Phase I clinical trial of AXL1717 for treatment of relapsed malignant astrocytomas: analysis of dose and response.

PURPOSE: Early phase I study of safety of AXL1717 in patients with recurrent or progressive malignant astrocytomas and evaluation of preliminary anti-tumor efficacy. PATIENTS AND METHODS: Nine patients fulfilling the set criteria were enrolled. Eight had recurrent glioblastoma and one gliosarcoma. Patients were treated with an oral suspension of AXL1717 (215-400 mg bid) cycle-by-cycle in 35-day cycles (28 days bid and 7 days off). Patients with progressive disease and/or toxicity-related dose delay of more than 14 days were withdrawn. RESULTS: Four patients had tumor responses (44%) to AXL1717 treatment. Two of these had stable disease for 12 months (10 cycles at 215-300 mg bid). Due to MRI-detected progression they were then taken off the study. They died 8 and 12 months later, respectively. One patient was treated 8 months (6 cycles with 215 mg bid). He was withdrawn because of disease progression but died after another 25 months. The fourth patient having stable disease died of sepsis due to pancytopenia in the end of cycle 2 on 400 mg bid. A fifth patient underwent surgery after two cycles with 300 mg bid. Pathological analysis demonstrated abundant necrosis and small areas of viable tumor. After one more cycle with 300 mg bid he was withdrawn due to clinical and radiographic worsening and died 11 months later. The other 4 patients did not have any detectable responses and died within 3-13 months after trial entry. Neutropenia was the main adverse effect, which was easily detected and reversible in all but one patient. CONCLUSION: This clinical phase I study indicates that AXL1717 as a single agent is capable of producing prolonged stable disease and survival of patients with relapsed malignant astrocytomas. The drug was well tolerated. A new formulation of the drug will be used in further investigations in order to better define the optimal dose.

Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer.

BACKGROUND: The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT). MATERIAL AND METHODS: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400 mg of AXL as daily BID treatment (58 patients) or DCT given as 75 mg/m2 in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles. RESULTS: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL. CONCLUSION: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.

A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer.

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.

Comparison between direct humidification and nebulization of the respiratory tract at mechanical ventilation: distribution of saline solution studied by gamma camera.

AIM: To study the effectiveness of this procedure, an intra-individual pilot study comparing the distribution of an instilled radiolabelled saline solution and an inhaled nebulized radiolabelled saline solution was performed using a scintigraphic technique. BACKGROUND: In patients treated with mechanical ventilation, we have routinely used instillation of saline solution in the endotracheal tube before suctioning with the aim of softening mucus and facilitating removal of secretions. In our experience, the effectiveness of this procedure is doubtful. It may also have adverse effects. METHODS: Nine patients on mechanical ventilation were examined with Single Photon Emission Computed Tomography on the same occasion using both humidification methods. The entire examination was carried out with the patient kept in a constant position in relation to the gamma camera, thereby allowing subtraction of the first registration from the second registration and subsequent evaluation and digital comparison of the two humidification methods. RESULTS: Most of the instilled fluid goes to the posterior portion of the right lower pulmonary lobe. Compared with direct instillation, nebulized solution is more uniformly distributed between and within the lungs. With nebulization, distribution is less influenced by gravitation than with instillation. The aerosol reaches the periphery of the lung to a larger extent. CONCLUSIONS: Through the use of an aerosol with specific size characteristics, it may be possible to optimize the distribution of a fluid in the respiratory tract and achieve a more homogenous humidification. It is recommended to replicate the study using 25 subjects. Relevance to clinical practice. Direct instillation of saline should not be used with mechanical ventilation.