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|Ref Type||Journal Article|
|Authors||Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Weiss GJ, Sachdev JC, Chadha M, Fulk M, Ejadi S, Mountz JM, Lotze MT, Toledo FG, Chu E, Jeffers M, Peña C, Xia C, Reif S, Genvresse I, Ramanathan RK|
|Title||First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.|
|Journal||Annals of oncology : official journal of the European Society for Medical Oncology|
|Abstract Text||To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL).Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially.Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years.Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL.NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.|
|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|
|PIK3CA||R88L||missense||unknown||PIK3CA R88L lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). R88L has been identified in sequencing studies (PMID: 28002797, PMID: 27672108), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Aug 2020).|
|PIK3CA||T1025K||missense||unknown||PIK3CA T1025K lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). T1025K has been identified in sequencing studies (PMID: 27672108), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Aug 2020).|
|PIK3CA||T1052K||missense||unknown||PIK3CA T1052K lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). T1052K has been identified in the scientific literature (PMID: 31410178, PMID: 21725289, PMID: 27672108), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Jan 2021).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA act mut||breast cancer||sensitive||Copanlisib||Phase I||Actionable||In a Phase I clinical trial, treatment with Aliqopa (copanlisib) resulted in partial response in one and stable disease in another patient with breast cancer harboring activating PIK3CA mutations (PMID: 27672108; NCT00962611).||27672108|
|Unknown unknown||Advanced Solid Tumor||not applicable||Copanlisib||Phase I||Actionable||In a Phase I clinical trial, treatment with Aliqopa (copanlisib) was well-tolerated and demonstrated preliminary activity in patients with advanced solid tumors, with complete response in 2% (1/48), partial response in 4% (2/48), and stable disease in 31% (15/48) of patients (PMID: 27672108).||27672108|