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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.

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Recent regulatory guidance has highlighted the importance of using pharmacokinetic-pharmacodynamic (PK-PD) modelling in the selection of starting doses in first-in-human trials of high-risk biologics.• However, limited examples exist in literature illustrating this procedure. WHAT THIS STUDY ADDS• An interpretation of the recommended dose-selection methodology and the minimum anticipated biological effect level (MABEL) principle, contained in the updated European Medicines Agency guidance on risk-mitigation strategies for first-in-human studies, is presented.• Some literature and simulation-based examples of the application of PK-PD modelling principles to starting dose selection using in vitro and in vivo data under the MABEL paradigm are highlighted, along with the advantages and limitations of this approach. AIMSTo illustrate the use of pharmacokinetic-pharmacodynamic (PK-PD) models to select rational starting doses in clinical trials within the minimum anticipated biological effect level (MABEL) principle using literature data and through simulations. METHODSThe new European Medicines Agency guidance on starting dose selection of high-risk biologics was analysed considering the basic pharmacological properties and preclinical testing limitations of many biologics. The MABEL approach to dose selection was illustrated through simulations and through literature-reported examples on the selection of starting doses for biologics such as antibodies based on in vitro biomarker data, in vivo PK and PK-PD data. RESULTSLiterature reports indicating the use of preclinical pharmacological and toxicological data to select successfully safe starting doses in line with the MABEL principle are summarized. PK-PD model-based simulations of receptor occupancy for an anti-IgE antibody system indicate that the relative abundance of IgE in animal models and patients and the turnover rate of the IgE-antibody complex relative to the off-rate of the antibody from IgE are important determinants of in vivo receptor occupancy. CONCLUSIONSMechanistic PK-PD models are capable of integrating preclinical in vitro and in vivo data to select starting doses rationally in first-in-human trials. Biological drug-receptor interaction dynamics is complex and multiple factors affect the dose-receptor occupancy relationship. Thus, these factors should be taken into account when selecting starting doses.

7009 Background: Hu5F9-G4 (5F9) is an antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers. CD47 blockade induces tumor phagocytosis and eliminates leukemia stem cells (LSC) in AML models. Azacitidine (AZA) synergizes with 5F9 by inducing “eat me” signals on AML, enhancing phagocytosis. This trial explored the safety/efficacy of 5F9 alone or with AZA in AML/MDS patients (pts). Methods: This Phase 1b treated: r/r AML/MDS pts with 5F9; and untreated AML (induction chemo ineligible) and higher risk MDS pts with 5F9+AZA. A 5F9 priming/intrapatient dose escalation regimen (1-30 mg/kg weekly) was used to mitigate on target anemia. Results: 10 (6 AML, 4 MDS) r/r pts received 5F9 (median 2 prior therapies (range 1-6). 24 untreated pts (15 AML, 9 MDS) received 5F9+AZA. In total, median age was 73, 62% of AML pts were intermediate or poor cytogenetic risk (38% unknown), all MDS pts were intermediate or high risk by IPSS-R. 5F9 alone or with AZA was well-tolerated with no MTD reached. 5F9 did not potentiate AZA toxicities. Treatment-related AEs ( > 10% of pts) for 5F9+AZA were anemia (25%), thrombocytopenia (20%), and infusion reactions (15%). In 25 efficacy evaluable pts, 8/15 (53%) untreated AML/MDS pts had a CR/CRi to 5F9+AZA (5/10 (50%) in AML, 3/5 (60%) in MDS). 1/10 (10%) r/r AML/MDS pts had a response (MLFS) to 5F9 alone. LSC frequency was reduced/eliminated in most 5F9+aza responders; 50% of responders were MRD negative by flow cytometry. 4/10 (40%) AML pts became RBC transfusion independent and 4/5 (80%) MDS pts had hematologic improvement. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. As of Jan 2019, no responder has relapsed (median follow-up of 3.4 mos (range 1.1 – 6.8 mos). 2 pts had successful allogeneic transplant. Conclusions: 5F9+AZA is a novel immunotherapy blocking a key macrophage checkpoint. It has been well tolerated with robust activity in AML/MDS pts with rapid CRs and MRD negativity. Adding 5F9 to cytotoxic agents may be a promising treatment strategy. An expansion cohort is ongoing. Funded by Forty Seven and the California Institute for Regenerative Medicine. Clinical trial information: NCT03248479.

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Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (SC) doses of 2.25 m g/kg every week and SC doses of 6.75 m g/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/ day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modifi ed indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after SC doses of 0.5 m g/kg every week to 15 m g/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The fi nal PkPd model adequately predicted hemoglobin response in a test data set, thereby confi rming the predictive capability of the model. Based on simulations, it was not possible to categorize the infl uence of any covariate as clinically important.