First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers

Abstract

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.

Patients and methods: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.

Results: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.

Conclusion: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

Trial registration: ClinicalTrials.gov NCT02216409.

FIG 1.

Hu5F9-G4 (5F9) pharmacokinetics and effects on hemoglobin and reticulocyte levels. (A) Concentration of 5F9 (mean ± standard deviation) versus time during week 5 over the evaluated weekly dose range (1 to 45 mg/kg; number of patients per dose range, three to 30). (B) Anemia with compensatory reticulocytosis in one patient.

FIG 2.

Pharmacodynamics of Hu5F9-G4. (A) RBC receptor occupancy. (B) WBC receptor occupancy. (C) IgG4 immunohistochemical staining in a lymph node with tumor involvement obtained from a 70-year-old patient with ovarian cancer treated with 30 mg/kg of 5F9. She remained on study for 7 months with a best overall response of stable disease. 1/3 is 1 mg/kg priming dose and 3 mg/kg weekly dosing. 1/10 is 1 mg/kg priming dose and 10 mg/kg weekly dosing. 1/20 is 1 mg/kg priming dose and 20 mg/kg weekly dosing. Po, post-infusion sample collection; Pr, pre-infusion sample collection.

FIG 3.

Hu5F9-G4 partial responses observed in (A) a patient with clear cell ovarian cancer and (B) a patient with fallopian tube cancer.