once safety is established, promising regimens can be rapidly transitioned to I-SPY2.2, K-SPY or other phase II/III trials. Citation Format: P. R. POHLMANN, D. A. Potter, N. Chen, N. Jahan, J. A. Mouabbi, H. S. Han, J. R. Diamond, M. Bhave, M. Rampurwala, S. Rayani, A. Discacciati, M. Eklund, A. G. Chappel, A. L. Delson, B. K. LeStage, C. Hendricks-Kretzer, S. Venters, L. Brown-Swigart, G. L. Hirst, E. Petricoin III, A. D. Borowsky, L. J. van 't Veer, S. M. Asare, S. Jafari, P. Henderson, D. Tripathy, H. Rugo, R. Nanda, E. Stringer-Reasor, D. Yee, F. Meric-Bernstam, L. J. Esserman. Pre-ispy trial: a phase i/ib oncology platform program (pre-i-spy-p1) nct05868226 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-12-19.