Background: IVPac is widely used to treat patients with breast cancer. oPac+E is oral paclitaxel in combination with Encequidar, an oral, minimally absorbed, specific p-glycoprotein inhibitor that enables the absorption of oral paclitaxel. Results of the phase III trial, KX-ORAX-001, were presented at SABCS, 2019, Abstract # GS6-01. At the time of the database lock for the final analysis of the primary endpoint of confirmed tumor response rate, analyses of PFS and OS were performed. The confirmed tumor response rate was significantly higher in the oPac+E group vs IVPac (35.8% vs 23.4%, p=0.011 ITT, population). The median overall survival, as of Sept 2020 presented at SABCS 2020, Abstract# PD1-08 was 22.7 months vs 16.5 months, respectively favoring oPac. Analysis of safety data demonstrated that patients with elevated liver tests (at screening or baseline), were at increased risk of serious and early complications of neutropenia including sepsis, septic shock, febrile neutropenia which could be fatal. A post hoc, subgroup analysis of survival for patients with elevated liver tests was conducted. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible patients were randomized 2:1 to receive oPac+E or IVPac. Patients received treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy, defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: A total of 402 mBC patients were randomized (oPac+E 265: IVPac 137) and represent the ITT population of which 399 subjects were dosed. 122 patients (oPac+E 74, IVPac 48) had elevated AST, or bilirubin (NCI ODWG mild category) at screening or predose/baseline. The subjects were generally balanced between treatment groups for mean age (55 vs 57 years), extent of tumor metastases, and tumor markers ER/PR+ HER2- (62% vs 63%), ER/PR- HER2- (11% vs 15%). For subjects receiving OPac+E, the median survival was 18.9 months vs 10.1 months for subjects receiving IVPac; with a hazard ratio of 0.593 (95.5% CI 0.382 - 0.921) favoring OPac+E.Greater than 65% of subjects had a survival event at the time of this analysis. Conclusion: Although patients with mBC and mild hepatic dysfunction at baseline are at increased risk of early serious neutropenic and infectious/septic complications after treatment with oPAC+E, this risk is counterbalanced by an increase in overall survival. (NCT 02594371) Citation Format: Gerardo Umanzor, Hope S Rugo, Francisco J Barrios, R H Vasallo, Marco A Chivalan, S Bejarano, Julio Roberto Ramirez, Luis Fein, R D Kowalyszyn, D L Cutler, D Kramer, H Wang, R MF Kwan. Oraxol + Encequidar (OPac+E) vs IV paclitaxel (IVPac) in the treatment of patients with metastatic breast cancer (mBC) (Study KX-ORAX-001): Subgroup survival analysis of patients with hepatic dysfunction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-05.

The combination of IV Pac + Pem has demonstrated preliminary antitumor activity in two NSCLC phase I studies. E at 15mg QD plus oPac at 205 mg/m2 QD x 3 days every week is safe and has demonstrated efficacy in treating mBC. E is a , minimally absorbed, oral PGP inhibitor to prevent intestinal oPac efflux. The aims were to determine the safety and tolerability, recommended phase 2 dose (RP2D) of oPac/E in combination with Pem and to evaluate early clinical activity.

