Table 3.

Summary of trials, outcomes and adverse events associated with dual PI3K/mTOR inhibitors in various phases of clinical studies.

Treatment	Status	Sponsor	Phase and NCT	Clinical Outcomes	Adverse Effects
Dactolisib/BEZ-235/NVP-BEZ235
Dactolisib in patients with advanced solid tumors [402]	Completed	SCRI Development Innovations, LLC in collaboration with Novartis Pharmaceuticals	I, NCT01343498	Dactolisib was well tolerated but demonstrated limited clinical response (n = 12). The MTD and R2PD were identified at 300 mg BID. PK parameters (day 28): The AUC(0–24) was 10028.3 ng × h/mL (range: 3228.8–49640 ng × h/mL). The Cmax and Tmax were 655.6 ng/mL (range: 232–2700 ng/mL) and 2 h (range 0–4 h), respectively. There was a consistent increase in Cmax and AUC with BID versus QD dosing schedule. At MTD, the median decrease in the standardized uptake value for 18F-FDG was 42% (rang: 6–67%). No PR and CR were reported. 45% of patients demonstrated SD.	Diarrhea, mucositis, nausea, hyperglycemia, anorexia and thrombocytopenia.
Dactolisib in adult Japanese patients with advanced solid tumors [403]	Completed	Novartis Pharmaceuticals	I, NCT01195376	35 Japanese patients were enrolled and received at least one dose of Dactolisib with either a QD (n = 27) or BID (n = 8) dosing schedule. The MTD was not reached. 2 DLTs including allergic reaction and thrombocytopenia were observed at 1200 and 1400 mg QD, respectively, while liver dysfunction was reported as a DLT at 400 mg BID. The maximum clinically tolerable dose was 1200 mg and the R2PD was 1000 mg QD. The median duration of exposure for QD and BID dosing was 56 days (range: 2–280 days) and 43.5 days (range: 21–115 days), respectively. As per RECIST v1.0 criteria, no CRs and PRs were observed. 14/27 (51.9%) patients evaluated for response demonstrated SD. Cmax and AUC increased in a dose-dependent manner. In patients treated with 400 mg QD Dactolisib, a 50% reduction in pS6 levels was observed.	Diarrhea, decreased appetite, nausea, stomatitis, vomiting, fatigue, liver dysfunction and thrombocytopenia.
Dactolisib in Everolimus resistant patients with advanced pancreatic neuroendocrine tumors [404]	Completed	Novartis Pharmaceuticals	II, NCT01658436	Dactolisib was poorly tolerated in these patients when treated using a 400 and 300 mg BID dosing schedule (n = 31). Best response at 16 weeks was SD in 16 (51.6%) patients, PD in 9 (29.0%) patients and unknown in six (19.4%) patients. The estimated 16 week PFS rate was 51.6% (90% CI: 35.7–67.3%). The study did not proceed to stage II of the trial. The efficacy of Dactolisib was limited due to high intra- and inter-patient PK variability. The drug demonstrated a challenging toxicity profile.	Diarrhea, nausea, hyperglycemia, stomatitis and vomiting.
Apitolisib/GDC-0980/RG7422
Apitolisib in patients with refractory solid tumors or NHL [405]	Completed	Genentech, Inc.	I, NCT00854152	Patients (n = 120) received 2–70 mg of Apitolisib on days 1–21 or 1–28 of 28 day cycles. Apitolisib demonstrated durable anti-tumor activity with a narrow therapeutic window and dose-proportional PK, PD effects (>90% suppression of the surrogate biomarker, platelet pAKT levels and decreased FDG-PET tumor uptake) with target modulation observed in patients treated with >16 mg dose. Stage I of the trial involved dose escalation to estimate MTD and stage II was dose expansion to establish the R2PD. The R2PD and MTD, respectively, were identified at 40 mg QD on a 28/28 dosing schedule except for malignant pleural mesothelioma (MPM) patients and 50 mg QD on a 21/28 dosing schedule. DLTs observed were Gr 4 fasting hyperglycemia at 40 mg (21/28-schedule) and Gr 3 maculopapular rash and Gr 3 fasting hyperglycemia at 70 mg (21/28-schedule). Apitolisib was rapidly absorbed and mean plasma concentration peaked after 1–2 h. The mean terminal elimination T1/2 was 11.3 h (range: 3.26–45.4 h). The drug accumulation was very low. The AUC showed dose proportionality. According to RECIST criteria, in stage I, 4/56 patients demonstrated PR and 2/56 patients demonstrated CR. 77% of patients demonstrated SD. Patients demonstrated tumor shrinkage and no PIK3CA mutations or loss of PTEN was identified. In stage II, 5/64 patients demonstrated PR and the median time for study was 2.9 months (range: 1–21.2 months). SD with tumor regression was observed in 20 patients treated with 40 mg drug.	Thrombocytopenia, neutropenia, hyperglycemia, hypercholesterolemia, increased AST/ALT, pneumonitis, rash, fatigue and mucosal inflammation.
