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 Patients with progressive disease and/or toxicity-related dose delay of more than 14 days were withdrawn.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 He was withdrawn because of disease progression but died after another 25 months.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 After one more cycle with 300 mg bid he was withdrawn due to clinical and radiographic worsening and died 11 months later.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.