A Phase 1 first-in-human study of MEDI0680, an anti-PD-1 monoclonal antibody (mAb) in adult patients (pts) with advanced tumors

Background

Programmed cell death-1 (PD-1) inhibits T-cell activation. Blocking the PD-1/programmed cell death ligand 1/2 (PD-L1/2) axis has an acceptable safety profile, induces antitumor responses, and provides clinical benefit across tumors. MEDI0680 is a humanized IgG4κ mAb specific for human PD-1 that blocks interaction with PD-L1/2.

Methods

This is an ongoing Phase 1, multicenter, open-label, first-in-human, dose-escalation and expansion study of single-agent MEDI0680 in immunotherapy-naïve pts with advanced solid tumors. Primary objectives are safety/tolerability and maximum tolerated dose (MTD). Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity (modified RECIST v1.1).

Results

As of 2 Nov 2015, 58 pts have enrolled across 9 cohorts (0.1–20 mg/kg given Q3W, Q2W, QWx2 then Q2W, or QWx4 then Q2W). MTD was not reached. Treatment-related AEs occurred in 46 pts; most common (>10%) were fatigue (21%), nausea (14%) and arthralgia (14%). Related Grade 3/4 AEs occurred in 10 pts; most common (>1 pt) were anemia, arthralgia and increased AST (3% each). 2 pts discontinued due to related AEs: pyrexia in 1 pt; and increased AST, myasthenia gravis and myositis in 1 pt. There were no Grade 5 related AEs. MEDI0680 had a linear PK profile with dose-proportional increases in peak serum concentration. Median PD-1 receptor occupancy on CD3+ T cells was ≥70% after 1 cycle of 10 or 20 mg/kg Q2W. Increased percentages of Ki67 + , ICOS+ and HLA-DR+ T cells; increased levels of plasma IFNɣ; and enhanced intra-tumor gene expression for these factors were seen after treatment, demonstrating biological activity of MEDI0680. Of 51 evaluable pts, 9 (18%) had an objective response (8 had renal cancer or melanoma), including 1 (2%) complete response (renal cancer). 14 (28%) pts had stable disease as their best response. The recommended dose is 20 mg/kg Q2W, based on PK, PD, safety and efficacy.

Conclusions

MEDI0680 has an acceptable safety profile, with preliminary signs of efficacy. A Phase 1 combination study with durvalumab to test the concept of complete PD-1/PD-L1 axis blockade is ongoing in advanced solid tumors.

Clinical trial identification

NCT02013804 (release date: December 12, 2013)

Legal entity responsible for the study

MedImmune

Funding

MedImmune

Disclosure

A. Naing: Research funding: NCI; EMD Serono; Medimmune; Healios Onc. Nutrition, ATTEROCOR; Amplimmune; ARMO BioSciences; Karyopharm Therapeutics; Incyte; Novartis. B. Curti: Honoraria: Prometheus Speaker Bureau: Prometheus Research funding: Prometheus, Viralytics, Galectin Therapeutics Travel, accommodation, expenses: BMS, Medimmune, AgonOx, Prometheus. J.P. Eder: Honoraria: Merck. S. Marshall: Employment and stock options: Medimmune, Amplimmune. C. Morehouse: Employment: Medimmune Stock/ownership: Medimmune (AstraZeneca). X. Li: Employment: MedImmune. J.J. Karakunnel: Employee of MedImmune and own stock or options in AstraZeneca. Also an employee of MedStar Montgomery Medical Center and Fauquier Hospital. J. Infante: Consulting/advisory: MedImmune Research funding: MedImmune. All other authors have declared no conflicts of interest.