Apitolisib in patients with metastatic renal cell carcinoma who progressed on or after VEGF-targeted therapy [406]	Completed	Genentech, Inc.	II, NCT01442090	Patients (n = 85) were randomized to receive Apitolisib at 40 mg QD or Everolimus 10 mg QD. The median PFS of Apitolisib versus Everolimus was 3.7 versus 6.1 months; hazard ratio, 2.12 (95% CI: 1.23–3.6). The ORR was 7.1% for Apitolisib versus 11.6% for Everolimus. Apitolisib PK profile indicated a direct relationship between exposure and adverse effects including rash and hyperglycemia. Retrospective biomarker analyses indicated a relationship between VHL mutation status and clinical outcome with Everolimus but not with Apitolisib dosing. High HIF-1α protein expression was associated with better outcome in both treatment arms. Apitolisib associated with higher-grade hyperglycemia and rash was less effective than Everolimus in this trial. This could be due to full blockade of PI3K/mTOR signaling which resulted in multiple on-target adverse events.	-
Apitolisib in patients with recurrent/persistent endometrial carcinoma (MAGGIE study) [407]	Completed	Genentech, Inc.	II, NCT01455493	56 patients including 23% of patients with well-controlled diabetes received oral Apitolisib at a dose of 40 mg QD during 28 day cycles until disease progression or intolerable toxicity occurred. The median duration of treatment was 57 days (range: 4–500 days). The six month PFS and median PFS rates were 20% (95% CI: 7–33%) and 3.5 months (95% CI: 2.7–3.7 months), respectively. The median OS was 15.7 months (95% CI: 9.2–17 months). The ORR was 6%. 3.6% and 1.8% of patients demonstrated CR and PR, respectively. 67% of patients had atleast 1 alteration in the PI3K pathway. Complete loss of PTEN and missense mutations in PIK3CA were found in 11% and 28% of patients, respectively. 24% of patients demonstrated concomitant PI3K pathway activating alterations. 5 of the patients who responded to the treatment had alterations in either PIK3CA, PTEN, AKT1 or ERBB2 genes. The anti-tumor activity observedat 40 mg QD Apitolisib was limited by tolerability mostly in diabetic patients.	Hyperglycemia, rash, fatigue, nausea, stomatitis, decreased appetite, vomiting, colitis and pneumonitis
Gedatolisib/PF-05212384/PKI-587
Gedatolisib in combination with Cisplatin and other anti-tumor agents in TNBC patients [408]	Completed	Pfizer	I, NCT01920061	Gedatolisib could be safely administered in combination with Docetaxel, Cisplatin or Dacomitinib and had a manageable toxicity profile in these patients (n = 52). MTD could not be determined. The 3 study groups were: Arm A: Gedatoilisib + Docetaxel Arm B: Gedatolisib + Cisplatin Arm C: Gedatolisib + Dacomitinib No DLTs were seen in arms A or B; in arm C, DLTs observed included Gr 3 mucositis, pneumonitis, rash and Gr 2 fatigue (<75% of planned dose received).	Mucositis, nausea, neutropenia, decreased appetite, diarrhea, dermatitis acneiform, rash, neutropenia, vomiting and hypomagnesaemia.
