Anti-cancer effects of DHP107 on canine mammary gland cancer examined through in-vitro and in-vivo mouse xenograft models.

BACKGROUND: Canine mammary gland cancer (CMGC) is a common neoplasm in intact bitches. However, the benefit of adjuvant chemotherapy is unclear. The aim of this study was to investigate the anti-proliferative effects of paclitaxel on CMGC in in-vitro and in-vivo settings. RESULTS: Paclitaxel dose-dependently inhibited viability and induced G2/M phase cell cycle arrest and apoptosis in both primary and metastatic CMGC cell lines (CIPp and CIPm). In animal experiments, the average tumour volume decreased significantly in proportion to the administered oral paclitaxel dose. By examining tumour tissue using a TUNEL assay and immunohistochemical staining with anti-CD31 as a marker of endothelial differentiation, respectively, it was confirmed that oral paclitaxel induced apoptosis and exerted an anti-angiogenetic effect in tumour tissues. Further, downregulation of cyclin D1 in tumour tissues suggested that oral paclitaxel induced cell cycle arrest in tumour tissues in-vivo. CONCLUSIONS: Our results suggest that paclitaxel may have anti-cancer effects on CMGC through cell cycle arrest, induction of apoptosis, and anti-angiogenesis. This study could provide a novel approach to treat CMGC.

Oral paclitaxel and encequidar in patients with breast cancer: a pharmacokinetic, safety, and antitumor activity study.

Background: Paclitaxel is widely used for the treatment of metastatic breast cancer (MBC). However, it has a low oral bioavailability due to gut extrusion caused by P-glycoprotein (P-gp). Oral paclitaxel (oPAC) may be more convenient, less resource-intensive, and more tolerable than its intravenous form. Encequidar (E) is a first-in-class, minimally absorbed, gut-specific oral P-gp inhibitor that facilitates the oral absorption of paclitaxel. Objectives: To investigate the pharmacokinetics (PK), overall response rate (ORR), and safety of weekly oral paclitaxel with encequidar (oPAC + E) in patients with advanced breast cancer. Design: This is a multicenter, single-arm, open-label study in six medical centers in Taiwan. Methods: Patients with advanced breast cancer were administered 205 mg/m2 oPAC and 12.9 mg E for 3 consecutive days weekly for up to 16 weeks. Plasma samples were collected at weeks 1 and 4. PK, ORR, and safety were evaluated. Results: In all, 28 patients were enrolled; 27 had MBC; 23 had prior chemotherapy; and 14 had ⩾2 lines of prior chemotherapy. PK were evaluable in 25 patients. Plasma paclitaxel area under the curve (AUC)(0-52 h) at week 1 (3419 ± 1475 ng h/ml) and week 4 (3224 ± 1150 ng h/ml) were equivalent. Best overall response in 28 evaluable patients was partial response (PR) in 11 (39.3%), 13 (46.4%) stable disease (SD), and 1 (3.6%) with progressive disease (PD). No patient achieved complete response (CR). The clinical benefit rate (CR + PR + SD) was 85.7%. Major adverse events among the 28 treated patients were grade 3 neutropenia (25%), grade 4 neutropenia (18%), with febrile neutropenia in 4%, and grade 3 diarrhea (4%). No treatment-related deaths occurred. Grade 2 peripheral neuropathy occurred in 1 (4%) patient and grade 3 peripheral neuropathy in 1 (4%) patient. Conclusions: oPAC + E produced a consistent therapeutic plasma paclitaxel exposure during treatment. There was a high rate of radiologically assessed clinical benefit, and a low rate of neurotoxicity which may provide advantages over IV paclitaxel. Registration: ClinicalTrials.gov Identifier: NCT03165955.

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies.

PURPOSE: Orally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1). METHODS: Fifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling. RESULTS: A pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67-1.33) and 0.46 (95%CI: 0.34-0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122-724). CONCLUSION: The developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.

A phase Ib study of Oraxol (oral paclitaxel and encequidar) in patients with advanced malignancies.

