A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors

Abstract

Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.

Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

“…Two examples of ADCs in clinical development that use warheads that inhibit topoisomerase I activity include trastuzumab deruxtecan targeting HER2 in breast and gastric cancers and sacituzumab govitecan targeting Trop2 in breast and lung cancers (22,23). A Biologics License Application has been filed for sacituzumab govitecan for metastatic triple-negative breast cancer, and trastuzumab deruxtecan is currently in multiple late-stage pivotal clinical trials.…”

“…In a phase I trial in third-line triple-negative breast cancer, sacituzumab govitecan demonstrated an ORR of 31% and a median progression-free survival of 5.5 months (Table 1). In this trial, sacituzumab govitecan was dosed at 10 mg/kg on days 1 and 8 every 21 days and showed improved tolerability compared with other ADCs targeting Trop2 such as PF-06664178, which had a MTD of 2.4 mg/kg, showed limited efficacy, and was terminated due to high toxicity (23).…”

The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target

“…This section focuses on two anti-TROP-2 ADCs that have been studied clinically, sacituzumab govitecan, using the topoisomerase inhibitor, SN-38 (an irinotecan metabolite) [ 66 , 99 – 107 ], and another agent, RN927C, coupled to a derivative of the microtubule inhibitor, auristatin [ 108 , 109 ]. Other TROP-2-targeted therapeutics have been described preclinically, one using a nanoparticle (carboxymethyl dextran) carrier linked with doxorubicin, which has activity in the MDA-MB-231 breast cancer cell line representative of TNBC [ 110 ], and another, utilizing doxorubicin conjugated to an anti-TROP-2 Fab, with activity in vitro and in vivo against pancreatic cancer [ 111 ].…”

“…A phase I clinical trial with this ADC was performed in 31 patients with a variety of metastatic epithelial cancers [ 109 ]. Nineteen of the patients provided tissue samples for TROP-2 expression, with 13 (68%) having medium to high expression (i.e., ≥50% of tissue cells having 2+ to 3+ staining).…”

Antibody Conjugates-Recent Advances and Future Innovations

“…In order to achieve sufficient efficacy with a relatively low DAR number, potent payloads such as PBD, a MDR1-resistant maytansine payload, and an auristatin payload Aur0101 have been developed. However, the DAR 2 site-specific conjugates with PBD and Aur0101 have shown limited therapeutic index in clinic thus far [173][174][175][176], while the clinical data for the DAR 2 maytansine ADC is pending [177]. While extensive characterization studies have been reported for antibody conjugated to cytotoxic payloads, there is a scarcity of literature on the molecular properties of conjugates with non-toxic small organic molecule payloads and nucleic acids.…”