Dose-Escalation Study of [225Ac]-FPI-1434 in Patients With IGF-1R-Expressing Advanced Solid Tumors: Preliminary Pharmacology and Dosimetry Results

Dose-Escalation Study of [225Ac]-FPI-1434 (FPI-1434) in Patients With IGF-1R-Expressing Advanced Solid Tumors: Preliminary Pharmacology and Dosimetry Results (NCT03746431) N Pandit-Taskar1, J Wong2, V Subbiah3, M Chénard-Poirier4, D Pryma5, A Berlin6, R Juergens7, I Puzanov8, H Jacene9, J Schindler10, J Kazakin10, AO Nawaz10, J Rhoden10, M Brown11, AM Scott12, F Saad13, D Yee14 1Memorial Sloan Kettering Cancer Center, New York City, NY, USA; 2City of Hope, Duarte, CA, USA; 3MD Anderson Cancer Center, Houston, Texas, USA; 4CHU de Québec - Université Laval, Quebec City, QC, Canada; 5University of Pennsylvania Perelman School of Medicine, Philadelphia PA, USA; 6Princess Margaret Hospital, Toronto, ON, Canada; 7Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; 8Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; 9Dana Farber Cancer Institute, Boston, MA, USA; 10Fusion Pharmaceuticals Inc., Hamilton, ON, Canada; 11Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia; 12Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg, VIC, Australia; 13Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal, QC, Canada; 14University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA Presented at: 2023 Society of Nuclear Medicine & Molecular Imaging | June 24-27, 2023 | McCormick Place, Chicago, IL • The insulin-like growth factor 1 receptor (IGF-1R) promotes cancer cell proliferation, migration, and invasion. It is associated with tumor metastasis, treatment resistance, and poor prognosis. • IGF-1R is overexpressed in several malignancies, including lung, breast, ovarian, colorectal, head and neck, and sarcomas. • Alpha particles are highly cytotoxic, cause direct double-strand DNA breaks with subsequent apoptosis, and produce indirect local damage (bystander effect) and a systemic/vaccine-like response (activation of antigen-specific CD8+ T cells). • Fusion has developed an IGF-1R-based theranostic pair: an α-emitting therapeutic ([225Ac]-FPI-1434) and a γ-emitting diagnostic ([111In]-FPI-1547) agent. FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody (Ab) FPI-1175 that binds to the external domain of IGF-1R, a proprietary bifunctional chelate, and the alpha- emitting radionuclide Ac-225. The In-111 analog, FPI-1547, with the identical Ab and bifunctional chelate, is used for patient selection. • Pre-administration of “Cold” Ab may improve tumor uptake of the therapeutic (“Hot”) agent by saturation of natural sinks and blocking Ab-binding sites in normal tissue and by increasing circulation time. The phase 1 study is designed to determine the safety, tolerability, pharmacokinetics, biodistribution, dosimetry, and preliminary antitumor activity of different dosing regimens of FPI-1434. • Dose escalationfollows a 3+3 design; dose-limiting toxicities (DLTs) are assessed during the first cycle (56 days in the single ascending dose; 42 days in all other segments) BACKGROUND References: 1. Juergens RA, et al. JCO. May 1, 2019;37(suppl. 15)TPS 3152. 2. Juneau D, et al. JNM. May 2021;62(suppl. 1):74. 3. Scott et al. JNM. June 2022;63(suppl. 2):2275. Acknowledgements: The authors thank the participants, their families, the clinical and research teams for their participation in this study and Richard Sparks, PhD, and his colleagues from CDE Dosimetry Services, Inc. for their help with the dosimetry data analyses • The Cold + Hot regimen (pre-administration of FPI-1175 at 0.5 mg/kg with FPI-1434 at the 15 kBq/kg dose level) demonstrated: – Decreased rate of systemic clearance from plasma, leading to increase exposure (area under the curve) at 15 kBq/kg (Cold + Hot) compared to the 40 kBq/kg (Hot only) dose level – There were no related DLTs, serious adverse events, or grade ≥3 adverse events at 15 kBq (Cold + Hot) compared to 40+kBq (Hot) • The Cold + Hot regimen demonstrated potential to improve the therapeutic index – No significant impact on organ-absorbed doses (kidney, lung, bone marrow), except in the liver (increased) and spleen (decreased) – Per-cycle organ-absorbed doses at 15 kBq/kg FPI-1434 + 0.5 mg/kg FPI-1175 levels were ≤7% of protocol-defined limits – Doubling of tumor absorbed dose • Exploration of FPI-1434 at 25 kBq/kg (with pre-administration of