A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. Material and methods. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. results and conclusion. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.
Background
The incidence of lung cancer has increased throughout the twentieth century and is today the most common cancer in the Western World. Lung cancer is divided into two major histological subtypes, non-small cell lung cancer (NSCLC) accounting for approximately 80% of all lung cancer cases and small cell lung cancer (SCLC) accounting for approximately 20 % of all lung cancer cases. The median age at diagnosis is 68 years for patients with non-small cell lung cancer (NSCLC) and 20% of lung cancer deaths occur in patients aged 80 or more. The overall objective of the present abstract is to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related Insulin receptor and its impact in patients with especially NSCLC.
Methods
AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7-28 days of increasing BID doses of AXL1717.
Results
In the present abstract we describe our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with AXL 1717. Despite the fact that at inclusion these patients had already received third or fourth line treatment, treatment with AXL1717 resulted in more than seven months of treatment response within the study protocol and the reported patients did not develop any additional metastases. Furthermore, these patients demonstrated large central necrotic areas, which may suggest tumor response.
Conclusion
This first clinical study of AXL1717 has shown that the agent can be administrated safely orally to advanced stage cancer patients resulting in good bioavailability and tolerability. Encouraging signs of tumor response were seen in patients with NSCLC. Further update of these patients as well as a compilation of all included patients with NSCLC, as well as their toxicity, will be reported at the meeting
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2011-1276
The acute hemodynamic response to captopril (8 patients) and enalapril (8 patients) was evaluated in congestive heart failure patients in NYHA functional class III. All patients had a history of congestive heart failure for more than six months. The results show marked interindividual variations but average values for cardiac output increase and decrease in filling pressures agree with findings in the literature. 6 patients in the captopril group and five in the enalapril group were started on maintenance therapy. One patient in the captopril group deteriorated and underwent a successful heart transplantation and one patient in the enalapril group returned with arrhytmias and hypertension (probably not drug-related) after 48 h of therapy. Our data indicate that activation of the renin-angiotensin system through excessive administration of loop-diuretics is associated with a risk of hypovolemia and thus drug-induced hypotension that deserves special attention when considering converting enzyme inhibitor therapy in congestive heart failure.
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