First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors
| Autor: | Alessandro D. Santin, George R. Blumenschein, Raffit Hassan, Johanna C. Bendell, John Nemunaitis, Dirk Laurent, Nenad Sarapa, Annette O. Walter, Stella K. Kim, Shelly Seward, Barrett H. Childs, Kathleen N. Moore, Anish Thomas, Cem Elbi, Hedy L. Kindler, Prabhu Rajagopalan |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research medicine.medical_specialty Immunoconjugates Maximum Tolerated Dose Nausea GPI-Linked Proteins Gastroenterology 03 medical and health sciences 0302 clinical medicine Antineoplastic Agents Immunological Pharmacokinetics Internal medicine Neoplasms medicine Humans Mesothelin Maytansine Progression-free survival Mesothelioma Neoplasm Metastasis Adverse effect Aged biology business.industry ORIGINAL REPORTS Middle Aged medicine.disease Progression-Free Survival Phase I and Clinical Pharmacology 030104 developmental biology Oncology Tolerability 030220 oncology & carcinogenesis Vomiting biology.protein Female medicine.symptom Neoplasm Recurrence Local business |
| Zdroj: | Journal of Clinical Oncology |
| ISSN: | 1527-7755 |
| Popis: | PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies. |
| Databáze: | OpenAIRE |
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