L. van Doorn

A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.

Conjunctive Therapy of Cisplatin With the OCT2 Inhibitor Cimetidine: Influence on Antitumor Efficacy and Systemic Clearance

The organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules, and inhibition of OCT2 protects against severe cisplatin‐induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors, such as cimetidine, can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV‐1 cells). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase‐tagged IGROV‐1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m2) in a randomized crossover fashion with or without cimetidine (800 mg × 2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs. 4.38 µg·h/ml; P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin‐induced nephrotoxicity.

A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours

Background:The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours.Methods:Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m−2 with 75 mg m−2 docetaxel, then from 30 to 35 mg m−2 with 100 mg m−2 docetaxel. Recommended phase II dose cohorts were expanded.Results:Fifty-eight patients were treated. Recommended phase II doses were 35 mg m−2 ombrabulin with 75 mg m−2 docetaxel (35/75 mg m−2; 13 patients) and 30 mg m−2 ombrabulin with 100 mg m−2 docetaxel (30/100 mg m−2; 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m−2 docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m−2 ombrabulin), eight lasting >3 months.Conclusions:Sequential administration of ombrabulin with 75 or 100 mg m−2 docetaxel every 3 weeks is feasible.

Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1–5 of a 3-weekly cycle in patients with advanced solid tumours

XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1–5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day−1. For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day−1, with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day−1 tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12–30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1–5 every 21 days. Alternative regimens are currently being explored.

Influence of OATP1B1 Function on the Disposition of Sorafenib‐β‐D‐Glucuronide

The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9‐mediated formation of sorafenib‐β‐D‐glucuronide (SG). Using transporter‐deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver‐to‐blood shuttling loop via ABCC3‐mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B‐type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2‐deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug–drug interaction studies of agents that undergo extensive phase II conjugation.

Molecular Variants of HPV Type 16 E6 Among Honduran Women.

Objective: In this study, we investigated the prevalence of human papillomavirus 16 (HPV-16) variants in Honduran women with normal cytology and with dysplasia and cervical cancer. Methods: Samples identified as positive for HPV-16 by SPF10-LiPA were tested for intratypic subtypes and variants by analysis of the E6/E7 region using a novel reverse hybridization assay (line probe assay). Results: We found that most infections in all clinical groups belong to the E6 European variants, suggesting that HPV-16 non-European variants do not represent an additional factor associated with increased occurrence of high-grade cervical lesions in the studied population. Among the 106 HPV-16-positive women analyzed, E-350G was the most prevalent variant in all different disease stages, being present in 18% of cervical cancer, 13% of cervical intraepithelial neoplasia grade III (CIN III), 5% of CIN II, 5% of CIN I, and 20% of control samples. Mixed variants of HPV-16 infections were detected in 7.7% of the samples, mostly in women with normal cytology. Conclusions: This study shows for the first time the diversity of HPV-16 variants in cervical samples of Honduran women.

486PINDIVIDUALIZED PHARMACOKINETICALLY-GUIDED DOSING OF PAZOPANIB: A FEASIBILITY STUDY IN CANCER PATIENTS

ABSTRACT Aim: Retrospective analyses of clinical studies of pazopanib showed an increased median PFS in patients with plasma trough levels (TLs) ≥ 20.6 mg/L compared to patients with lower TLs (49.4 wks vs. 20.3 wks). This is in line with preclinical data showing optimal efficacy at concentrations above 17.5 mg/L. Due to inter-individual variability in plasma exposure, target TLs are not reached in ∼30% of patients with the current dosing schedule of 800 mg daily. Therefore, a Phase I study was performed to determine the safety and feasibility of pharmacokinetically (PK)-guided dosing of pazopanib. Methods: 30 patients with solid tumors with a potential benefit from pazopanib treatment were included. Weekly TLs were measured by LC-MS/MS. At week 3, 5 and 7 the dose could be increased when the measured TL was Results: At data cut-off (April 2014) the planned total of 30 patients was included of which 26 patients had completed the PK evaluation period of 8 weeks or had stopped treatment due to toxicity (n = 4). 14 out of 26 patients had at least one TL below the target during this period. Of these, 8 patients had successful dose increases of 25% to 125% (1,000 to 1,800 mg), without non-tolerable toxicity. The mean TL (CV%, range) increased from 12.3(41.9, 7.80 – 22.5) to 22.4 (44.0, 8.77 – 43.1) mg/L. In the remaining 6 patients dose escalation was not possible due to toxicity. 12 out of 26 patients had all TLs above target. Of these 12 patients, 8 patients needed a dose reduction due to grade 3 and 4 toxicity and, therefore, the mean TL in this group decreased from 49.1 (39.9, 30.2 – 79.5) to 26.3 (27.5, 17.8 – 36.0) mg/L. Conclusions: Individualized pharmacokinetically guided dosing of pazopanib is feasible and safe and leads to a higher proportion of patient reaching the desired target exposure. Additional (randomized) clinical trials on outcome parameters such as response rate and progression free survival are needed. Disclosure: All authors have declared no conflicts of interest.

Contralateral Breast Cancer in BRCA1/2 Mutation Carriers: Risk Assessment by Age at Diagnosis of the First Primary Breast Cancer.

PurposeAge at diagnosis of the first breast cancer is a known predictive factor of the risk of contralateral breast cancer (CBC) in BRCA1/2 mutation carriers. However, accurate risk estimates for different age subgroups are scarce.Methods We studied the risk of CBC in 560 women with a primary breast cancer (PBC) from families with a proven BRCA1 or BRCA2 mutation in relation to the age at diagnosis of the first PBC, taking into account history of oophorectomy. Time at risk was the period between diagnosis of the first PBC and date of contralateral breast cancer, contralateral mastectomy, metastatic disease, death or last follow-up. Oophorectomy was treated as a time-dependent covariate. Patients with bilateral breast cancer diagnosed before the first visit at the family cancer clinic were excluded.Results We observed 96 CBCs in 423 BRCA1 mutation carriers and 21 cases in 137 BRCA2 mutation carriers. Actuarial risk of CBC at 5, 10 and 15 years was 14%, 34% and 39%, respectively, for BRCA1-, and 13%, 22% and 27%, respectively, for BRCA2 mutation carriers. For BRCA1 carriers 10-year actuarial risk of CBC was 54% for women with a PBC ≤ 30 years, 39% for the group with PBC between 31-40 years, 26% for the 41-50 group and 17% for those with PBC > 50 years. In BRCA2 carriers 10-year risk of CBC was 28% for women with a PBC ≤ 40 years, 19% for the 41-50 group and 10% for those with PBC > 50 years. For BRCA1 carriers who had an oophorectomy, 10-year risk of CBC was 33% and 26%, respectively, for those with PBC younger and older than 40 years, against 44% and 24% in women who had no such treatment. In BRCA2 carriers with a history of oophorectomy 10-year risk of CBC was 21% and 14%, respectively, for those with PBC younger and older than 40 years, while the risk was 29% and 17%, respectively, in women without oophorectomy. Effect of adjuvant therapy is being analyzed and will be presented at the meeting.Conclusions The availability of risk estimates of CBC by more detailed age groups at PBC is a helpful tool in the counselling process concerning screening and/or preventive surgery for breast cancer patients with a BRCA1 or BRCA2 mutation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 903.