Abstract Background: There is a need for more effective and less toxic treatments for patients with mBC. Patients may prefer oral vs IV cytotoxic therapies to avoid frequent hospital visits. In addition, oral therapies allow frequent or metronomic dosing regimens which may alter the toxicity or activity profile of agents vs infrequent IV administration. oPac+E is oral paclitaxel combination with Encequidar, a specific, minimally absorbed, oral p-glycoprotein inhibitor that facilitates the absorption of oral paclitaxel. mBC patients who received oPac+E had significantly greater confirmed tumor response and longer survival with lower rates and severity of neuropathy but increased GI AE compared to IV paclitaxel (IVPac) (Study KX-ORAX-001 presented at SABCS, 2019, Abstract # GS6-01). Methods: Study KX-ORAX-001 was a phase III, randomized, study in women with mBC for whom treatment with IVPac was recommended. Patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: All IVPac patients received high-dose dexamethasone and antihistamine premedication, which have significant anti-emetic activity and may have received additional anti-emetic agents as needed. The protocol did not allow any prophylaxis for GI AE for oPac+E patients nor were they to receive predose corticosteroids, nor antihistamines. The protocol was amended after approximately 30% of patients were enrolled to allow prophylactic anti-emetic medications for patients randomized to oPac+E. Patients were also given loperamide to take at home and were instructed to initiate loperamide with the onset of diarrhea. The rates of Grade ≥2, vomiting and diarrhea for patients treated with IVPac, the patients treated with oPac+E prior to after the amendment are summarized in the table below. Prophylactic anti-emetic therapy and early use of loperamide markedly decreased the incidence of ≥Grade 2 vomiting and diarrhea although there was a greater incidence than IVPac. The most frequently prescribed anti-emetic agents for oPac+E treated patients were ondansetron (54%), metoclopramide (21%), domperidone (4%) and aprepitant (3%). For patients randomized to IVPac, the most frequently prescribed agents were ondanesteron (59%), granisetron (24%), palenosetron (7%) and aprepitant (2%). Oral administration of the oral NK1 inhibitor aprepitant appeared to be associated with increased incidence of oral paclitaxel systemic toxicity, potentially due to inhibition of metabolism of oPac by cytochrome P450 3A4. Conclusions: oPac+E was associated with greater efficacy in the treatment of mBC and lower rates and severity of peripheral neuropathy, but increased GI AE compared to IVPac 175mg/m2. GI AE in oPac+E treated patients can be managed by prophylactic use of anti-emetics, primarily 5-HT3 inhibitors and early intervention with the anti-diarrhea agent loperamide. The use of the oral NK1 inhibitor aprepitant in combination with oPac+E is not recommended.(NTC02594371) IVPacoPac+E Pre-AmendmentoPac+E Post AmendmentGrade 2Grade 3Grade 4Grade 2Grade 3Grade 4Grade 2Grade 3Grade 4Vomiting4%1%0%24%7%0%7%4%0%Diarrhea7%1%0%27%9%0%16%3%0.5% Citation Format: H S Rugo, G Umanzor, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-11.

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity associated with IVPac. Primarily sensory, CIPN is an often irreversible condition primarily affecting the hands and feet associated with pain, numbness, tingling, and sensitivity to cold and has a significant impact on quality of life and treatment tolerance. Risk of CIPN increases with age, dose intensity, cumulative dose, and preexisting conditions including diabetes. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: A total of 402 mBC patients were enrolled, 265 randomized to oPac+E and 137 to IVPac (ITT population). 399 patients were treated and comprise the safety population. The confirmed response rate was significantly greater in the oPac+E group vs IVPac (35% vs 23%) for the ITT population. Median overall survival was (27.7 vs 16.7 months, ITT) at the time of the analysis. Long-term follow up for final determination of PFS and OS is ongoing.Incidence of neuropathy-related TEAEs were lower in patients receiving oPac+E vs IVPac: Overall (21% vs 64%; all grades), grade ≥3 (2% vs 15%). Cumulative risk for neuropathy with IVPac was >50% by week 8 and was 83% at week 88. In contrast, the cumulative risk of neuropathy with oPac+E rose slowly and plateaued at 34% at week 88. Treatment discontinuations due to neuropathy occurred only in the IVPac arm (8%). Dose reductions due to neuropathy were reported in 8% of IVPac treated patients and in 2% of oPac+E treated patients. In agreement with the lower rates of peripheral neuropathy in patients treated with oPac+E, there was lower use of medications used for the treatment of neuropathic symptoms. Use of gabapentin or pregabalin was 12% for patients receiving oPac+E vs 40% for IVPac treated patients. Conclusions: oPac+E was associated with greater efficacy in the treatment of patients with mBC and a lower incidence of neuropathy, slower onset and lesser severity of neuropathic events compared to IVPac 175mg/m2 administered every three weeks. Fewer patients receiving oPac+E required dose reduction due to neuropathy and no patients receiving oPac+E discontinued treatment due to neuropathy. Reduction in neuropathy may improve quality of life and allow longer administration of effective therapy while maintaining dose intensity. Citation Format: H S Rugo, G Umanzor, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Lower rates of neuropathy with oral paclitaxel and encequidar (oPac+E) compared to IV paclitaxel (IVPac) in treatment of metastatic breast cancer (mBC): Study KX-ORAX-001 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-06.