Gedatolisib in combination with Paclitaxel and Carboplatin in patients with advanced solid tumors (IOSI-NDU-001) [409]	Completed	Oncology Institute of Southern Switzerland	I, NCT02069158	Gedatolisib demonstrated an acceptable safety profile when administrated weekly in combination with Carboplatin and Paclitaxel in these patients (n = 17). The RP2D for Gedatolisib was 110 mg/m2 IV and Paclitaxel 80 mg/m2 IV. 65% of patients achieved an objective response. 47% and 18% of patients achieved a PR and CR, respectively. 17% of patients demonstrated SD. DLTs were observed in 4/16 evaluable patients which included two (Gr 2 and Gr 3 neutropenia) at 110 mg/m2, two (Gr 2 and Gr 3 mucositis) at 130 mg/m2 and no DLT at 110 mg/m2. Anti-tumor activity was observed in 8 out of 10 patients with clear cell ovarian cancer.	Neutropenia, fatigue, thrombocytopenia, hypokalemia, peripheral neuropathy, hypomagnesemia, colitis and aortic intramural hematoma.
Gedatolisib in patients with advanced solid tumors [410]	Completed	Pfizer	I, NCT00940498	Gedatolisib had a manageable safety profile with an anti-tumor activity in these patients (n = 78). The MTD and RP2D for Gedatolisib was 154 mg (administered via IV route once weekly). Majority of the patients had received surgery and radiotherapy along with systemic anti-neoplatic treatments. Heavily pretreated patient population demonstrated anti-tumor activity. Mean plasma Gedatolisib concentration on single-dose administration declined rapidly in 4–24 h and more slowly for next 25–168 h. Cmax and AUC increased proportionally with increasing dose of Gedatolisib. On multiple Gedatolisib administration, a biphasic concentration-time curve with a slower concentration decline in first 24 h for Gedatolisib was observed. The mean T1/2 values was identified at 33–41 h across all dose levels. T1/2 was ~36 h in the MTD group. The objective tumor response rate was 2.6%. The CBR was 13%. 10.4% of patients had an SD lasting for more than 6 months. Paired tumor biopsies indicated that Gedatolisib inhibited downstream effectors of the PI3K pathway. For patients treated at MTD, there was a 10.6% reduction in pAKT Ser473 levels as compared to baseline.	Stomatitis, muscosal inflammation, vomiting, fatigue, hyperglycemia, nausea, vomiting, constipation, increased AST/ALT, asthenia and decreased appetite.
Gedatolisb in combination with PTK7-ADC (Wnt pathway inhibitor) in metastatic TNBC patients [411]	Completed	Indiana University	I, NCT03243331	Patients with metastatic TNBC or low estrogen expressing breast cancer were enrolled. The primary objective of the trial was to evaluate the safety of Gedatolisib (administered weekly at 110 mg or 180 mg via IV route) in combination with PTK7-ADC (administered every 3 weeks at 1.4 mg/kg or 2.8 mg/kg dose) and the secondary objective was to determine the efficacy of this drug combination assessed by ORR, CBR and PFS.	-
Samotolisib/LY3023414
Samotolisib in Japanese patients with advanced cancer [412]	Completed	Eli Lilly and Company	I, NCT02536586	Samotolisib upto 200 mg BID was safe and tolerable in the Japanese patients (n = 12). No DLTs were seen in 3 patients enrolled on the 150 mg dosing schedule. However, 2/9 patients who received 200 mg Samotolisib BID experienced DLTs (Gr 3 stomatitis). Samotolisib was rapidly absorbed and eliminated. The Cmax and Tmax at day 15 for group treated with 200 mg Samotolisib (n = 7) was 1010 ng/mL and 1.97 h (range: 0.97–2.95 h), respectively. The T1/2 for this cohort was 1.83 h (range: 1.47–2.64 h). The AUC(0–tlast) and AUC(0–∞) was 4100 ng × h/mL and 4210 ng × h/mL, respectively. According to RECIST v1.1 criteria, no CR and PR were observed. The DCR was 55.6% and 5 patients had best overall response. Samotolisib increased fasting glucose levels and C-peptide post-administration.	Stomatitis, nausea, diarrhea, decreased platelet count, decreased appetite, hyperglycemia, hypophosphatemia, anemia, vomiting and rash.
