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.

Subacute toxicity and toxicokinetics study of DHP107, an oral paclitaxel formulation with once-weekly dosing in mice.

DHP107, an oral formulation of paclitaxel, is effectively and systemically absorbed in intestinal endothelial cells. Although the in vivo efficacy of DHP107 has been reported, the potential toxicity of DHP107 has not been evaluated. Therefore, this study was conducted to evaluate the toxicity and toxicokinetics of DHP107 orally administered to ICR mice at 25, 50, and 100 mg/kg via once-weekly dosing for six weeks. DHP107-related clinical signs were observed in both sexes at 100 mg/kg. There were significant increases in the number of platelets and percentages of reticulocytes and basophils in male mice. Also in males, there was a significant decrease in the absolute and relative weights of testes, epididymides, kidneys, and heart. Relative spleen weights were significantly increased in males treated with doses ≥50 mg/kg which had histopathological correlates. These changes were reversible after a two-week recovery period with the exception of the findings in the reproductive organs. Systemic exposure to paclitaxel increased with DHP107 doses in single and multiple dosing with no marked differences between sexes. In conclusion, the target organs were determined to be the reproductive and hematopoietic organs in male mice, suggesting of sex difference and the NOAEL of DHP107 was established to be < 25 mg/kg for males and 50 mg/kg for females.

Predicting the efficacy of an oral paclitaxel formulation (DHP107) through modeling and simulation.

PURPOSE: DHP107 is an oral paclitaxel under development. The present study characterized the pharmacokinetic properties of DHP107 and predicted the efficacy in comparison to that of intravenous paclitaxel, using modeling and simulation of data from the early phase of clinical development. METHODS: In the first-in-human study of the pharmacokinetic characteristics of DHP107 and intravenous paclitaxel, patients received DHP107 60 to 600 mg/m(2), followed by intravenous paclitaxel 175 mg/m(2). Using the pharmacokinetic model of DHP107 from the present analysis and from a previously published pharmacodynamic analysis of the association between paclitaxel concentration and neutropenia, phase I clinical trial for DHP107, with a modified Fibonacci dose escalation scheme, were simulated to predict the maximal tolerated dose (MTD). Additional simulations of paclitaxel concentration over time were conducted to compare the efficacy of DHP107 with that of intravenous paclitaxel, based on time over minimum effective concentration. FINDINGS: In the clinical trial simulation, 480 mg/m(2) was the most frequently predicted MTD of DHP107. In the simulations for efficacy, the times over minimum effective concentration with DHP107 at the predicted MTD were greater than those of intravenous paclitaxel in weekly regimens. IMPLICATIONS: The findings from this analysis suggest the possibility of efficacy of DHP107 in weekly regimens and provides a scientific rationale for further development. Based on findings from modeling and simulation, DHP107 was predicted to be more efficacious compared with intravenous paclitaxel in weekly regimens, and this finding should be confirmed in further clinical trials.

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.

Novel oral taxane therapies: recent Phase I results.

The oral taxanes are analogues of existing taxanes with a possible broad range of antitumor activity. They also have the potential advantages of ease of administration, better efficacy and lesser toxicity than currently available taxanes. These drugs have been used in several Phase I clinical trials, the methodology and results of which will be reviewed here.