Abstract Background: IVPac is widely used to treat patients with breast cancer. oPac+E is oral paclitaxel in combination with Encequidar, an oral, minimally absorbed, specific p-glycoprotein inhibitor that enables the absorption of oral paclitaxel. Results of the phase III trial, KX-ORAX-001, were presented at SABCS, 2019, Abstract # GS6-01. At the time of the database lock for the final analysis of the primary endpoint of confirmed tumor response rate, analyses of PFS and OS were performed. The confirmed tumor response rate was significantly higher in the oPac+E group vs IVPac (35.8% vs 23.4%, p=0.011 ITT, population). The median overall survival was 27.7 months vs 16.7 months, respectively favoring oPac. An update of the duration of response, PFS and OS data comprising an additional 14 months follow-up will be presented. At the time of the update it is projected that approximately 60% of subjects will have had a survival event. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: A total of 402 mBC patients were randomized (oPac+E 265: IVPac 137) and represent the ITT population of which 399 subjects were dosed. Updated data for duration of response, PFS and OS for the ITT and prespecified mITT populations will be presented. (NCT 02594371) Citation Format: G Umanzor, H S Rugo, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Oral paclitaxel and encequidar (oPac+E) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (study KX-ORAX-001): Progression free survival (PFS) and overall survival (OS) updates [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-08.

e15518 Background: Oraxol consists of oral paclitaxel (PTX) administered with the novel P-glycoprotein inhibitor HM30181A which enables the oral absorption of PTX. Ramucirumab (RAM) + intravenous weekly PTX is FDA approved 2nd line treatment of gastric cancer. Oraxol (oral PTX) 200mg/m2 days 1-3, weekly results in similar exposure to weekly 80/m2 intravenous PTX. This phase 1 clinical trial is to determine the maximum tolerated dose (MTD) of Oraxol + RAM. Methods: Eligible patients (pts) have gastric or esophageal cancers and failed prior fluoropyrimidine or platinum containing chemotherapies. Dose escalation followed the standard 3+3 design: Cohort 1: Oraxol 200mg/m2 days 1-3, weekly. Cohort 2: Oraxol 250mg/m2 days 1-3, weekly. Cohort 3: Oraxol 300mg/m2 days 1-3, weekly. Dose of RAM is standard 8 mg/kg IV every 2 weeks. Pts were monitored for dose limiting toxicity (DLT) by week 4. Adverse events (AEs) were assessed per CTCAE v4.03 and response by RECIST v1.1. Results: Cohort 1: One febrile neutropenia (DLT) observed in 6 pts. Partial response (PR) = 2/6, stable disease (SD) = 1/6 and progressive disease (PD) = 3/6 pts. Cohort 2: One grade-3 neutropenia with treatment delay (DLT) in 7 pts. PR = 3/6 and PD = 3/6 in 6 evaluable pts. Cohort 3: One febrile neutropenia (DLT) in 3 pts and study is ongoing. All pts had complete recovery of their DLT. PK showed increase of plasma PTX exposure with dose. Conclusions: The MTD for Oraxol has not been reached yet in combination with RAM. Preliminary results showed that Oraxol + RAM is tolerable and have encouraging anti-tumor activity in gastric or esophageal cancers pts who failed prior chemotherapies. Final results of this study will be presented. Clinical trial information: NCT02970539.

Background Paclitaxel has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells. Oral paclitaxel may reduce IV access, avoid risks of allergic reaction to cremophor, forego steroid premedication, reduce hospital stay, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel and HM30181, a novel orally active, potent and specific inhibitor of P-gp with minimal or undetectable systemic exposure. We report the results of a bio-equivalence study of Oraxol compared to IV paclitaxel. Methods An international randomized crossover pharmacokinetic (PK) study using HM30181 15mg plus oral paclitaxel 205mg/m2 was given on days 1-3 and compared to a single dose of IV paclitaxel (80 mg/m2) in patients with advanced solid tumors. PK blood samples were taken days 1-9 for oral paclitaxel and days 1-5 for IV paclitaxel. Results 44 patients were randomized. 35 patients were evaluable. The first cohort included 6 patients as a feasibility study. The second cohort included 29 patients and showed: Table . 477P Oraxol 205mg/m2 days 1-3 Paclitaxel 80mg/m2 IV AUC0-∞ (hr*ng/mL) 5001.18 5589.70 Cmax (ng/mL) 366.39 (0-24 hr), 324.26 (24-48 hr), 296.10 (48-72 hr) 2710.48 AUC0-t 4797.08 5425.59 GMR (%, 90% CI) 89.10 (83.53, 95.03) Intra-subject CV (%) 16.05 Conclusions Oraxol (oral paclitaxel + HM30181) given daily for 3 days can show bio-equivalence to single dose of IV paclitaxel 80mg/m2 at 80% power with 90% CI of the GMR within the limits of 80 – 125%. Clinical trial identification ACTRN 12615000894594. Legal entity responsible for the study Athenex. Funding Athenex. Disclosure C.G.C.A. Jackson: Travel / Accommodation / Expenses: Athenex. N.A. Hung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zentech. D. Cutler: Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. D. Kramer: Full / Part-time employment: Athenex. J. Zhi: Full / Part-time employment: Athenex. W. Chan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. M.R. Kwan: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment: Athenex. C. Hung: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Patent: Athenex; Shareholder / Stockholder / Stock options: Zentech. All other authors have declared no conflicts of interest.

