Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	12	2016 Jun 15	2874-84	Clin Cancer Res

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
PIK3CA E545K	head and neck squamous cell carcinoma	predicted - sensitive	Apitolisib	Case Reports/Case Series	Actionable	In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in an unconfirmed partial response in a patient with head and neck squamous cell carcinoma harboring PIK3CA E545K (PMID: 26787751; NCT00854152).	26787751
PIK3CA E545K	ovarian clear cell carcinoma	predicted - sensitive	Apitolisib	Case Reports/Case Series	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 harboring PIK3CA E545K, who remained on treatment for 282 days (PMID: 26787751; NCT00854152).	26787751
PIK3CA E542K	head and neck squamous cell carcinoma	predicted - sensitive	Apitolisib	Case Reports/Case Series	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; NCT00854152).	26787751
PIK3CA R88Q	malignant pleural mesothelioma	predicted - sensitive	Apitolisib	Case Reports/Case Series	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; NCT00854152).	26787751
PIK3CA mutant	Advanced Solid Tumor	predicted - sensitive	Apitolisib	Case Reports/Case Series	Actionable	In a Phase I trial, Apitolisib (GDC-0980) treatment resulted in a partial response in 21% (3/14) and stable disease in 64% (9/14) of patients with advanced solid tumors harboring PIK3CA mutations (PMID: 26787751; NCT00854152).	26787751