Paclitaxel has poor oral bioavailability due to active excretion by p-glycoprotein (Pgp) on intestinal epithelial cells. Oral administration is preferable to IV administration to minimize IV access, avoid allergic reactions to cremaphor, obviate steroid pre-medication, reduce day stay, provide cost-savings, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel and HM30181, a novel oral non-absorbed specific inhibitor of intestinal Pgp. Following a previously reported phase 1 dose-escalation study, we report the preliminary bio-equivalence results of a three-day schedule of Oraxol compared to IV paclitaxel.
We conducted a randomized crossover study recruiting patients from 2 sites in New Zealand. HM30181 15mg plus oral paclitaxel 205mg/m2 (®Oraxol) were administered orally once daily for 3 consecutive days and compared to a single dose of IV paclitaxel (80 mg/m2) in patients with advanced solid tumours. PK blood samples were taken up to day 9 for Oraxol and day 5 for IV paclitaxel.
A scheduled interim analysis of the first 6 patents’ Oraxol PK (AUC0-∞) compared to IV paclitaxel showed: - Geometric mean ratios (GMR) = 87.09%, (90% CI 74.61-101.66%) - Intra-subject coefficients of variation (CV) = 12.62% - Time over minimum effective concentration was approximately 6 hours for IV paclitaxel, and 30 hours for Oraxol. Further results will be presented. The safety profile of Oraxol was acceptable without grade 3-4 toxicities. A total sample size of 30 subjects is required to demonstrate bioequivalence between Oraxol and IV paclitaxel (90% CI of the GMR is within the limits of 80% – 125%), with 80% power.
Oraxol 615mg/m2 orally over three days achieved paclitaxel AUC comparable to IV paclitaxel 80mg/m2. A three-day schedule of Oraxol is within predicted range needed to demonstrate bioequivalence, and further patients are being enrolled to achieve adequate power. A phase 3 study is now underway.
ACTRN 12615000894594.
ACTRN 12615000894594.
Athenex
Athenex
G. Fetterly, R. Kwan, W-K. Chan: Employee of Athenex, D. Cutler: Employee and shareholder in Athenex, D. Kramer: Employee of Athenex; Shareholder in Athenex, All other authors have declared no conflicts of interest.
Angiogenesis is an important hallmark of cancer and a well-established target for anti-tumor treatment. Recent concept of tumor vessel normalisation (TVN) suggests a new approach to affect tumor microenvironment and opens novel therapeutic opportunities. PFKFB3, a rate-limiting enzyme, which can boost glycolysis through PFK-1 by production of its allosteric activator fructose-2,6-bisphosphate (F2,6BP), was shown to play an important role in endothelial cells (EC) metabolism. It was demonstrated that PFKFB3 knockdown resulted in 2-fold reduction of the total sprout length in human umbilical vein endothelial cells (HUVECs) (De Bock K. 2013) as well as inhibition of PFKFB3 in vivo could be beneficial for TVN, reduction of metastasis and promotion of chemotherapy (Cantelmo A.R. 2016).
Enzymatic activity was measured in cell free assay using recombinant full-length human PFKFB3. Relative F2,6BP level was measured in A549 cell extracts. Absolute level of fructose-1,6-bisphosphate (F1,6BP) in A549 cells was estimated by LCMS/MS and F1,6BP with isotopic tag for quantitative analysis. For in vitro studies of angiogenesis we used human EC spheroids. VEGF-A was added after polymerization as a stimulation factor. EC sprouting was quantified by measuring the sprout length cumulatively. In vivo studies are performed on syngeneic and xenograft models. Immunohistochemistry staining is used to describe angiogenesis together with standard tumor assessment.
Using our proprietary molecular modelling tool, we designed a series of novel small molecule PFKFB3 inhibitors to target the F2,6BP binding pocket, rather than occupying the ATP-pocket, which leads to highly selective inhibition and strong reduction of potential off-target binding. Lead seria has IC50 of 1-10 nM range in cell free assay, completely suppresses cellular level of F2,6BP (direct product of PFKFB3) and reduces the cellular level of F1,6BP (product of PFK-1) twice at EC50 < 1 µM. Inhibitors reduced HUVEC sprouting in vitro to basic level with EC50 1-10 µM in a dose-dependent manner. The additional results of tumor angiogenesis in vivo will be presented.
Pharmacological PFKFB3 inhibition using novel small molecule compounds impairs angiogenesis and has potential in anti-tumor treatment.