Background Angiosarcomas (AS) are rare and aggressive tumors of endothelial cell origin. About half of patients present with a primary cutaneous lesion, most commonly over the scalp. Intravenous (IV) weekly paclitaxel (Pac) is the current accepted standard-of-care in inoperable or progressive disease. Median PFS is 3.8 months. IV Pac is associated with dose-limited toxicities including peripheral neuropathy, development of infusional reactions and anaphylaxis, in part due to the Cremophor EL formulation vehicle. Pac is a P-glycoprotein (P-gp) substrate. Pac is a substrate for the Pgp pump in the intestinal cells which leads to efflux of Pac back into the intestinal lumen, thereby making the drug nonbioavailable when taken orally. ORAXOL is a combination product of 2 separate drugs; oral Pac and a novel Pglycoprotein (Pgp) inhibitor, HM30181 methanesulfonate monohydrate (HM30181A). This allows for intestinal absorption and systemic exposure of Pac. ORAXOL has been studied in bioavailability and bioequivalence studies confirming its safety profile. A multi-center phase III study comparing ORAXOL and IV Pac in women with metastatic breast cancer is on-going. We are currently recruiting patients on a multi-center pilot study to determine the efficacy of ORAXOL in cutaneous AS. Trial design This is a multi-center, international, open-label, pilot study to evaluate the activity, safety, and tolerability of ORAXOL in subjects with cutaneous AS who have not been treated previously with taxanes. ORAXOL (15mg oral HM30181A & 205mg/m2 oral Pac) will be administered once daily for 3 consecutive days every week from Weeks 1 through 25; HM30181A is administered 1 hour before oral Pac on dosing days. Subjects who do not have disease progression at the end of treatment period are eligible to continue ORAXOL in the treatment extension phase. Primary objective is to determine the response rate (RR) within 6 months of initiation of treatment. Secondary objectives include (i) safety and tolerability, (ii) PFS and (iii) OS, (iv) duration of- and (v) time to-best response. Up to 25 evaluable subjects across 4 study sites will be enrolled in this study. The first patient has started dosing in December 2018. Clinical trial identification NCT03544567. Legal entity responsible for the study Athenex Inc. Funding Athenex Inc. Disclosure M.R. Kwan: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex Inc. D. Cutler: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex Inc. D. Kramer: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex Inc. W. Chan: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex Inc. All other authors have declared no conflicts of interest.

Objective: Ertugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing.The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID).This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC 24 )) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE 24 )) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD. Materials and methods: In this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days.Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period.Results: The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC 24 was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD.GMR (90% CI) of UGE 24 for BID vs. QD administration was 110.2% (103.0%,117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg.The 90% CIs of the GMR of AUC 24 and UGE 24 for BID vs. QD dosing were within the acceptance range for equivalence (80 -125%) and the prespecified criterion for similarity (70 -143%), respectively.All treatments were well tolerated.Conclusion: There are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.

Background: Intravenous (IV) paclitaxel is approved for the treatment of numerous cancers including MBC. Oraxol (Athenex, USA), is an oral formulation of paclitaxel in combination with a novel, orally active, potent and specific inhibitor of P-gp (HM30181A). Oraxol is expected to be less toxic with comparable efficacy to its iv counterpart. We report the interim results of an ongoing study of Oraxol in MBC patients. Methods: Multicenter, single-arm, open-label, study of Oraxol (HM30181A at 15mg, plus oral paclitaxel 205mg/m2) administered orally for 3 consecutive days/week for up to 16 weeks. Paclitaxel PK was determined in the first and fourth week of Oraxol. Tumor Response by CT/MRI was measured using RECIST criteria 1.1 at weeks 8 and 16. Results: Sixteen MBC patients have been enrolled with a mean (range) age of 56.9 years (range: 38 - 79 yrs). Most had previous combination chemotherapies and/or monotherapy. There were seven (50%) partial responses and 7 (50%) with stable disease in 14 evaluable patients who had post-treatment CT scans. There was no progressive disease for the patients that reached 16 weeks of treatment. Three patients had treatment-related SAEs (grade ≥3 neutropenia); and there was 1 non-treatment related death. Preliminary PK results showed that the daily mean AUC of oral paclitaxel was similar at week-1 and week-4 (1397 vs. 1137 ng-hr/mL). Other studies have shown that oral paclitaxel can achieve exposure similar to that of IV paclitaxel. Conclusions: Oral paclitaxel showed very encouraging activity in MBC patients with acceptable toxicity. PK of oral paclitaxel is reproducible. Clinical trial identification: NCT03165955. Legal entity responsible for the study: The authors. Funding: Athenex, Buffalo, NY. Disclosure: G. Gerald Fetterly, D.L. Cutler, R. Kwan, D. Douglas Kramer, W-K. Chan: Sockholder and employee: Athenex. T. Hung: Stockholder: Athenex. All other authors have declared no conflicts of interest.

