Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer

Abstract

A B S T R A C T PurposeTwo phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4. Patients and MethodsPatients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti-SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study). ResultsThirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 g/kg (NSCLC and PC) and 15 g/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 g/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56. ConclusionABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

“…There are currently 2 5T4-targeting agents in clinical development for oncology indications: a vaccine consisting of 5T4-expressing vaccinia virus (26)(27)(28) and an anti-5T4 antibody fragment conjugated to superantigen from Staphylococcal enterotoxin A (29,30). Both of these agents engage the host immune system to attack the 5T4-expressing cells.…”

Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Treated in a Phase I Clinic

“…In addition, data obtained from our phase I clinic on 683 participants having various tumor types showed that patients treated with low dose levels did not fare worse [31]. Previously reported RRs in heavily pretreated NSCLC patients treated in disease-specific phase I clinical trials were in the range of 3%-15% [32][33][34]. Most of our patients with NSCLC (77 of 85, 90.5%) were enrolled in studies that administered targeted agents.…”

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

“…[193]. In the second trial, ABR-217620 (naptumomab estafenatox), a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to a Fab fragment that recognizes the tumor-associated antigen 5T4, was given alone or in combination with docetaxel [194]. The treatment was well tolerated with evidence of immunological and antitumor activity.…”