A Phase I Study of Safety, Pharmacokinetics, and Pharmacodynamics of Concurrent Everolimus and Buparlisib Treatment in Advanced Solid Tumors
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American Association for Cancer Research Inc.
Abstract
Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. Patients and Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. Results: We enrolled 43 patients, median age of 63 (range, 39–78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8–4.2) and 9 (6.4–13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic. Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule. © 2020 American Association for Cancer Research.
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Adult, Aged, Aminopyridines, Antineoplastic combined chemotherapy protocols, Everolimus, Female, Follow-up studies, Humans, Male, Maximum tolerated dose, Middle aged, Morpholines, Neoplasms, Prognosis, Survival rate, Tissue distribution, Buparlisib, Mammalian target of rapamycin, Phosphatidylinositol 3 kinase, Aminopyridine derivative, Antineoplastic agent, Morpholine derivative, Nvp-bkm120, Acute kidney failure, Akt signaling, Anemia, Anorexia, Anxiety disorder, Area under the curve, Article, Black person, Bladder cancer, Blood analysis, Body weight loss, Breast cancer, Cancer chemotherapy, Cancer growth, Cancer patient, Cancer survival, Caucasian, Cellulitis, Clinical article, Cohort analysis, Colorectal cancer, Concentration at steady-state, Constipation, Coughing, Dehydration, Diarrhea, Dizziness, Drug safety, Dry eye, Dyspepsia, Dyspnea, Dysuria, Ear infection, Edema, Erectile dysfunction, Fatigue, Fever, Gastroenteropancreatic neuroendocrine tumor, Headache, Human, Human tissue, Hyperbilirubinemia, Hypercholesterolemia, Hyperglycemia, Hypertension, Hypertransaminasemia, Hypertriglyceridemia, Hyperuricemia, Hypoalbuminemia, Hypocalcemia, Hypokalemia, Hypomagnesemia, Hyponatremia, Hypophosphatemia, Hypotension, Insomnia, Leukopenia, Lung cancer, Lung embolism, Maximum concentration, Memory disorder, Mucosa inflammation, Multiple cycle treatment, Musculoskeletal pain, Nausea, Neuropathy, Neutropenia, Nocturia, Nose obstruction, Oral mucositis, Ovary cancer, Overall survival, Parainfluenza virus infection, Pharmacokinetic parameters, Phase 1 clinical trial, Phase 2 clinical trial, Pneumonia, Priority journal, Progression free survival, Pruritus, Rash, Rectum hemorrhage, Respiratory failure, Salivary gland cancer, Sepsis, Side effect, Skin biopsy, Soft tissue sarcoma, Solid malignant neoplasm, Thrombocytopenia, Thymus cancer, Thyroid cancer, Tongue swelling, Treatment response, Upper respiratory tract infection, Urinary tract infection, Vagina bleeding, Clinical trial, Follow up, Neoplasm, Pathology