Abstract
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Objectives: Neurotensin receptor 1 (NTSR1) is overexpressed in a range of solid tumors including pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). The receptor is therefore a promising target for systemic radiation therapy (SRT). 177Lu-IPN01087 (also called 177Lu-3BP-227) is a DOTA (tetraxetan)-conjugated NTSR1 antagonist that has demonstrated anti-tumor activity in vitro and in vivo. This study (NCT03525392; EudraCT: 2017-001263-20) will evaluate 177Lu-IPN01087 safety and efficacy, including objective response rate (ORR), in patients with metastatic or locally advanced solid tumors expressing NTSR1 who have not responded to or are unsuitable for standard-of-care treatments.
Methods: This is a phase 1/2, multicenter, open-label study. Tumor types may include PDAC, CRC, gastric cancer, gastrointestinal stromal tumor, squamous-cell carcinoma of head and neck, and Ewing sarcoma. Phase 1 will have a dose-escalation design, with potential for expansion cohorts; phase 2 will further explore safety and efficacy and will be conducted in specific indications in which suitable safety and anti-tumor activity have been demonstrated in phase 1. Phase 2 will have a basket design or optimal Simon’s two-stage design. Phase 1: approximately 30 patients will receive 177Lu-IPN01087. There will be up to six dose-escalation steps, starting with 5 GBq fractionated in two administrations (2 x 2.5 GBq) at least 4 weeks apart, up to a maximum of 15 GBq (2 x 7.5GBq). Three to five patients will be treated at each dose level to establish the maximum tolerated cumulative activity (MTCA). Patients with PDAC and CRC may be most likely to proceed to phase 2; other cohorts may also be included. Approximately 125 patients (PDAC, n = 55; CRC, n = 70) will be enrolled. Phase 2 will investigate whether 177Lu-IPN01087 produces a better ORR than the accepted threshold of current standard-of-care treatment for metastatic or locally advanced disease.
Results: The phase 1 primary endpoint is MTCA determined using dose-limiting toxicities and organ exposure to radiation, or the maximum administered cumulative activity. The phase 2 primary endpoint is ORR assessed every 8 weeks or at disease progression, evaluated using Response Evaluation Criteria in Solid Tumors. Secondary endpoints include: phase 1 - pharmacokinetics, biodistribution, dosimetry, pharmacodynamics and efficacy; and phase 2 - efficacy, quality of life, safety, pharmacokinetics, biodistribution and dosimetry. Conclusion: This ongoing phase 1/2 study will provide safety, efficacy and pharmacokinetics data for 177Lu-IPN01087 SRT in patients with NTSR1-positive solid tumors, including PDAC and CRC. Research support: Research funding for this study and medical writing support for the abstract were provided by Ipsen.