Phase I study of anti fibronectin 131I-L19-small immunoprotein (SIP): Preliminary dosimetric, pharmacokinetics (PK) and therapeutic results

947 AIM: L19-SIP is a human recombinant antibody fragment designed for tumor-targeted radioimmunotherapy (RIT). It was constructed using the variable regions of the L19 mAb directed against the Extra Domain B (ED-B) of fibronectin. ED-B is a glycoprotein of the subendothelial extracellular matrix of newly formed blood vessels in tumors and in tissues undergoing extensive remodeling (wound healing, chronic inflammatory disease). Primary objective: dosimetric evaluation of 131I-L19-SIP as a possible RIT for solid cancers. Secondary objectives: toxicity, PK and therapeutic efficacy evaluation. METHODS: Patients (pts) with progressive solid tumors of at least one lesion ≥ 2.5 cm underwent dosimetric and PK evaluation after iv administration of 87-193 MBq of 131I-L19-SIP. After 14-35 days, pts with a lesion/red marrow absorbed dose ratio ≥ 10 received a therapeutic dose of approx. 3700 MBq of 131I-L19-SIP. Dosimetric evaluation was conducted on double head whole body multi-static scans. The red marrow dose was evaluated assuming a fixed red marrow to blood concentration ratio of 0.19/(1 - hematocrit), typical for antibodies which initially distribute in a volume of 2.5-4 L. CT scans are performed at baseline and 4 weeks post therapeutic dose. Pts are followed for toxicity for at least 4 weeks after the therapeutic dose . RESULTS: So far 9 pts (7M/2F, median age 54 [range 38-74yrs] median ECOG PS 0 [range 0-1]) entered the dosimetric phase with the following tumors : colorectal (3), adrenocortical (1), renal cell (1), breast (1), NSCLC and urothelial (1) carcinomas, melanoma (2). The median number of prior chemotherapies for advanced disease was 3 (range 1-3). To date 5 pts have received the therapeutic dose. The median Vd 6.56 L is larger than expected, likely due to the molecular size of L19-SIP, smaller than that of a full size antibody. Median blood t1/2 is 38.2 h. The median absorbed doses are (Gy): heart wall 2.41, kidneys 3.74, liver 3.68, lungs 2.24, testes 3.69, red marrow 0.69, therapeutic-phase patient tumors 8.5. Grade 3/4 drug-related toxicity post therapeutic dose was limited to one severely malnourished patient, who developed grade 4 thrombocytopenia. No other hematological toxicity was noted. Though no objective tumor response was observed, clinical benefit was seen in 2 pts. A significant, durable reduction in daily morphine intake was reported in a breast cancer patient with a brachial plexus neoplastic infiltration. Cutaneous disease stabilization was observed in a melanoma patient with daily appearance of cutaneous lesions. CONCLUSION: Unexpectedly low red marrow specific absorbed dose, absence of toxicities, and a high tumor uptake, suggests to safely increase the therapeutic administered activity of 131I-L19-SIP to further characterize toxicity and efficacy. Study sponsored by PHILOGEN SpA, Siena (Italy) and supported by Schering AG, Berlin (Germany).