Gero LLC
Gero LLC
Gero LLC
K. Khodova: Employee and management team member in Gero LLC, T. Eremeeva, D. Shishov: Employee and patent co-author in Gero LLC, P. Fedichev: Co-founder, employee, management team member and patent co-author in Gero LLC
The use of food supplements as a treatment for cancer in the Philippines has been competing with surgery, chemotherapy, and radiation therapy, which are the standard treatment. For the past years, Annona muricata (soursop) supplements have dominated the market after a paper from the Philippine Department of Science and Technology revealed that it has anti-angiogenic activity on chick chorioallantoic angiogenic (CAM) assays. However, to date, there are no human cancer studies to support this claim. This study aimed to compare the level of anti-angiogenic activity of A. muricata leaf extracts with bevacizumab, a pure anti-angiogenic drug and paclitaxel, a chemotherapy agent with an anti-angiogenic property on CAM assays.
Ninety-six duck embryos were inoculated with
Mean branching points for
Bevacizumab and paclitaxel are far better anti-angiogenic agents than A. muricata extracts on CAM assays. While these are not human studies, our study clearly shows the superiority of bevacizumab and paclitaxel.
De La Salle University Manila- Chemical Engineering Department
De La Salle University Manila- Chemical Engineering Department
None
All authors have declared no conflicts of interest.
The isoflavone idronoxil has been shown to be an effective chemosensitizing agent across various tumour cell lines, with its selective inhibition of tumour specific NADH oxidase (ENOX2) identifying it as a prime drug candidate. Clinical trials of oral idronoxil, however, showed no clinical efficacy, due to rapid and complete Phase 2 metabolism and elimination of idronoxil. NOX66 is a formulation of idronoxil within a fatty acid base which, when delivered rectally, may protect idronoxil from complete Phase 2 metabolism and rapid elimination. Here we will present interim results from the first human study, discussing the safety of NOX66 at two doses and inital efficacy findings of low dose NOX66 in combination with low dose carboplatin.
Patients (16) with end stage, refactory solid tumours, and no further therapy options available, were allocated to one of two treatment cohorts, receiving NOX66 at a dose of 400mg or 800mg of idronoxil daily.
Recruitment for the study was completed in September 2017. As of October 2017, there have been no adverse events associated with NOX66 that have led to study discontinuation. Cohort 1, Low dose (AUC4) carboplatin treatment with NOX66 (400mg) has completed, with 5 of the 8 patients reporting Stable Disease and one patient reporting Disease Progression. Two patients could not be evaulated (1 withdrawal, 1 non-evaluable lesion).
NOX66 in combination with carboplatin is well tolerated, with efficacy data for patients receiving low dose-low dose combination therapy providing evidence to suggest that NOX66 may sensitize end stage solid tumours to chemotherapy.
Protocol NOX66-001A; NCT02941523
Noxopharm Limited
Noxopharm Limited
G. Kelly, I. Minns: Employee of the sponsor organization, Noxopharm Limited. M. Messina: Employee and shareholder of the sponsor company, Noxopharm Limited.
A recent Phase I study of metronomic oral vinorelbine (60mg, 90mg and 120mg) per week and 200mg BID sorafenib in Asian NSCLC patients performed by our group showed that the combination of 60mg/week vinorelbine and 200mg BID sorafenib correlated with better survival and response. We herein report the pharmacokinetics (PK) profile of metronomic vinorelbine at these three doses in combination with 200mg BID sorafenib in Asian NSCLC patients to better understand the pharmacology of this low dose combination treatment.
Thirty-five NSCLC patients were randomly allocated into two treatment schedules S1 (N = 19) and S2 (N = 16) and sub-grouped to receive either oral vinorelbine at three dose levels on Day 1 followed by 200mg sorafenib BID on Day 17 (S1) and vice-versa (S2). PK analysis of samples collected at steady-state on Days 15 and 29 from each group were quantified using LC-MS/MS. PK parameters were derived using non-compartmental analysis. Statistical analyses were performed on GraphPad Prism 6.0c.
Higher exposure of vinorelbine as determined by these PK parameters (average vinorelbine concentrations (Cav), area under the plasma-concentration curve (AUC0-∞) and vinorelbine clearance (CL/F)) was observed in 60mg/week cohort compared to that of 90mg/week group in S1 on Day 15. [60mg/week vs 90mg/week respectively Cav: 2.62 ng/mL vs 0.57 ng/mL,
This pilot study illustrates that 60mg/week vinorelbine confers a more superior PK profile and improved clinical response compared to 90mg/week or 120mg/week. Future studies should investigate the combined therapeutic effect of 60mg/week vinorelbine and 200mg BID sorafenib in a Phase II efficacy trial.
National Cancer Centre Singapore
National Cancer Centre Singapore
National Medical Research Council
All authors have declared no conflicts of interest.