Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival

Abstract

Fifty-seven stage 4 patients with refractory/relapsed neuroblastoma were enrolled in a phase I trial (Clinicaltrials.gov NCT01757626) using humanized anti-GD2 monoclonal antibody hu3F8 in combination with granulocyte-macrophage colony-stimulating factor. The influence of body weight and human anti-human antibody (HAHA) on the pharmacokinetics (PK) of hu3F8, and the effect of de novo anti-GD2 response on patient outcome were explored. Serum samples before hu3F8 infusion, and serially up to day 12 during treatment cycle #1, and at 5 min after each hu3F8 infusion for all subsequent cycles were collected. PK was analyzed using non-compartmental modeling. Immunogenicity was assayed by HAHA response, and vaccination effect by induced host anti-GD2 response measured periodically until disease progression or last followup. Progression-free and overall survival was estimated by the Kaplan-Meier method. Despite dosing being based on body weight, smaller patients had consistently lower area-under-the-curve and faster clearance over the 15 dose levels (0.9 to 9.6 mg/kg per treatment cycle) in this trial. Positive HAHA, defined by the upper limit of normal, when measured within 10 days from the last hu3F8 dose received, was associated with significantly lower serum hu3F8. Despite prior sensitization to other anti-GD2 antibody, e.g. mouse 3F8 or ch14.18, 75% of the patients never developed HAHA response even after getting more treatment cycles. Hu3F8 induced a de novo anti-GD2 response in patients, which was prognostic of progression-free survival. We conclude that hu3F8 had low immunogenicity. During treatment, positive HAHA and low body weight affected PK adversely, whereas induced anti-GD2 response was an outcome predictor.

Keywords: Hu3F8; anti-GD2 antibody; body weight; immunogenicity; pharmacokinetics; vaccination effect.

Figures

Figure 1.

At individual dose level, cycle 1 AUC correlated with patient's body weight.

Figure 2A.

Strong correlation between body weight and body surface area.

Figure 2B.

Broad range of body weight for patients of similar age.

Figure 3.

Strong linear correlation between peak serum hu3F8 concentration and AUC in treatment cycle #1.

Figure 4.

Concomitant determination of serum hu3F8 and HAHA in cycle #1 samples collected within 10 d of last hu3F8 dose received. Negative HAHA is defined as

Figure 5.

Prognostic outcome of anti-GD2 response among 40 patients in this phase I trial.

Figure 6.

Antibody dependent cell mediated cytotoxicity was demonstrated in sera from patients with induced anti-GD2 antibodies.