Samotolisib in combination with Enzalutamide in men with mCRPC after progression on Abiraterone [413]	Completed	Eli Lilly and Company	II, NCT02407054	The combination of Samotolisib (200 mg BID) and Enzalutamide (160 mg QD) was tolerable and had a clinically manageable safety profile. In the two cohorts: Samotolisib + Enzalutamide (n = 65): The median PCWG2-PFS was 3.7 months. The PFS for AR-V7-positive and -negative patients was 5.5 months and 13.2 months, respectively. 20% of patients had more than a 50% reduction in PSA. Placebo + Enzalutamine (n = 64): The median PCWG2-PFS was 2.96 months (hazard ratio: 0.66; 95% CI: 0.43–0.99; p = 0.02085). The PFS for AR-V7-positive and -negative patients was 3.6 months (hazard ratio: 0.52; 95% CI:0.28–0.95; p = 0.028) and 5.3 months (hazard ratio: 0.99; 95% CI: 0.27–3.63; p = 0.991), respectively. 25% of patients had more than a 50% reduction in PSA.	Diarrhea, nausea and fatigue.
Samotolisib in patients with advanced cancer [414]	Active, not recruiting	Eli Lilly and Company	I, NCT01655225	Samotolisib (200 mg BID) was well tolerated and had a manageable safety profile in patients with advanced mesothelioma (n = 42). The median duration of treatment was 11.2 weeks (range: 1.1–53 weeks). The median PFS was 2.83 months (95% CI: 2.53–3.98 months). According to RECIST criteria, the ORR and DCR were 2.4% and 43%, respectively. 41% of patients exhibited SD. The mean apparent clearance and volume of distribution were 71.2 L/h and 159 L, respectively, which led to a short T1/2 of 1.55 h. Alterations in BAP1 (11/19 patients), NF2 (5/19 patients) and SETD2 (5/19 patients) genes were observed. The most common reason for study discontinuation was PD (48%).	Fatigue, nausea, vomiting, hyperglycemia, rash, decreased appetite and diarrhea.
Bimiralisib/PQR309
Bimiralisib in patients with advanced solid tumors [415]	Completed	PIQUR Therapeutics AG in collaboration with Roswell Park Cancer Institute M.D. Anderson Cancer Center Mayo Clinic Hospital Clinic of Barcelona University College London Hospitals Churchill Hospital Case Western Reserve University University Hospital, Zürich	I, NCT02483858 and NCT01940133	41 patients were enrolled and administrated. As per two compartmental analysis, the absorption rate was 2.1 h−1, the absorption time lag was 0.4 h, the clearance rate was 4.2 L/h, the central volume was 84.4 L and the peripheral volume 211.9 L. The mean Cmax at steady state for the 80 and 100 mg dosing groups were found to be 0.96 μg/mL and 1.46 μg/mL, respectively, and the mean AUC24h at steady state was identified to be 16.28 μg h mL−1 and 23 μg h mL−1, respectively. The T1/2 was establsihed at 51 h. Compared to a typical 70 kg patient, the Cmax was 27% higher for a 50 kg patient and 20% lower for a 100 kg patient at a steady state.	-
Bimiralisib in patients with advanced solid tumors [416]	Completed	PIQUR Therapeutics AG	I, NCT01940133	28 patients were enrolled and received QD Bimiralisib at range of 10–150 mg. The Cmax and AUC(0–last) increased with increasing doses of Bimiralisib in a roughly dose-proportional manner. The T1/2 was estimated to be ~40 h from the 0–24 h profile. The MTD and RP2D of Bimiralisib were defined as 80 mg QD for patients with activating PIK3CA mutations. There was no significant upregulation or downregulation of PI3K/mTOR-related mRNAs at transcriptional levels although there was a trend of PDGFRA upregulation post-21 days of Bimiralisib treatment. However, there was a significant inhibition of several PI3K/mTOR-associated phosphoproteins. Gr 3 or Gr 4 DLTs were seen in 13 (46%) and 3 (11%) patients, respectively.	Fatigue, nausea, hyperglycaemia, constipation, diarrhea, anorexia, rash and vomiting.
