A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody–drug conjugate, in patients with breast cancer and other advanced solid tumors
| Autor: | Anthony W. Tolcher, Steven Pirie-Shepherd, Robert Wesolowski, Brenda Gibson, Lee S. Rosen, Steven Y. Hua, Kai-Hsin Liao, Raffaele Baffa |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Antibody-drug conjugate Immunoconjugates Maximum Tolerated Dose Nausea Breast Neoplasms Antibodies Monoclonal Humanized Gastroenterology Young Adult 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine Breast cancer Pharmacokinetics Neoplasms Internal medicine Clinical endpoint medicine Humans Tissue Distribution Pharmacology (medical) Receptor Notch3 Aged Retrospective Studies Aged 80 and over Pharmacology business.industry Cancer Middle Aged Prognosis medicine.disease 030104 developmental biology Oncology 030220 oncology & carcinogenesis Toxicity Vomiting Female medicine.symptom business Oligopeptides Follow-Up Studies |
| Zdroj: | Investigational New Drugs. 38:120-130 |
| ISSN: | 1573-0646 0167-6997 |
| Popis: | Background PF-06650808 is a novel anti-Notch3 antibody–drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER+) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER+/PR+/HER2− BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER+ BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC. |
| Databáze: | OpenAIRE |
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