Phase I Dose Escalation Study Of 177lu-Humab-5b1 (Mvt-1075) In Combination With Mvt-5873 As Radioimmunotherapy (Rit) In Subjects With Relapsed / Refractory Pancreatic Cancer Or Other Ca19-9+Malignancies

Objectives and Background: The study is designed to establish a recommended phase 2 dose (RP2D) for the treatment of CA19-9+ malignancies with MVT-1075/MVT-5873 radioimmunotherapy (RIT). 177Lu-CHX-A″-DTPA-HuMab-5B1 (MVT-1075) consists of the fully-human IgG1 mAb Mab-5B1 (MVT-5873) conjugated to CHX-A″-DTPA and radiolabelled with 177Lutetium (177Lu). MVT-5873 targets the sialyl Lewis A (sLea) epitope of CA19-9, which is often overexpressed in pancreatic (PDAC) and other GI cancers and is a marker of aggressive disease. 177Lu is a low-energy β-emitter (max. energy, 0.5 MeV) with relatively short tissue penetration (max. 1.6 mm) that also emits γ-radiation (113 keV, 7%; 208 keV, 11%) suitable for scintigraphic imaging and dosimetry. Methods: An RIT cycle comprises dosing on Days 1 and 15 with a 57 day DLT assessment period. On Day 1, a blocking dose of MVT-5873 70 mg IV is given followed 2-4 hours later by 50% of the MVT-1075 dose estimated to produce a Cohort-defined target bone-marrow exposure. Between Days 1 and 8, dosimetry is obtained with multiple gamma camera planar images and at least 1 SPECT/CT scan. On Day 15, a second MVT-5873 blocking dose is given followed by a dose of MVT-1075 calculated to complete the total bone-marrow exposure for the cycle. Key entry criteria include previously-treated locally-advanced or metastatic PDAC or other CA19-9+ malignancy (CA19-9 ≥ 1.5 x ULN or IHC+ biopsy) and ECOG PS ≤1. Up to 4 cycles of RIT are permitted provided safety criteria (e.g. allowable cumulative organ exposures, adequate resolution of toxicities, and permitted timing between cycles) are met. Trial endpoints include safety, MTD, dosimetry, pharmacokinetics (PK), tumor response, and changes in serum CA19-9 levels. Preliminary Data: As of 23-Jan-2018, data from Cycle 1 are available from 3 subjects in Cohort 1 (n = 4). Median age was 61 (range 60-61); all subjects had PDAC. The mean total dose in Cycle 1 was 60.4 mCi (range 54.6-96.7), calculated to deliver 0.5 Gy to bone marrow. Hematologic toxicities with MVT-1075/MVT-5873 by highest Grade (Gr) in subjects (n) were: WBC - Gr 1,2 (1,1); platelets - Gr 1,2,3 (1,1,1) and Hgb - Gr 1,2 (2,1). Non-hematologic AE9s included chills - Gr 1 (1), AST - Gr 1 (3), and ALT - Gr 1,2 (1,1). No responses were seen after one cycle. MVT-1075 dosimetry to bone marrow and other critical organs were compatible with predictions from human experience with 89Zr-DFO-HuMab-5B1 (MVT-2163). MVT-1075 median biologic half-times were 273 h, 4.7 h and 65 h for whole body, serum α, and serum β, respectively. Dosimetry data illustrate MVT-1075 accumulation on target lesions. Conclusions: RIT with MVT-1075/MVT-5873 was associated with manageable hematologic toxicities, consistent with predictions. MVT-1075 demonstrated target accumulation. Accrual is ongoing and dose escalation is planned. Citation Format: Eileen A. O9Reilly, Christian Lohrmann, Joseph A. O9Donoghue, Erkut Borazanci, Hayley Estrella, Rebecca Teng, Terri Melink, Kirsten Dorr, Christine Kearns, Marvin Peterson, Jack Ostrowski, John Gutheil, Paul W. Maffuid, Jason S. Lewis, Wolfgang Weber. Phase I dose escalation study of 177Lu-HuMab-5B1 (MVT-1075) in combination with MVT-5873 as radioimmunotherapy (RIT) in subjects with relapsed / refractory pancreatic cancer or other CA19-9+ malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT140.