2569 Background: Paclitaxel has poor oral bioavailability due to the active excretion by p-glycoprotein (Pgp) present on intestinal epithelial cells. Oraxol (Kinex) is a combination of oral paclitaxel and HM30181, a novel, orally administered, non-absorbed specific inhibitor of intestinal Pgp. Oral paclitaxel would avoid the need for IV injections, avoid severe anaphylactic reactions and the side-effects of steroid pre-medication, cost savings and greater patient convenience. We report the absolute bioavailability of Oraxol compared to IV paclitaxel. Methods: We conducted an open label, randomized cross-over pharmacokinetic (PK) study to determine the bioavailability (PK, AUC) and safety of escalating doses of Oraxol over 2 days compared to IV paclitaxel 80mg/m2 over 1 hour in patients with incurable cancer receiving weekly paclitaxel. Following written informed consent, patients were randomized to receive either Oraxol followed one week later by IV paclitaxel or the reverse sequence. Six patients (4 F 2 M) received two daily doses of 270mg. Following review of safety and PK results, two patients were treated with Oraxol 274mg/m2 x 2 days, and then two patients received 313mg/m2 x 2 days. Results: Oraxol was well tolerated with no grade 3/4 drug toxicities at any of the dose levels. AUC0-∞ and Cmax increased with increasing Oraxol dose from 270mg to 274mg/m2 but not with dose escalation to 313mg/m2. Conclusions: Oraxol 615 mg/m2 over 2 days achieved paclitaxel AUC comparable to IV paclitaxel 80 mg/m2. Oraxol safety profile was acceptable without grade 3-4 toxicities. Oraxol represents an ideal drug candidate to replace IV paclitaxel. Clinical trial information: 12614000365662.Oraxol concentration normalised to 615 mg/m2 compared to IV paclitaxel 80 mg/m2 for all subjects. Oraxol Paclitaxel IV AUC0- ¥ (ng.hr/ml) 8638.80±8155.07 (3074.24 – 29773.62) 6824.85±3181.03 (4039.04 – 13862.91) AUC0-t (ng.hr/ml) 6336.42±3408.91 (2928.44 – 12566.67) 6289.23±2397.61 (3911.52 – 10531.10) Cmax0-24 (ng/ml) 572.59±301.88 (330.37 – 1122.34) Cmax24-48 (ng/ml) 448.15±229.01 (292.74 – 913.91) Cmax (ng/ml) 2492.47±362.46 (2025.67 – 3127.89) T1/2 (hr) 48.78±30.76 (21.31 – 128.32) 21.85±8.17 (11.38 – 42.04)
2569 Background: Paclitaxel has poor oral bioavailability due to active excretion by p-glycoprotein (Pgp) on intestinal epithelial cells. An oral formulation would reduce IV access, avoid allergic reaction to cremophor, forego steroid premedication, reduce day stay, and improve convenience. With a lower Cmax, oral therapy may have toxicity advantages. Oraxol (Athenex, USA) is a combination of HM30181, a novel, orally active, potent and specific inhibitor of Pgp with low systemic exposure and oral paclitaxel. We report the results of the first scheduled interim analysis of a bio-equivalence study of Oraxol compared to IV paclitaxel, and the results of an extension study with repeat PK sampling after 4 weeks administration. Methods: We conducted a randomized crossover study at 3 sites in New Zealand. HM30181 15mg plus paclitaxel 205mg/m2 was given PO on days 1-3 and compared to a single dose of IV paclitaxel (80 mg/m2) in patients (pts) with advanced solid tumours. PK blood samples were taken d1-9 for PO paclitaxel and d1-5 for IV paclitaxel. Pts who completed were permitted to enroll on an extension study of Oraxol 205mg/m2 d1-3 q1w with repeat PK sampling at week 4. Results: Paclitaxel PK was compared from the first 6 pts in the bioequivalence study, to 10 pts that were enrolled in the extension study. There was one treatment related SAE (tachycardia) which resolved. Treatment related toxicities were mostly GI and haematological, and manageable. One pt remains on study > 1 year without neuropathy. Clinical trial information: ACTRN12615000894594. Conclusions: Oraxol 615mg/m2 PO d1-3 achieved paclitaxel AUC comparable to IV paclitaxel 80mg/m2. This schedule of Oraxol is within predicted range needed to demonstrate bioequivalence. 4-week PK results show PK profile is not altered with repeated dosing. A phase 3 study in patients with metastatic breast cancer is ongoing. Paclitaxel 80mg/m2 IV (n = 6) Mean (SD) Oraxol, Baseline (n = 6) Mean (SD) Oraxol Week 4 (n = 10) Mean (SD) AUC0-∞, (hr*ng/mL) 5652 (1013) 5078 (1723) Cmax (ng/mL) 2269.44 (227.11) 230.99 (133.84) 238.8 (86.11) AUC0-56 2493.4 (731.96) 2615.04 (707.14) GMR (%, 90% CI) 87.09 (74.61-101.66) Intra-subject CV (%) 12.62
Dermatomyositis has a known association with malignancy. We report a case of dermatomyositis occurring in early-stage testicular cancer where the patient was in remission. It stresses the importance of considering testicular cancer as an association with dermatomyositis, as it is a potentially curable malignancy.
Background and purpose: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80mg/m2. Experimental approach: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615mg/m2 divided over three days and encequidar 15mg orally one-hour prior, followed by IVP 80mg/m2, or the reverse sequence. PK blood samples were taken up to day 9 for oPac+E and day 5 for IVP. Key Results: 42 pts were enrolled; 35 completed both treatment periods. AUC0-∞was 5033.5 +/- 1401.1 ng.h/mL for oPac+E and 5595.9 +/- 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.5% (90% CI 83.9-95.5). Mean absolute bioavailability of oPac+E was 12%. PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment emergent adverse events occurred in 7 (18%) pts with oPac+E and 2 (5%) with IVP. 75% of pts preferred oPac+E over IVP. Conclusion and Implications: GMR for AUC was within the predefined acceptable range of 80%-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E is a candidate to replace IVP.
Abstract There is limited published literature on the risk of breast cancer in transgender patients. We report a case of an aggressive triple negative inflammatory breast cancer in a male‐to‐female transsexual. This patient had a complicated psychiatric history with significant antipsychotic use, and the case raises several questions about the pathogenesis of this breast cancer. The literature on breast cancer in transgender patients and in relation to hyperprolactinaemia is reviewed.
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