A phase Ib open-label dose escalation study of the safety, pharmacokinetics, and pharmacodynamics of cobimetinib (GDC-0973) and ipatasertib (GDC-0068) in patients with locally advanced or metastatic solid tumors
| العنوان: | A phase Ib open-label dose escalation study of the safety, pharmacokinetics, and pharmacodynamics of cobimetinib (GDC-0973) and ipatasertib (GDC-0068) in patients with locally advanced or metastatic solid tumors |
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| المؤلفون: | Ilsung Chang, Johanna C. Bendell, Raymond D. Meng, Premal Patel, Sandra M. Sanabria-Bohórquez, Daniel C. Cho, Patricia LoRusso, Matthew Wongchenko, Geoffrey I. Shapiro, Iris T. Chan, Yibing Yan, Luna Musib |
| المصدر: | Investigational New Drugs. 39:163-174 |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Pharmacology, Oncology, Cobimetinib, medicine.medical_specialty, business.industry, Endometrial cancer, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Breast cancer, Tolerability, Pharmacokinetics, chemistry, 030220 oncology & carcinogenesis, Internal medicine, Pharmacodynamics, medicine, Pharmacology (medical), business, Ovarian cancer, Adverse effect |
| الوصف: | Background: This Phase Ib study explored combination dosing of the allosteric MEK1/2 inhibitor cobimetinib and the ATP-competitive pan-AKT inhibitor ipatasertib. Methods: Patients with advanced solid tumors were enrolled to two dose escalation arms, each using a 3 + 3 design in 28-day cycles. In Arm A, patients received concurrent cobimetinib and ipatasertib on days 1–21. In Arm B, cobimetinib was administered intermittently with ipatasertib for 21 days. Primary objectives evaluated dose-limiting toxicities (DLTs), maximum tolerated doses (MTD), and the recommended Phase II dose (RP2D). Secondary objectives included analysis of pharmacokinetic parameters, MAPK and PI3K pathway alterations, changes in tissue biomarkers, and preliminary anti-tumor efficacy. Expansion cohorts included patients with PTEN-deficient triple-negative breast cancer and endometrial cancer. Results: Among 66 patients who received ≥1 dose of study drug, all experienced an adverse event (AE). Although no DLTs were reported, 6 patients experienced Cycle 1 DLT-equivalent AEs. The most common treatment-related AEs were diarrhea, nausea, vomiting, dermatitis acneiform, and fatigue. Thirty-five (53%) patients experienced drug-related AEs of ≥ grade 3 severity. Cobimetinb/ipatasertib MTDs were 60/200 mg on Arm A and 150/300 mg on Arm B; the latter was chosen as the RP2D. No pharmacokinetic interactions were identified. Biomarker analyses indicated pathway blockade and increases in IFNγ and PD-L1 gene expression following the combination. Three patients with endometrial or ovarian cancer achieved partial response, all with PTEN-low disease and two with tumor also harboring KRAS mutation. Conclusion: There was limited tolerability and efficacy for this MEK and AKT inhibitor combination. Nonetheless, pharmacodynamic analyses indicated target engagement and suggest rationale for further exploration of cobimetinib or ipatasertib in combination with other anticancer agents. ClinicalTrials.gov identifier: NCT01562275. |
| تدمد: | 1573-0646 0167-6997 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::b9452c83b98676f0b80dbf0103f07238Test https://doi.org/10.1007/s10637-020-00975-6Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi...........b9452c83b98676f0b80dbf0103f07238 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15730646 01676997 |
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