Two phase I studies of PTI-188, a radiolabeled murine antimelanin antibody, in patients with metastatic melanoma (MM).

Abstract

8555 Background: Two completed single-dose Phase I studies explored the feasibility of treating MM by targeting melanin with a 188-Rhenium-labeled IgM mAb (PTI-188) to deliver high energy β radiation to tumors. This strategy is attractive because it does not rely on patients’ genotype or immune status, and thus has potential to be used alone or in combination with other therapies in a wide pt population. The objectives of these Phase I studies were to evaluate the safety, pharmacokinetics, dosimetry and anti-tumor activity of a single dose of PTI-188. Methods: Pts with stage IIIC/IV MM who progressed after chemotherapy, immunotherapy, radiotherapy or surgery were enrolled in both studies, at least 3 pts/cohort. In Phase IA, pts were given the same dose of PTI-188 (10 mCi/10 mg) while a cold antibody pre-load was escalated from 0-50 mg in 4 cohorts. In Phase IB, pts were assigned to cohort 1 (20-30 mCi/20mg) or cohort 2 (40-60mCi/50mg). Whole body planar and tomographic (SPECT/CT) scintigraphy were performed post-infusion to determine tumor targeting and dosimetry. Toxicity and efficacy were evaluated at weeks 2 and 6 post-treatment, and monthly thereafter. Results: No dose limiting toxicities or clinically meaningful effects in safety lab tests were seen in the 13 pts dosed in Phase IA and 7 pts in Phase IB, suggesting the MTD was not met. No treatment related serious AEs occurred. Transient human anti-murine Abs were observed in 9 pts. Tomographic imaging revealed PTI-188 uptake in melanoma tumor deposits mostly in the soft tissues. The highest radiation absorbed dose to normal organs was in the kidney (13% of the allowable dose to kidney at the highest dose level of PTI-188). The mean effective half-life of PTI-188 was 12.4 hr across cohorts. Although no therapeutic benefit was expected in a single dose Phase I study, 6 pts met the RECIST criteria for stable disease at 6 weeks. 2 pts had durable disease stabilization for 14 weeks and 1 for 22 weeks. Preliminary ad-hoc analysis indicates a median overall survival of 20 months (n=17). Conclusions: The data demonstrate that a single dose of PTI-188 was well tolerated, localized in melanoma metastases and suggest antitumor activity.