Phase I study of anti fibronectin 131I-L19-small immunoprotein (SIP): Preliminary dosimetric, pharmacokinetics (PK) and therapeutic results
Authors: Diego Tosi, Angela Coliva, Carlo Chiesa, Cristiana Sessa, Antonella Perotti, Giuseppe Capri, Marco Maccauro, Ettore Seregni, Silvia Marsoni, Monica Miani, Hans Menssen, Dario Neri, Luciano Zardi, Emilio Bombardieri, Luca Gianni
Journal: Cancer Research (2007)

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).