Paxalisib/GDC-0084/RG7666
Paxalisib in patients with progressive or recurrent high-grade glioma [417]	Completed	Genentech, Inc	I, NCT01547546	47 patients enrolled in 8 dose-escalation cohorts (2-65 mg QD). DLTs observed included Gr 2 bradycardia, Gr 3 myocardial ischemia at 15 mg, Gr 3 stomatitis at 45 mg and 2 cases of Gr 3 mucosal inflammation at 65 mg. The MTD was established at 45 mg QD. PK analysis indicated linear and dose-proportional enhancement in exposure, with a T1/2 ~19 h associated with QD schedule. At steady-state concentrations (45 mg), consistent anti-tumor activity was observed in xenograft models. On FDG-PET, 5 of 27 (18.5%) evaluable patients showed a metabolic PR. At doses ≥45 mg QD, decreased median SUV in normal brain was observed, indicating CNS penetration of Paxalisib. Of all the evaluable patients, 26 patients (55.3%) had a best overall response of PD, 19 patients (40.4%) had SD.	Hyperglycemia, fatigue, nausea, rash, hypophosphatemia, hypertriglyceridemia, diarrhea, decreased appetite and stomatitis
Voxtalisib/XL765/SAR245409
Voxtalisib in combination with Letrozole in HR+, HER2- MBC patients refractory to non-steroidal aromatase inhibitor [231]	Completed	Sanofi	I/II, NCT01082068	The combination had an acceptable safety profile (n = 35) but showed limited efficacy in these pateints. The MTD of Voxtalisib plus Letrozole was identified as 50 mg BID (Voxtalisib) and 2.5 mg QD (Letrozole). 1 DLT, Gr 3 rash was seen in Voxtalisib 50 mg BID treatment group. The median PFS and PFS rate at six months was 7.9 weeks (90% CI: 7.1–15.7 weeks) and 2% (90% CI: 1.4–22.3%), respectively. No patient had an objective response. 22% of patients had PFS at 24 weeks. 31% and 46.2% of patients had SD and PD, respectively. No association between efficacy and PIK3CA mutations was established. Voxtalisib did not show any drug–drug interaction with Letrozole.	Rash, increased AST/ALT, diarrhea, hyperglycemia, pruritus, lymphopenia, nausea, vomiting and fatigue.
Voxtalisib in patients with advanced solid tumors [418]	Completed	Sanofi	I, NCT00485719	Total n = 83 patients were enrolled and 52 patients received Voxtalisib 15–120 mg BID and 70–100 mg QD. Voxtalisib had a manageable safety profile and was efficient in inhibiting PI3K/mTOR signaling. The MTD was established at 90 mg QD or 50 mg BID. The median duration of treatment was 41 days (range: 4–371 days). 24% of patients demonstrated SD. Voxtalisib showed a relatively short plasma T1/2 of 2.96–7.52 h. Voxtalisib in both a once- or twice-a-day dosing schedule showed similar PK profiles. In addition, most of Voxtalisib got cleared from plasma in 12 or 24 h. The Tmax of voxtalisib was identified at 1–4 h. Voxtalisib treatment also increased plasma insulin levels in these patient populations. pAKTT308, pAKTS473 and pEBP1 levels were reduced by 45% to 88%; 45% to 94% and 55% to 89%, respectively, in paired tumor biopsises. The best overall response was SD in 24 of 50 evaluable patients (48%) and 7 patients demonstrated tumor regression. No relationship could be establsihed between tumor molecular alterations and clinical outcomes associated with Voxtalisib treatment in this patient population.	Nausea, diarrhea, hyperglycemia, decreased appetite, fatigue, rash, dry skin, asthenia, vomiting and increased AST/ALT.
Voxtalisib in combination with Erlotinib in patients with advanced solid tumors [419]	Completed	Sanofi	I, NCT00777699	46 patients with advanced solid tumors were enrolled, which included n = 37 lung cancer patients who had prior anti-EGFR therapy. Voxtalisib was administrated in a 30, 50, 70, or 90 mg QD or 20/30 mg BID dosing schedule in combination with 100 mg QD Erlotinib, in a 28 day cycle. The median duration of treatment for Voxtalisib and Erlotinib was 56 (range, 0–346) and 70 (range, 9–360) days, respectively. MTDs were identified as 70 mg QD Voxtalisib in combination with 100 mg QD Erlotinib in cohort 1, and Voxtalisib (20 mg BID) plus Erlotinib (100 mg QD) in cohort 2. The MTDs in both cohorts were below the RP2D of Voxtalisib (90 mg QD or 50 mg BID) and below the registered dose of Erlotinib (150 mg QD). Best overall response was SD found in 12/32 (37.5%) of the patients. When Voxtalisib was administered in combination with Erlotinib, Voxtalisib was absorbed with median Tmax and T1/2 of 1.6–2 h and 4.3–8.03 h, respectively. Increased dosing of Voxtalisib enhanced the AUC and Cmax proportionally. Molecular profiling of tumor samples of these patients identified mutations in PIK3CA, EGFR, KRAS, TP53 and LKB1 genes. Suppression of PI3K and EGFR/MAPK pathway biomarker expression were increased over time post-treatment as follows pAKTT308: 40–73%; p4EBP1T70: 43–67%; pEGFRY1045: 31–62%; and pERKT202/Y204: 37–75%.	Diarrhea, nausea, rash, stomatitis, vomiting, elevated AST/ALT and photophobia.