FPI-1175 at 0.5 mg/kg) dose level is ongoing Conclusion #630 Screening and Treatment • Eligibility includes adequate hematologic, renal, hepatic, and cardiovascular function and sufficient tumor uptake defined as a tumor to background ratio (skeletal muscle) of 2:1 in at least 1 lesion Demographics and Baseline Characteristics Variable N=36 (54 patients consented; 7 did not meet imaging eligibility) Gender Male / Female 21 / 15 ECOG 0 / 1 17 / 19 Median age 59 years (range 34-78) Racea White / Asian 31 / 2 Number of prior systemic treatment regimens** Media: 4 (range: 1-13) 1-2 3-5 ≥6 7 17 10 Tumor indications (>3 patients) Prostate (9); colorectal cancer (7); ovarian (4); adenoid cystic (3) a 3 not reported. b 2 pending. The Most Common (≥3 Patients) Treatment-Related Adverse Eventsa Preferred Term All n=30 (%) FPI-1434 (only) 10-20 kBq n=9 FPI-1434 (only) 40 kBq n=9 (incl. CASS=5) FPI-1434 (only) 55-75 kBq n=9 FPI-1434 (15 kBq) + FPI-1175 (0.5 mg) n=3 Any grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 14 (47%) 5 (17%) 2 (22%) 0 5 (56%) 1 (11%) 6 (67%) 4 (44%) 1 (33%) 0 Anemia 6 (20%) 4 (13%) 0 0 1 (11%) 0 5 (56%) 4 (44%) 0 0 Leukopenia 8 (27%) 2 (7%) 1 (11%) 0 2 (22%) 1 (11%) 4 (44%) 1 (11%) 1 (33%) 0 Neutropenia 10 (33%) 5 (17%) 0 0 4 (44%) 1 (11%) 5 (56%) 4 (44%) 1 (33%) 0 Lymphopenia 5 (17%) 3 (10%) 1 (11%) 0 2 (22%) 1 (11%) 2 (22%) 2 (22%) 0 0 Fatigue 9 (30%) 0 2 (22%) 0 2 (22%) 0 4 (44%) 0 1 (33%) 0 Decreased appetite 4 (13%) 0 0 0 0 0 4 (44%) 0 0 0 Nausea 5 (17%) 0 2 (22%) 0 1 (11%) 0 2 (22%) 0 0 0 Diarrhea 3 (10%) 0 0 0 1 (11%) 0 2 (22%) 0 0 0 a Percentage is based on safety population that includes all patients who received at least 1 dose of FPI-1547 (FPI-1547 ± FPI-1434 ± FPI-1175). • FPI-1547-related adverse events regardless of grade were fatigue and constipation in 1 patient each; FPI-1175 + FPI-1547-related adverse event was adrenal insufficiency in 1 patient; all 3 patients received FPI-1434. • 16 patients received FPI-1175 as part of their imaging/treatment regimens, and no FPI-1175-related adverse events were reported. 0 200 400 600 1 10 100 1000 10000 Time Post-Injection (hr) FPI-1434 Plasma Concentration (ng-Eq/g) [225Ac]-FPI-1434 (10 kBq/kg, ~0.007 mg/kg) [225Ac]-FPI-1434 (20 kBq/kg, ~0.013 mg/kg) [225Ac]-FPI-1434 (40 kBq/kg, ~0.026 mg/kg) [225Ac]-FPI-1434 (75 kBq/kg, ~0.049 mg/kg) [225Ac]-FPI-1434 (55 kBq/kg, ~0.036 mg/kg) Cold+Hot Cohort 1 (15 kBq/kg + 0.5 mg/kg FPI-1175) [225Ac]-FPI-1434 Plasma Pharmacokinetics 0 10 20 30 40 50 0.0 0.5 1.0 1.5 2.0 Platelet Count Following FPI-1434 Administration Days Post FPI-1434 Dose Relative Platelet Count Cold+Hot Cohort 1 (15 kBq/kg + 0.5 mg/kg FPI-1175) 40 kBq/kg Hot Only • Cold + Hot demonstrates increased exposure but minimizes thrombocytopenia compared to Hot only Study FPX-01-01: [225Ac]-FPI-1434 Radiation Absorbed Dose Estimates for Dosimetry-Evaluable Patients Target Organ Hot Only (N=19) Mean [Range] mGy-Eq/MBq Cold + Hot (N=5) Mean [Range] mGy-Eq/MBq Kidneys 1,060 [615-1820] 1,060 [890-1,290] Liver 905 [535-1660] 1580 [929-1,840] Lungs 588 [328-910] 629 [333-1,380] Spleen 4,115 [1,740-9,060] 2,190 [686-3,430] Red marrow 776 [398-1,450] 950 [785-2770] Note: Radiation doses are presented in units of mGy-Eq to denote a relative biologic effectiveness value of 3.4 for alpha emitters. Absorbed dose estimates performed by CDE. Plasma PK, Platelet Counts, and Radiation Absorbed Doses Mean Cumulative Lesion Dosea at [225Ac]-FPI-1434 Dosimetric Limit Hot Only Cold + Hot 29.3 Gy 59.2 Gy a Relative biologic effectiveness = 3.4 for alpha emissions applied. 70 kg body weight assumed. Within prespecified critical organ limits, the Cold + Hot regimen is estimated to deliver ~2x the radiation dose compared to the Hot only regimen, 10 kBq/kg Single Ascending Dose 40 kBq/kg 20 kBq/kg FPI-1175 (0.5mg/kg) + [111In]-FPI-1547 (185 MBq) FPI-1175 (1.5mg/kg) + [111In]-FPI-1547 (185 MBq) (CASS) 75 kBq/kg 55 kBq/kg Multiple Ascending Dose FPI-1175: 0.5 mg/kg FPI-1434: 15 kBq/kg FPI-1175: 0.5 mg/kg FPI-1434: 25 kBq/kg Cold + Hot – Ongoing FPI-1175: 0.5 mg/kg FPI-1434: TBD FPI-1175: 0.5mg/kg FPI-1434: RP2D Expansion • Cumulative radiation dose to critical organs should not exceed 18 Gray (Gy) for kidneys, 31 Gy for liver, and 16.5 Gy for lungs by more than 10% No Cold mAb 0.5 mg/kg Cold mAb

The release as fetched from its publisher. fusionpharma.com ↗