1950 - Phase 1 Dose Escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients (pts) with advanced solid tumors: Updated results

Background

Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine, highly expressed in a subset of tumors and correlates with poor prognosis. LIF is hypothesized to contribute to tumor microenvironment (TME) immunosuppression and regulation of cancer initiating cells. MSC-1 is a first-in-class humanized IgG1 monoclonal antibody that potently and selectively inhibits LIF. MSC-1 decreased tumor growth in mouse tumor models and generated durable regressions when combined with anti-PD-1.

Methods

Eligible pts had advanced relapsed/refractory solid tumors (regardless of pretreatment LIF tumor levels). The study employed an accelerated 3 + 3 escalation design to explore safety, dose-limiting toxicities (DLTs), preliminary efficacy, and define a recommended phase II dose (RP2D). Pts received treatment with MSC-1 intravenously (75mg-1500 mg) once every 3-weeks until disease progression. The three highest dose cohorts were expanded to further assess safety, PK, LIF peripheral target engagement, and to assess immuno-regulatory tumor activity in paired pre- and on treatment tumor tissue.

Results

Dose escalation enrollment was completed on March 6, 2019 with 41 pts (14 in dose escalation; 27 in expanded cohorts). There were no DLTs. As of April 26, 2019, there were 38 AEs (30 grade (Gr) 1,7 Gr 2, and 1 Gr 3), reported as possibly related to MSC-1 (fatigue in 10 pts and nausea in 4 pts were the most common). Overall PK profile was linear with estimated terminal half-life of ∼17 days and a benign anti-drug antibody profile. There was evidence of durable peripheral LIF saturation at higher doses or after multiple doses. Stable disease (≥ 16 weeks) was noted in 7 pts. Comparison of paired pretreatment and on treatment biopsies in the 1125mg expanded cohort, showed at least one mechanism-based change in all 4 evaluable patients, and in the two patients continuing therapy beyond 16 weeks, evidence of reversal of TME immunosuppression through infiltration of CD8 T cells and changes in macrophage populations.

Conclusions

MSC-1 holds promise as an anti-cancer therapy and should be readily combinable with other agents. Updated safety, efficacy, PK, LIF stabilization analyses, and paired tumor biopsy data will be presented.

Clinical trial identification

NCT03490669.

Editorial acknowledgement

Legal entity responsible for the study

Northern Biologics Inc.

Funding

Northern Biologics, Inc.

Disclosure

E. Borazanci: Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Fujifilm; Advisory / Consultancy: Concept; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Minneamrita; Research grant / Funding (institution): Fujifilm; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Bioline; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Ambry; Research grant / Funding (institution): Mabvax. A. Schram: Research grant / Funding (institution): Northern Biologics. I. Brana: Research grant / Funding (institution): Northern Biologics; Advisory / Consultancy, Research grant / Funding (self): Orion Pharmac; Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Gliknik; Research grant / Funding (self): GSK; Research grant / Funding (self): Jannsen; Research grant / Funding (self): Kura; Research grant / Funding (self): MSD; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche. M. Vieito Villar: Research grant / Funding (institution): Northern Biologics. E. Garralda: Research grant / Funding (institution): Northern Biologics; Advisory / Consultancy, Research grant / Funding (self): Roche Genentech Inc; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: Neomed Therapeutics1 Inc; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services; Speaker Bureau / Expert testimony: BMS; Research grant / Funding (self), Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Glycotope ; Research grant / Funding (self), Travel / Accommodation / Expenses: Menarini; Research grant / Funding (self): Novartis; Leadership role: ESMO; Research grant / Funding (self): Principia Biopharma Inc; Research grant / Funding (self): Lilly, S.A ; Research grant / Funding (self): Loxo Oncology Inc ; Research grant / Funding (self): Symphogen A/S ; Research grant / Funding (self): Incyte; Research grant / Funding (self): Pharma Mar; Research grant / Funding (self): MacroGenics; Research grant / Funding (self): Kura Oncology,Glycotope, Pierre Fabre, Blueprint Medicines , Beigene, Sierra Oncology, Genmab. A. Spreafico: Research grant / Funding (institution): Northern Biologics. M. Oliva: Research grant / Funding (institution): Northern Biologics. N. Lakhani: Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Forty Seven Inc; Research grant / Funding (institution): INhibRx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Arqule; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Livzon; Research grant / Funding (institution): Ascentage; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Apexian; Research grant / Funding (institution): Asana Biosciences; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Formation Biologics/Forbius; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Constellation Pharma,; Research grant / Funding (institution): TaiRx, CytomX, Coordination Pharma, Symphogen, Cerulean, Jounce Therapeutics. R. Wasserman: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Northern Biologics. K. Hoffman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Northern Biologics. R. Hallett: Shareholder / Stockholder / Stock options, Full / Part-time employment: Northern Biologics. J. Anido: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Northern Biologics. P. Giblin: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Northern Biologics. N. Pandya: Shareholder / Stockholder / Stock options: Northern Biologics. A. Kelly: Advisory / Consultancy: Northern Biologics. J. Seoane: Advisory / Consultancy, Research grant / Funding (self), Shareholder / Stockholder / Stock options, Officer / Board of Directors: Northern Biologics; Research grant / Funding (self): Mosaic Biomedicals; Research grant / Funding (self): Roche-Glycart. D.D. Von Hoff: Research grant / Funding (institution): Northern Biologics; Advisory / Consultancy, Research grant / Funding (institution): Celgene. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (self): GlaxoSmithKine; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Northern Biologics, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks; Spouse / Financial dependant: Agios. D.M. Hyman: Advisory / Consultancy, Travel / Accommodation / Expenses: Chugai Pharma; Advisory / Consultancy: CytomX Therapeutics; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech / Roche; Research grant / Funding (self): Loxo Oncology; Research grant / Funding (self): PUMA Biotechnology; Research grant / Funding (self): Bayer Pharmaceuticals; Research grant / Funding (institution): Northern Biologics. J. Tabernero: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Beigene; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genentech, Inc; Advisory / Consultancy: Genmab, A/S; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Imugene Limited; Advisory / Consultancy: Inflection Biosciences Limite; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Kura Oncology; Advisory / Consultancy: MSD; Advisory / Consultancy: Menarini; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen; Research grant / Funding (institution): Northern Biologics, Symphogen A/S, Servier SL, Roche Farma SA, Pharma Mar, Novartis Farmacéutica SA, Amgen, Debiopharm International SA, Janssen-Cilag SA, Mologen AG; Leadership role: ESMO.