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Ref Type Journal Article
PMID (26787751)
Authors Dolly SO, Wagner AJ, Bendell JC, Kindler HL, Krug LM, Seiwert TY, Zauderer MG, Lolkema MP, Apt D, Yeh RF, Fredrickson JO, Spoerke JM, Koeppen H, Ware JA, Lauchle JO, Burris HA, de Bono JS
Title Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 12
Date 2016 Jun 15
URL
Abstract Text This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases.Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed.Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas).Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874-84. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown malignant pleural mesothelioma not applicable GDC-0980 Phase I Actionable In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in a partial response in 7.4% (2/27) and stable disease in 74.1% (20/27) of malignant pleural mesothelioma patients, including one with PTEN loss and another with PIK3CA E545K (PMID: 26787751). 26787751
PIK3CA mutant Advanced Solid Tumor sensitive GDC-0980 Phase I Actionable In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in partial response in 21% (3/14) and stable disease in 57% (8/14) of patients with advanced solid tumors harboring PIK3CA mutations (PMID: 26787751). 26787751
PIK3CA E542K head and neck squamous cell carcinoma sensitive GDC-0980 Phase I Actionable In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in a partial response in a patient with head and neck squamous cell carcinoma harboring a PIK3CA E542K mutation (PMID: 26787751). 26787751
Unknown unknown peritoneal mesothelioma not applicable GDC-0980 Phase I Actionable In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in tumor regression in two patients with peritoneal mesothelioma (PMID: 26787751). 26787751
PIK3CA R88Q malignant pleural mesothelioma sensitive GDC-0980 Phase I Actionable In a Phase I trial, treatment with Apitolisib (GDC-0980) resulted in a partial response in a patient with malignant pleural mesothelioma harboring PIK3CA R88Q (PMID: 26787751). 26787751
PIK3CA E545K Advanced Solid Tumor sensitive GDC-0980 Phase I Actionable In a Phase I trial, Apitolisib (GDC-0980) resulted in a partial response in two patients, one with head and neck squamous cell carcinoma and another with ovarian cancer, both harboring PIK3CA E545K (PMID: 26787751). 26787751
Unknown unknown ovarian clear cell carcinoma not applicable GDC-0980 Phase I Actionable In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in tumor regression by 48.3% in a patient with ovarian clear cell carcinoma (PMID: 26787751). 26787751