K. Mross

Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study

Background:In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC).Methods:Patients received oral regorafenib 60–220u2009mg daily (160u2009mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics.Results:Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160u2009mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66–161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients.Conclusion:Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500u2009mg BID continuous dosing. Telatinib was rapidly absorbed with median tmax of 3 hours or less. Geometric mean Cmax and AUC0−12 increased in a less than dose-proportional manner and plateaued in the 900–1500u2009mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC0−12 of telatinib. Telatinib is safe and well tolerated up to a dose of 1500u2009mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900u2009mg telatinib BID continuously administered was selected as the recommended phase II dose.

Phase I dose-escalation and pharmacokinetic (PK) study of a(6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) in patients with advanced cancers

2125 Background: The anthracyclines are among the most useful agents in the treatment of solid malignancies and exhibit a wide range of antitumor activity. Adriamycin is most commonly used, but therapy is associated with significant bone marrow and organ toxicities. Therefore, an albumin-binding prodrug of adriamycin with acid-sensitive properties, i.e. (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), was developed that binds to circulating albumin with high affinity after intravenous application in a first step thus preventing rapid diffusion of adriamycin into healthy tissue. Due to a passive accumulation of albumin in solid tumors, DOXO-EMCH is targeted to the tumor and releases adriamycin in the acidic environment of tumor tissue. DOXO-EMCH has shown superior antitumor efficacy and an improved toxicity profile in various animal models compared to adriamycin. The objectives of this phase I trial is to evaluate the safety profile and pharmacokinetics of DOXO-EMCH in order to assess the maximum tolerated dose (MTD), evaluate dose-limiting toxicity (DLT), and to preliminarily assess the antitumor activity of intravenous single dosing in 3 week intervals in patients with advanced cancer.nnnMETHODSnCohorts of 3 patients with advanced cancer disease were treated with an intravenous infusion of DOXO-EMCH over 30 minutes once every 3 weeks at dose levels 27 mg/m2 (20 mg/m2 adriamycin equivalent), 54 mg/m2 (40 mg/m2 adriamycin equivalent) and 108 m2 (80 mg/m2 adriamycin equivalent) so far. Blood sampling for of PK analysis was performed.nnnRESULTSn10 patients (6 female, 4 male) were treated with DOXO-EMCH so far, median age was 55.8 years. Treatment with DOXO-EMCH was well tolerated up to 40 mg/m2 adriamycin equivalent, whereas treatment with 54mg/m2 adriamycin equivalent was still ongoing. The MTD was not established. One out of 3 patients evaluable for response had a minor response after 2 cycles of DOXO-EMCH dosed with 27 mg/m2.nnnCONCLUSIONSnIntravenous infusion once every 3 weeks of DOXO-EMCH was well tolerated and showed potential antitumor activity. The study is ongoing. No significant financial relationships to disclose.