SUPERANTIGEN-TARGETED THERAPY - PHASE-I ESCALATING REPEAT DOSE TRIAL OF THE FUSION PROTEIN PNU-214565 IN PATIENTS WITH ADVANCED GASTROINTESTINAL MALIGNANCIES

Antibody-directed, superantigen-induced cytotoxicity has been shown to have potent in vitro and in vivo antitumor effects in preclinical mod els, In the present study, PNU-214565, a recombinant fusion protein co nsisting of the Fab of the monoclonal antibody C242 and staphylococcal enterotoxin A (SEA), was used in an escalating repeat dose Phase I cl inical trial in patients with advanced gastrointestinal malignancies. A prior single-dose Phase I clinical trial had demonstrated safety at doses of 1.5 ng/kg with toxicities of fever and hypotension that were not dose related, Twenty-seven patients (age range, 36-75 years; media n, 62; 14 males and 13 females; 23 colorectal and 4 pancreatic) were t reated in the present study with one cycle of four consecutive daily 3 -h infusions of PNU-214565 at doses of 0.15 ng/kg (n = 3); 0,5 ng/kg ( n = 3), 1.5 ng/kg (n = 4), 2.75 ng/kg (n = 12), and 3.5 ng/kg (n = 5), All patients had a good performance status [Eastern Cooperative Oncol ogy Group: PS = 0 (n 15), PS = 1 (n = 12)]. As in the single-dose tria l, fever and hypotension were the most common toxicities, Dose-limitin g toxicity (DLT), consisting of transient hypotension responsive to do pamine, was experienced by one patient treated at the 2.75 ng/kg dose level. One patient with pancreatic cancer metastatic to the liver expe rienced a partial response of hepatic metastases with stable pancreati c head abnormalities by computed tomography scan. Further dose escalat ion was suspended when two patients treated in a companion repeat dose Phase I study experienced DLT at the 4 ng/kg dose level, Multiparamet er analyses on all patients treated in the two companion single-dose a nd two-repeated-dose Phase I trials revealed that the levels of patien ts' pretreatment anti-SEA antibodies protected against toxicity at a g iven drug dose. By jointly considering weight and the baseline anti-SE A concentration in a patient, it is possible to assign a PNU-214565 do se that will induce systemic cytokine release (a surrogate test to ass ess for the presence of uncomplexed drug and its ability to induce sys temic cellular activation) without DLT. This pharmacodynamically based dosing scheme will be tested in future repeated-dose clinical trials and will define maximally tolerated doses of this powerful new immunot herapy approach.