A phase I, open-label, multiple-ascending-dose trial to investigate the safety, tolerability, pharmacokinetics, biological, and clinical activity of M7824, a novel bifunctional fusion protein targeting the PD-L1 and TGF-ß pathways, in patients with metastatic or locally advanced solid tumors

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S103
• Main Authors: Strauss, J, Heery, C, Schlom, J, Madan, RA, Lamping, E, Marte, J, Cordes, L, Lan, Y, Mahnke, L, Helwig, C, Lo, KM, Gulley, J
• Format: Article
• Language: English
• Subjects: Anemia; Biological activity; Cancer; Cervix; Diarrhea; Dosage; Fusion protein; Immunoglobulins; Leukopenia; Ligands; Lipase; Lymphopenia; Metastases; Pancreas; Patients; PD-L1 protein; Pharmacodynamics; Pharmacokinetics; Pharmacology; Proteins; Safety; Solid tumors; Toxicity; Transaminase; Transforming growth factor-b1; Tumor markers; Tumors; Xerostomia
• ISSN: 0959-8049; 1879-0852

Background: M7824 is a novel Afunctional fusion protein that simultaneously blocks two major mechanisms of tumor immune evasion. It combines an anti-programmed death ligand 1 (PD-L1) antibody, and the soluble extracellular domain of tumor growth factor beta (TGFβ) receptor type 2, forming a TGFβ"trap". We report preliminary safety, tolerability, pharmacodynamics, pharmacokinetics and efficacy data from a phase I dose-escalation study (NCT02517398) of M7824 in patients (pts) with advanced solid tumors. Methods: Four dose levels (DL 1, 3, 10, and 20mg/kg) were escalated in a 3+3 design. Dose-limiting toxicities (DLT) were evaluated over 3 weeks. Results: As of May 4. 2016, 12 pts with advanced cancer had enrolled, with 3 pts treated with M7824 at each dose level: 1,3, 10, and 20mg/kg Q2W. Median age was 56.5 years (range 34-78). All had ECOG PS 0 or 1, with a median of 4 prior therapies (range 2-7). 8/12 pts (67%) had drug-related treatment-emergent adverse events (TEAEs). One pt had grade 3 asymptomatic elevated lipase. All other drug-related TEAEs were grade 1 or 2: maculopapular rash (2 pts; 15%), pruritis (2 pts; 15%), xerostomia {1 pt; 8%), diarrhea (1 pt; 8%), elevated transaminase (2 pt; 15%), elevated amylase (1 pt; 8%), lymphopenia (2 pts; 15%). leukopenia (1 pt; 8%), and anemia (1 pt; 8%). No pt had a DLT and no treatment was discontinued for drug-related TEAEs. Two pts had elevated tumor markers at study entry declining to within normal limits on treatment: 1 (cervical Ca, DL3) has ongoing SD at 4 months; 1 (pancreatic Ca, DL2) has an ongoing confirmed PR by RECIST at 6 months. Also, 1 pt (carcinoid, DL1) had SD for 8 months and 1 pt (pancreatic Ca, DL2) had SD for 6 months. To date, 7 pts (58%) have discontinued treatment for PD; 5 pts (42%) remain on treatment. All patients from the first 3 dose levels were evaluable for PK analysis showing dose-linear pharmacokinetics at 3 and 10mg/kg. Patients from the 3 and 10 mg/kg dose levels were evaluable for PD-L1 target occupancy, which reached saturating levels throughout the entire dosing interval. All pts from the first 3 dose levels were evaluable for TGFβ1, 2, 3 plasma concentrations. After M7824 infusion, TGFβ1 and 3 concentrations were undetectable in all pts at all doses and remained suppressed throughout the dosing interval. TGFβ2 suppression was also evident in all patients, but its degree was dependent on dose and drug concentrations. Conclusions: Preliminary data suggest that the bifunctiona