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

Purpose: Two 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 methods: Patients 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).

Results: Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 microg/kg (NSCLC and PC) and 15 microg/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 microg/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.

Conclusion: ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.

Fig 1.

ABR-217620 proposed mechanism of action. The ABR-217620 fusion protein binds to the 5T4 tumor-associated antigen and activates a T lymphocyte through its T-cell receptor (TCR). The T cell produces cytokines (tumor necrosis factor [TNF] –α and interferon [IFN]-γ) and executes direct tumor killing if it is a cytotoxic T lymphocyte.

Fig 2.

ABR-217620 pharmacology. Geometric mean of (A) interleukin-2 (IL-2) and (B) interferon (IFN)-γ levels in plasma at before and 3 hours after first infusion of ABR-217620 in the MONO (ABR-217620 dose escalation monotherapy) study. Renal cell carcinoma (RCC; n = 9, red lines), non–small-cell lung cancer (NSCLC), and pancreatic cancer (PC; n = 8, black lines) patients receiving more than 15 μg/kg ABR-217620; patients receiving 2.5 to 15 μg/kg (n = 9, dashed lines) and less than 2.5 μg/kg ABR-217620 (n = 12, dotted lines). Plasma samples were taken before and 3 hours after each injection of ABR-217620. (C) Each bar represents an individual subject at the distinct time point. Percentage of T lymphocytes expressing T-cell receptor (TCR)-Vβ6.4 (percentage TCR-Vβ6.4 cDNA of total TCR-Vβ cDNA) in peripheral blood from patients before and after treatment with ABR-217620 in the MONO (black) and COMBO (ABR-217620 dose escalation combination with docetaxel; red) studies. (D) Median with first and third quartiles of anti-SAg antibodies before and 28 days after start of treatment with ABR-214936 (anti-staphylococcal enterotoxin E [SEA], black line), ABR-217620 MONO (anti-SEA/E-120, red line), and ABR-217620 COMBO (anti-SEA/E-120, blue line).

Fig 3.

Immunohistochemistry for T-lymphocyte (anti-CD3) infiltration in biopsies taken before treatment (archival tissue) and at the third day of the second cycle treatment with ABR-217620 for patient number 2. The T lymphocytes stain brown and the arrows indicate unstained tumor cells. This patient had a partial response that continues at 30+ months.