Voxtalisib in patients with solid tumors [420]	Completed	Sanofi	I, NCT01596270	49 patients were enrolled and received Voxtalisib treatment as follows: 3 patients in the 50 mg QD cohort, 17 patients in the 60 mg QD cohort, 12 patients in the 70 mg QD cohort, 7 patients in the 50 mg BID cohort, 6 patients in the 40 mg BID cohort and 4 patients in the 30 mg BID dosing cohort, respectively. The median duration of treatment in the QD cohorts was 5.9 weeks (range, 0.9–8.1) and the median duration of treatment in in the BID cohorts was 7.7 weeks (range, 0.9–8.1). The MTD of Voxtalisib was established as 40 mg BID and 60 mg QD. Of 31 and 16 patients evaluable for anti-tumor activity in the QD and BID cohorts, respectively, 9/31 patients (29%) and 8/16 patients (50%) had SD as best response. Voxtalisib exhibited a linear PK profile, with an increase in plasma concentration with increased dosing. Voxtalisib showed no significant accumulation owing to its short T1/2 of 3–4 h. Drug accumulation with BID dosing was greater versus QD dosing regimen. High variability in Cmax and AUC values was observed. Administration of Voxtalisib with food decreased drug exposure. Overall, Voxtalisib had a manageable safety profile in these patients.	Fatigue, nausea, diarrhea, maculopapular rash, dyspnea, decrease in appetite, anemia and hyponatremia.
Voxtalisib in combination with a MEK inhibitor, Pimasertib in patients with advanced or metastatic solid tumors [421]	Completed	EMD Serono in collaboration with Sanofi	I, NCT01390818	146 patients with advanced cancer were treated, which included 63 patients in the dose escalation and 83 patients in the expansion part of the study. The MTD was identified as Pimasertib 90 mg QD and Voxtalisib 70 mg QD. The RP2D was established at 60 mg Pimasertib and 70 mg Voxtalisib. The best overall responses included a CR in one patient (1%), PR in 5 patients (5%), SD in 51 patients (46%) and PD in 45 patients (41%). At the RP2D, 74 patients needed dose interruption (73%), 20 patients had dose reduction (20%) and 26 had discontinued treatment because of TEAEs (26%). Both drugs were absorbed rapidly and had a median Tmax ~ 1–2 h each. Voxtalisib PK profile demonstrated close proportionality as compared to Pimasertib in the daily regimens. The half-lives using daily dosing schedule were similar across both the groups in the dose-escalation part of the study. The half-lives were 4.3 to 6.1 h on day 1 and 5.5 to 7.2 h on day 15 for Pimasertib; and 3.1 to 3.6 h on day 1 and 3.4 to 5.2 h on day 15 for Voxtalisib treatment, respectively. There was variable accumulation across doses by day 15 post-QD Pimasertib and no known accumulation was seen with Voxtalisib administration. Pimasertib dosing reduced Voxtalisib exposure AUC(0–t) by 11% (90% CI: 67.0–118.8) and Voxtalisib treatment enhanced Pimasertib exposure AUC(0–t) upto ~49% (90% CI: 106.2–208.9). No CR or PR was achieved; therefore no conclusion could be drawn in terms of the correlation between clinical activity of Voxtalisib and mutational profile for predictive genomic markers involving BRAF, KRAS, NRAS, or PIK3CA mutationsin the patient dosed at RP2D. In addition, near complete suppression of both pERK and pS6 expression was identified across for both drugs at most of the dosing interval. Overall, the combination of Voxtalisib with Pimasertib demonstrated poor long-term tolerability and limited anti-tumor activity in these patients (n = 146).	TEAEs were diarrhea, fatigue and nausea.