PURPOSE: Oraxol is an oral formulation of paclitaxel administered with a novel, minimally absorbed P-glycoprotein inhibitor encequidar (HM30181A). This phase Ib study was conducted to determine the maximum-tolerated dose (MTD) of Oraxol administered at a fixed dose for up to 5 consecutive days in patients with advanced malignancies. METHODS: Part 1 of this study utilized a 3 + 3 dose-escalation design to determine the MTD of oral paclitaxel 270 mg plus oral encequidar 15 mg administered daily. Dose escalation was achieved by increasing the number of consecutive dosing days per week (from 2 to 5 days per week). Dosing occurred for 3 consecutive weeks out of a 4-week cycle. Part 2 treated additional patients at the MTD to determine tolerability and recommended phase II dose (RP2D). Adverse events, tumor responses, and pharmacokinetic profiles were assessed. RESULTS: A total of 34 patients (n = 24 in Part 1, n = 10 in Part 2) received treatment. The MTD of Oraxol was determined to be 270 mg daily × 5 days per week per protocol definition and this was declared the RP2D. The most common treatment-related adverse events were fatigue, neutropenia, and nausea/vomiting. Hypersensitivity-type reactions were not observed. Of the 28 patients evaluable for response, 2 (7.1%) achieved partial response and 18 (64.3%) achieved stable disease. Pharmacokinetic analysis showed rapid absorption of paclitaxel when administered orally following encequidar. Paclitaxel daily exposure was comparable following 2-5 days dose levels. CONCLUSION: The oral administration of encequidar with paclitaxel was safe, achieved clinically relevant paclitaxel levels, and showed evidence of anti-tumor activity.

Phase II study of DHP107 (oral paclitaxel) in the first-line treatment of HER2-negative recurrent or metastatic breast cancer (OPTIMAL study).

BACKGROUND: Standard intravenous (IV) paclitaxel is associated with hypersensitivity/toxicity. Alternative IV formulations have improved tolerability but still require frequent hospital visits and IV infusion. DHP107 is a novel oral formulation of paclitaxel that is approved in South Korea for the treatment of gastric cancer. METHODS: This multicenter, phase II study using a Simon's two-stage design investigated the efficacy and safety of DHP107 200 mg/m2 administered orally twice daily on days 1, 8, and 15 every 4 weeks for the first-line treatment of recurrent or metastatic HER2-negative breast cancer. RESULTS: Thirty-six patients were enrolled and 31 were assessable for efficacy. Patient median age was 57 years (range = 34-81) and 11 (31%) had triple-negative disease. A median of seven cycles (range = 1-28) of DHP107 was administered. Objective response rate was 55% (17 patients), all partial responses, according to the investigator's decision and independent central review (ICR), and 44% (4/9 patients) in those with triple-negative disease. Disease control rate (partial response and stable disease) was 74% (23 patients) according to the investigator's decision and ICR. In the intention-to-treat (ITT) population of all enrolled participants, the objective response rate was 50% (18/36 patients). Median progression-free survival was 8.9 months [95% confidence interval [CI]: 5.2-12.3) and median time to treatment failure was 8.0 months (95% CI: 4.2-10.0). DHP107 had an acceptable toxicity profile. All patients experienced treatment-emergent adverse events; the most common adverse events were decreased neutrophil count (81% all grades and 78% grade ⩾ 3) followed by peripheral sensory neuropathy (61% all grades and 8% grade 3). However, there was no febrile neutropenia or sepsis. CONCLUSION: DHP107 showed promising efficacy and acceptable tolerability in this phase II study and is currently being investigated in the OPTIMAL phase III study (NCT03315364). TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov identifier: NCT03315364.

A Phase 1 Dose-Escalation Study of Low-Dose Metronomic Treatment With Novel Oral Paclitaxel Formulations in Combination With Ritonavir in Patients With Advanced Solid Tumors.

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low-dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open-label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice-daily 30-mg paclitaxel combined with twice-daily 100-mg ritonavir (MP5/r 30-30/100-100) in 9 dose levels. Dose-limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20-20/100-100, the maximum paclitaxel plasma concentration and area under the concentration-time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20-20/100-100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted.

Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer.

OBJECTIVE: The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer. METHODS: To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 µL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls. RESULTS: Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses). CONCLUSION: Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model.

Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer / 부인종양

OBJECTIVE: The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer. METHODS: To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 microL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls. RESULTS: Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses). CONCLUSION: Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model.