e16048 Background: Intravesical BCG (Bacillus Calmette-Guérin) is the gold standard for treatment of superficial bladder cancer. Recurrence is a significant problem. Intravesical interferon α (IFN) demonstrated complete response (CR) in ∼40% patients with most relapsing <1 year. Intravesical Ad-IFN takes advantage of the bladder to allow prolonged exposure to high concentrations of IFN; this is expected to potentiate durable therapeutic responses. Syn3 is an excipient used to increase adenoviral vector (Ad) transfection. Methods: The phase I study is a nonrandomized, open-label, rising-dose, multi-center study of Ad-IFN in patients with papillary bladder cancer, or carcinoma in situ refractory to BCG. Patients with T1 were not enrolled unless they refused cystectomy. A minimum of 3 subjects were enrolled at each dose level. Adverse events and lab abnormalities were graded according to CTC version 3 criteria. The occurrence of treatment-related Grade 3 or Grade 4 toxicity is considered dose-limiting toxicity (DLT). The maximum tolerated dose is defined as the dose which results in DLT in ≤1/6 subjects. Urine from pre-treatment, posttreatment days 0–7, 10, 14, and 28 were tested for IFN, Syn3, Ad-IFN DNA, and research biomarkers. Blood was assayed for IFN, Syn3, Ad-IFN DNA, anti- adenovirus and anti-IFN antibodies. Results: Intravesical administration of 3×10 9 , 1×10 10 , 3x10 10 , 1×10 11 , or 3×10 11 particles/ml of Ad-IFN (75ml) in 1mg/ml Syn3 is safe with only minor initial urgency controlled with anticholinergic medication. Of the 13 evaluable patients, 6 are CR, defined as a negative cytology and biopsy at 3 months. CR patients were offered a second dose. Response duration is variable with longest >1 year. Urinary IFN was seen for all patients in a dose-dependent fashion. TRAIL, IP-10, M65, and M30 were also seen. Conclusions: Initial safety and response activity justify further clinical development. [Table: see text]

Ertugliflozin is a highly selective and potent inhibitor of the sodium‐glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. The glycemic efficacy of sodium‐glucose cotransporter 2 inhibitors such as ertugliflozin depends on glucose filtration through the kidney. This phase 1, open‐label study evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and tolerability of ertugliflozin (15 mg) in type 2 diabetes mellitus and healthy subjects with normal renal function (estimated glomerular filtration rate not normalized for body surface area ≥90 mL/min) and type 2 diabetes mellitus subjects with mild (60‐89 mL/min), moderate (30‐59 mL/min), or severe (<30 mL/min) renal impairment (n = 36). Blood and urine samples were collected predose and over 96 hours postdose for pharmacokinetic evaluation and measurement of urinary glucose excretion over 24 hours. Log‐linear regression analyses indicated predicted mean area under the concentration‐time curve values for mild, moderate, and severe renal function groups that were ≤70% higher relative to subjects with normal renal function. Generally consistent results were obtained with categorical analysis based on analysis of variance. The increase in ertugliflozin exposure in subjects with renal impairment is not expected to be clinically meaningful. Regression analysis of change from baseline in urinary glucose excretion over 24 hours vs estimated glomerular filtration rate showed a decrease in urinary glucose excretion with declining renal function. A single 15‐mg dose of ertugliflozin was well tolerated in all groups.

Understanding genetic variations that influence pharmacokinetics (PK) in humans is important for optimal clinical use of drugs. Guidances for making decisions on when to conduct pharmacogenetic research during drug development have been proposed by regulatory agencies, but their uniform adoption presents problems due to an inherent lack of flexibility. A questions-based approach (QBA) was developed to enable drug development teams at Merck to iteratively and flexibly evaluate the potential impact of pharmacogenetics (PGx) on clinical pharmacokinetic variability.