Voxtalisib in combination with Temozolamide (TMZ) ± radiotherapy (RT) in patients high-grade glioma [422]	Completed	Sanofi	I, NCT00704080	Total n = 54 patients were enrolled and received Voxtalisib 30–90 mg QD or 20–50 mg BID in combination with 200 mg/m2 IV TMZ (n = 49), or Voxtalisib 20 mg QD with 75 mg/m2 IV TMZ and RT (n = 5). The combination had a favorable safety profile in these patients with DLTs reported in 7 patients (13%). The MTDs for Voxtalisib in combination with 200 mg/m2/day TMZ were established at 90 mg QD and 40 mg BID dosing. However, the MTD of Voxtalisib plus RT and TMZ treatment could not be determined. The best overall response included PR and SD in 2/47 (4%) and 32/47 (68%) of the patients, respectively evaluated for response. The Tmax for Voxtalisib and Voxtalisib plus Temozolamide was 0.75–2 h (range: 0.5–4 h) and 1.5–6 h (range: 1–8 h), respectively. Compared with cycle 1 day 1, the mean Cmax and AUCτ on cycle 1 day 22 were 1.4-fold and 1.5-fold higher, respectively, for QD dosing and 1.7-fold and 1.4-fold higher, respectively, for BID dosing of Voxtalisib. The mean Cmax of TMZ on cycle 1 day 1 post-200 mg/m2/day TMZ administration plus different doses of Voxtalisib, ranged from 3650 ng/mL to 8490 ng/mL and achieved a median Tmax of 1.50–6.00 h (range 1.00–8.00 h). The mean TMZ AUC(0–24) ranged from 24,800 to 35,900 ng × h/mL when administered in combination with Voxtalisib. Voxtalisib in combination with TMZ demonstrated moderate inhibition (31–49%) of PI3K/mTOR signaling.	Fatigue, nausea, diarrhea, maculopapular rash, thrombocytopenia, increased AST/ALT, lymphopenia and decreased platelet counts.
Voxtalisib in patients with recurrent glioma who were surgical resection candidates [423]	Completed	Sanofi	I, NCT01240460	Total n = 21 patients enrolled in cohort 1 (n = 6), 2 (n = 6) and 3 (n = 7), received Voxtalisb at 50 mg BID, 200 mg QD and 90 mg QD, respectively for >10 days prior to tumor resection and were evaluated for PK/PD analysis. PK analyses indicated a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2, respectively. Voxtalisib when administered in a 50 mg BID or 90 mg QD dosing schedule demonstrated higher distribution in CNS of these patients along with an acceptable safety profile. Treatment with Voxtalisib decreased pS6K1 levels and Ki67 expression as revealed by IHC staining.	-
Voxtalisib in combination with Rituximab and Bendamustine in patients with R/R B-cell malignancies [424]	Completed	Sanofi	I, NCT01403636	Total n = 37 patients enrolled and received Voxtalisib in combination with Rituximab plus Bendamustine in 3 treatment arms. Arm A: iNHL, MCL or CLL patients (n = 15) received Rituximab (375 mg/m2 IV) weekly on days 1, 8, 15 and 22 of a 28 day cycle for 2 cycles and increasing doses of Voxtalisib (30 or 50 mg BID orally). Arm B1: iNHL or MCL patients (n = 8) received fixed doses of Bendamustine (initially 90 mg/m2 IV subsequently reduced to 70 mg/m2 on days 1 and 2 and Rituximab (375 mg/m2 IV) on day 1 of each 28 day cycle for upto 8 cycles and increasing doses of Voxtalisib (30 or 50 mg BID orally). Arm B2: Patients (n = 12) with R/R CLL administrated with fixed doses of Bendamustine (70 mg/m2 IV) on days 1 and 2 and Rituximab (375 mg/m2 IV on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 to 6) for upto 6 cycles, and increasing doses of Voxtalisib (30 or 50 mg BID orally). PK analysis: Voxtalisib exposure was similar for patients in all the 3 treatment arms, both after the first dose (cycle 1 day 1) and at steady state (cycle 2 day 1). Daily BID dosing did not cause