Table 1.

Summary of trials, outcomes and adverse effects associated with PI3K inhibitors in various phases of clinical studies.

Treatment and reference	Phase and NCT	Clinical outcomes	Adverse effects
BKM120/Buparlisib
Buparlisib in combination with Everolimus (Eve) in patients with advanced solid tumors123	I, NCT01470209	The combination was well tolerated and safe in these patients. The MTD and RP2D for Eve and Bup was 5 and 60 mg, respectively, when on continuous daily schedule. There was no evidence of drug–drug interaction with concurrent administration of Eve and Bup. Paired skin biopsies for baseline and cycle 1 patients demonstrated target engagement with modulation of mTOR/PI3K signaling pathway biomarkers. There was a marked reduction in pS6 and p4EBP1 levels in cycle 1 biopsies compared to baseline.	Diarrhea, nausea, hyperglycemia, hypokalemia, muscular pain, anorexia, fatigue and elevated ALT/AST. 7 patients had additional DLTs such as mucositis, acute kidney injury and urinary tract infection. Gr 4 and 5 adverse effects were rarely observed.
Buparlisib in combination with MEK162/Binimetinib in patients with advanced solid tumors124	I, NCT01363232	The combination showed promising activity in patients with ovarian cancer with RAS/BRAF mutation. The MTD for Bup and MEK162 was established at 90 mg/day and 45 mg twice daily dose, respectively. The RP2D for Bup was determined as 80 mg/day and MEK162 45 mg twice daily dose. Other dosing strategies such as pulsatile dosing should be adopted for further trials as continuous dosing led to intolerable toxicities.	Central serous retinopathy, diarrhea, stomatitis, pneumonia, vomiting, nausea, maculopapular rash, increase in ALT and elevation in blood creatine phosphokinase.
Buparlisib in combination with Temozolamide (Tem) and Radiation Therapy in newly diagnosed125 glioblastoma patients	I, NCT01473901	Due to challenging safety profile and inability to achieve the MTD, the sponsor decided not to pursue the use of Bup in newly diagnosed glioblastoma patients.
Buparlisib in combination with mAb targeting EGFR, Panitumumab (Pani) in patients with metastatic/advanced RAS-WT colorectal cancer126	Ib, NCT01591421	The combination of Bup (given 5 days a week) and Pani (6 mg/kg by IV route biweekly) was well tolerated (n = 19). Both drugs were administrated in 3 DLs. The median PFS was 2 months. 9 patients had PD and 7 patients exhibited SD (the median duration was 5.4 months [range: 3.7–8.4 months]). The phase II study was stopped, as the predefined futility rule for response was not achieved.	mucositis, fatigue, palmar-plantar erthrodyesthesia, rash, acneiform, hypomagnesemia and increased AST/ALT.
Buparlisib in combination with tyrosine kinase inhibitor, Imatinib in patients with gastrointestinal stromal tumor for whom treatment failed prior to Imatinib and Sunitinib therapy127	Ib, NCT01468688	The combination failed to provide additional benefits compared to current therapies that are available for these patients (n = 60). Further development of this combination was terminated due to lack of objective response.
Buparlisib in combination Carboplatin or Lomustine in patients with recurrent glioblastoma multiforme128	Ib/II, NCT01934361	The combination did not demonstrate sufficient anti-tumor efficacy compared to single-agent Lom or Carbo. The study did not proceed to phase II trial.
Buparlisib in R/R CLL patients129	II, NCT02340780	Bup demonstrated significant toxicities and further testing of Bup in these patients was ceased (n = 14). The data also indicated that basal raptor expression in CLL patients correlated with clinical response to Bup.
Buparlisib in TNBC patients130	II, NCT01790932 and NCT01629615	No confirmed objective responses were observed and Bup was not associated with a strong clinical efficacy in TNBC patients as a single agent (n = 50).
Buparlisib in combination with LGX818/Encorafenib (BRAF inhibitor) and MEK162/Binimetinib (MEK inhibitor) in patients with advanced BRAFV600-mutant melanoma (LOGIC-2)131	II, NCT02159066	The triple therapy was feasible depending on genetic alterations but low clinical activity was observed (n = 6). Further exploration is needed to identify the patterns of resistance susceptible to use this combination in these patients.
Copanlisib/BAY 80-6946/Aliqopa
Copanlisib plus the MEK inhibitor, Refametinib (Ref) in advanced cancer patients132	I, NCT01392521	In this dose-escalation (n = 49) and expansion (n = 15) study, the MTD was defined at Cop 0.4 mg/kg weekly and Ref 30 mg twice daily dose. There was no drug–drug interaction observed. MEK-ERK inhibition and decreased tumor FDG uptake were reported during treatment. Best response was SD in n = 21 patients.	Fatigue, diarrhea, nausea and acneiform rash. DLTs included oral mucositis increased ALT/AST, rash acneiform, hypertension and diarrhea.
Copanlisib in patients with solid tumors and NHL patients133	I, NCT02155582	PRP pAKT levels demonstrated sustained reductions from baseline post-Cop treatment [median inhibition: 0.4 mg/kg, 73.8% (range-94.9 to 144.0); 0.8 mg/kg, 79.6% (range-96.0 to 408.0)]. Tumor pAKT was lowered versus baseline with Cop 0.8 mg/kg in paired biopsy samples. Dose-related transient plasma glucose elevations were seen. Cop plasma exposure significantly correlated with alterations in plasma pAKT levels and glucose metabolism markers.	Hyperglycemia, fatigue and hypertension.
Copanlisib in Chinese patients134	I, NCT03498430	Cop PK exposure profiles were in the same range as of those from previous studies of Cop in non-Chinese patients in clinical dose of 60 mg. The ORR was 50% (95% CI: 21.1, 78.9) with 6 patients achieving a best response of a PR in 1 patient and SD in 6 patient.	Hyperglycemia, transient hypertension both Gr 3. However, no Gr 4 or Gr 5 adverse events observed.