A Phase I Study of [225Ac]-FPI-1434 Radioimmunotherapy in Patients with IGF-1R Expressing Solid Tumors

0 50 100 150 200 0 500 1000 1500 Days after Treatment Initiation Tumor Volume (mm3) Vehicle Control [225Ac]-FPI-1434 (1.85 kBq) [225Ac]-FPI-1434 (7.4 kBq) [225Ac]-FPI-1434 (14.8 kBq) A Phase I Study of [225Ac]-FPI-1434 Radioimmunotherapy in Patients with IGF-1R Expressing Solid Tumors Rosalyn A. Juergens1, Katherine A. Zukotynski2, Daniel Juneau3, Ryan Simms4, John Forbes4, Eric S. Burak4, John Valliant4, Lily Krnezich2, Lauren Stafford4, Thomas Armor4, Istvan Molnar4, Fred Saad3 1Juravinski Cancer Centre, McMaster University, Hamilton, ON; 2Nuclear Medicine and Radiology, McMaster University, Hamilton, ON; 3Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal, QC; 4Fusion Pharmaceuticals, Hamilton, ON and Boston, MA Background Type I insulin-like growth factor receptor (IGF-1R) is a transmembrane protein which is overexpressed in solid tumors including non–small cell lung, prostate, sarcomas, and breast cancers. [225Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody (AVE1642) that binds to the external domain of IGF-1R, a proprietary bifunctional chelate, and the alpha-emitting radionuclide actinium-225 (Ac-225). Internalization of the radioimmunoconjugate and decay of Ac-225 causes tumor cell death primarily through double stranded DNA breaks. The indium-111 analog, [111In]-FPI-1547, with the identical antibody and bifunctional chelate is used for patient selection and quantification of IGF-1R expressing targets prior to therapy. Based on anti-tumor activity of [225Ac]-FPI-1434 in non-clinical models, favorable toxicology studies in cynomolgus monkeys, and prior human experience with the unconjugated antibody, the first-in-human trial was initiated. Inclusion: • Age ≥18 years old • Pathologically documented, definitively diagnosed, advanced solid tumor that is refractory to all standard treatment, for which no standard treatment is available • At least 1 measurable lesion (≥20 mm in largest diameter [≥20 mm in shortest diameter if lymph node]) • Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1 • Life expectancy equal to or greater than 3 months as judged by the treating physician • Available tumor tissue (either archival or fresh biopsy) for IGF-1R immunohistochemistry • Adequate bone marrow reserves without the use of hematopoietic growth factors, red cell or platelet transfusion • Adequate renal function as evidenced by a creatinine clearance ≥60 mL/min using the Cockcroft-Gault Equation • Adequate hepatic function • Sufficient target expression in at least one tumor lesion following the [111In]-FPI-1547 Injection • Dosimetry estimate of the planned [225Ac]-FPI-1434 Injection does not exceed predetermined limits for kidney, liver and lungs Key Eligibility Criteria Study Status  Study FPX-01-01 (NCT03746431)  Open-label, multi-center phase I study of a single injection of Ac-225 radioimmunotherapy conjugate (option for a second dose if clinical benefit)  Modified 3+3 dose-escalation (5 dose cohorts)  Followed by an 8-week DLT evaluation period. Currently enrolling patients at the following locations: • Juravinski Cancer Center (Hamilton Health Sciences) – Hamilton, Ontario • Quebec Hospital/Laval – Quebec City, Quebec • Universite de Montreal (CHUM) – Montréal, Québec Figure 1. Mechanism of Action Study Design OO O H N O O O O N N N N O O OO O N H O 111In 4-Arm DOTA Chelator PEG3 Linker AVE1642 [111In]-FPI-1547 OO O H N O O O O N N N N O O OO O N H O 225Ac 4-Arm DOTA Chelator PEG3 Linker AVE1642 [225Ac]-FPI-1434 Imaging Therapy 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Infuse only if IGF-1R positive on at least one lesion and dosimetry estimate for 225Ac is acceptable Planar scintigraphy x4 days IGF-1R positive lesion is defined as tumor to background ratio 2 or higher 111In SPECT/CT x2 Emw [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)] Radioactive Decay of Actinium-225 • 4 high energy α particle emissions • Half-life: 10 days IGF-1R IGF-1R has been implicated in: • Increased cellular proliferation • Metastatic potential • Cell survival • Chemotherapy and radiotherapy resistance IMAGING SCREENING [111In]-FPI-1547 Injection GENERAL SCREENING • Informed consent • Safety laboratory assessments • Tumor biopsy if needed • Baseline tumor imaging • Patient meets general eligibility criteria FOLLOW-UP PERIOD Until tumor progression / initiation of a new systemic anticancer therapy, or 6 months post [225Ac]-FPI-1434 Injection, whichever is later: • Tumor assessments every 8 weeks for 6 months then every 3 months until progression or until initiation of new systemic anticancer therapy, whichever is sooner • Safety assessments at 3, 4, 5, and 6 mos. dependent on patient’s clinical condition TREATMENT PERIOD [225Ac]-FPI-1434 Injection Weekly safety assessments for DLT period (56 days) Primary • Evaluate the safety and tolerability of [111In]-FPI-1547 Injection and [225Ac]- FPI-1434 Injection in patients with advanced refractory solid tumors • Determine the maximum tolerated dose of a single [225Ac]-FPI-1434 Injection Objectives Exclusion: • Systemic therapeutic radiopharmaceutical within 6 months prior to enrollment • Contraindications to or inability to perform the imaging procedures required in this study • Uncontrolled brain metastasis, including but not limited to need for treatment with steroids, surgery or radiation therapy • Anticancer therapy (including investigations agents) or external beam radiation therapy within 14 days of the dosing of [111In]-FPI-1547 (6 weeks for mitomycin-C) • Prior organ transplantation, including stem cell transplantation. • Any prior treatment with nitrosoureas and actinomycin-D • Clinical relevant proteinuria • Known or suspect allergies or contraindications to the Investigational Products or any component of the investigational drug formulation • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements • Received > 20 Gy prior radiation to large areas of the bone marrow IGF-1R is expressed on nearly all tumor types Breast Colorectal Prostate Recurrent Thyroid Sarcomas NSCLC Pancreatic / NETs Adrenocortical carcinoma HCC H&N Dose Cohort Administered Dosage of [225Ac]-FPI-1434 1 10 kBq/kg body weight (0.27 µCi/kg body weight) 2 20 kBq/kg body weight (0.54 µCi/kg body weight) 3 40 kBq/kg body weight (1.1 µCi/kg body weight) 4 80 kBq/kg body weight (2.2 µCi/kg body weight) 5 120 kBq/kg body weight (3.2 µCi/kg body weight) Secondary • Obtain preliminary data on tumor uptake of [111In]-FPI-1547 Injection in cancer patients • Estimate the dosimetry for [225Ac]-FPI-1434 Injection (whole body and individual regions) • Determine the pharmacokinetics of [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection • Describe efficacy of [225Ac]-FPI-1434 Injection • Assess the effect of [225Ac]-FPI-1434 on QTc prolongation • Assess changes in human growth hormone (hGh), insulin-like growth factor (IGF)-1 and insulin-like growth binding protein 3 (IGFBP-3) following [111In]-FPI-1547 and [225Ac]-FPI- 1434 injections Figure 2. Single Dose Therapeutic Efficacy in a Colorectal Cancer Tumor Xenograft Model (Colo-205) Days after Treatment initiation Tumor Volume (mm3) 0 10 20 30 0 500 1000 1500 Vehicle Control [225Ac]-1434 (7.4 kBq) [225Ac]-1434 (14.8 kBq) P = 0.005 vs. Vehicle @ 28 daysP < 0.005 vs. Vehicle @ 52 days Average Initial Tumor Volume ~200 mm3 Average Initial Tumor Volume ~450 mm3 clinicaltrials.gov NCT# 03746431 OO O H N O O O O N N N N O O OO O N H O 111In OO O H N O O O O N N N N O O OO O N H O 225Ac [email protected] @FusionPharmaInc Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster. Abstract TPS3152 Therapy Imaging

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