accumulation of Voxtalisib in plasma of these patienst. Rituximab PK parameters were similar for patients in all 3 treatment arms. Voxtalisib did not pharmcokinetically interact with Rituximab or Bendamustine. The best overall response rate (ORR; CR + PR) was 48.6% for all patients. A total of 17 patients (48.6%) were reported as progression free at six months. The median PFS was 32.1 weeks for all patients. Arm A: The median PFS was 33.4 weeks (95% CI: 26.3–60.1 weeks). The ORR was 40%. The CR, PR and SD were 6.7%, 33.3% and 46.7%, respectively. Arm B1: The median PFS was 33.4 weeks (95% CI: 0.7–53.4 weeks). The ORR was 50%. The CR, PR and SD were 12.5%, 37.5% and 37.5%, respectively. Arm B2:The median PFS was 26.1 weeks (95% CI: 8.4–44 weeks). The ORR was 58.3%. The CR, PR and SD were 16.7%, 41.7% and 33.3%, respectively. The RP2D for Voxtalisib in combination with both drugs was established at 50 mg BID. This drug combination demonstrated activity in heavily pretreated patients.	Headache, fatigue, neutropenia, pyrexia, constipation, rash, vomiting, anemia, thrombocytopenia and decreased appetite.
Voxtalisib in patients with relapsed or refractory NHL or CLL [425]	Completed	Sanofi	II, NCT01403636	Total 167 patients were enrolled, which included 42 patients with MCL, 47 with FL, 42 with DLBCL and 36 patients with CLL/SLL. These patients received 50 mg BID Voxtalisib orally. Voxtalisib showed an acceptable safety profile and was efficacious in the patients with FL but demonstrated limited efficacy in patients with MCL, DLBCL or CLL/SLL. The median duration of treatment was 10.7 weeks (IOQ: 5.9–31.9 weeks). The ORR for all patients was 18.3% (95% CI: 12.7–25.1%). The overall CR, PR and SD for all patients were 5% and 13.4% and 33.5%, respectively. The median PFS was 14.4 weeks (95% CI: 9–19.43 weeks). 32.3% of patients had a PFS of more than 24 weeks. The main reasons for treatment discontinuation were disease progression (overall 107 patients of 167 (64.1%); 73.8% (31/42) in the MCL, 42.6% (20/47) in the FL, 76.2% (32/42) in the DLBCL and 66.7% (24/36) in the CLL/SLL groups, respectively. The clinical response seen in patients with different cancers is mentioned below: MCL patients: The median duration of treatment was 8 weeks (IQR: 5.6–19.9 weeks). The ORR was 11.9% (95% CI: 4–25.6%). The CR, PR and SD were 7.1%, 4.8%, 33.3%, respectively. The median PFS was 8.9 weeks (95% CI: 7.86–12.86 weeks). 21.4% of patients had a PFS of more than 24 weeks. FL patients: The median duration of treatment was 29 weeks (IQR: 8.1–64 weeks). The ORR was 41.3% (95% CI: 27–56.8%). The CR, PR and SD were 10.9%, 30.4% and 30.4%, respectively. The median PFS was 58 weeks (95% CI: 26 weeks–not calculated). 54.3% of patients had a PFS of more than 24 weeks. DLBCL patients: The median duration of treatment was 6 weeks (IQR: 3.6–8.1 weeks). The ORR was 4.9% (95% CI: 0.6–16.5%). The PR and SD were 4.9% and 9.8%. No patients achieved CR. The median PFS was 7.1 weeks (95% CI: 5.14–8.14 weeks). 7.3% of patients had a PFS of more than 24 weeks. CLL/SLL patients: The median duration of treatment was 19.8 weeks (IQR: 11.8–36.9 weeks). The ORR was 11.4% (95% CI: 3.2–26.7%). The PR and SD were 11.4% and 65.7%. No patients achieved CR. The median PFS was 24.1 weeks (95% CI: 16.57–31.57 weeks). 45.7% of patients had a PFS of more than 24 weeks. No genetic alterations were established in response to Voxtalisib treatment in any patient samples.	Fatigue, diarrhea, nausea, cough, dyspnea, pyrexia, anemia, decreased appetite, pneumonia, increased AST/ALT and thrombocytopenia.