Phase I/II Trial of AXL1717 in the Treatment of Recurrent Malignant Astrocytomas

Inclusion criteria

1. Be informed of the nature of the study and have provided written informed consent
2. At least 18 years of age
3. ECOG performance of 0, 1, or 2, or KPS (Karnofsky performance status) ≥ 60.
4. Pathological verification of a WHO grade 4 astrocytoma (glioblastoma or gliosarcoma), or WHO Grade 3 anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplastic ependymoma.
5. Documented recurrent glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplastic ependymoma after at least one failed treatment of chemotherapy and radiation
6. Expected survival of at least 3 months
7. At least 2-weeks from cytoreductive surgery, if performed, 4-weeks from bevacizumab or other chemotherapy (6-weeks if prior chemotherapy was nitrosourea) and 12-weeks from completion of radiotherapy.
8. Ability to undergo MRI scanning without and with imaging dye on a periodic basis as defined in the protocol
9. Preserved major organ functions, i.e: Blood leukocyte count ≥ 3.0 x 109/L Blood absolute neutrophil count ≥ 1.5 x 109/L Blood platelet count ≥ 100 x109/L Blood hemoglobin ≥ 100 g/L (transfusions are allowed) Plasma total bilirubin level ≤ 1.5 times the upper institutional limit (ULN) of the ‖normal‖ (i.e. reference) range Plasma AST (aspartate aminotransferase) or ALT ≤ 2.5 times upper institutional limit (ULN) of the ‖normal‖ range Plasma creatinine ≤ 1.5 times upper institutional limit (ULN) of the ‖normal‖ range 12-lead ECG with normal tracings; or changes that are not clinically significant and do not require medical intervention, and QTc \< 500 ms At least seven (7) days off of medications which inhibit or induce CYP2C9 or CYP3A4 before first study treatment day

Exclusion criteria

1. Any or other major recent or ongoing disease that, according to the Investigator, poses an unacceptable risk to the patient
2. Grade 3 or higher constipation within the past 28 days or grade 2 constipation within the past 14 days before randomization. (Patients with grade 2 constipation within the past 14 days could be re-screened if constipation decreases to ≤ grade 1 with optimal management of constipation.)
3. Coexisting uncontrolled medical condition.
4. Hepatitis B or Hepatitis C, or HIV infection requiring anti-retroviral therapy
5. Active malignancy other than basal cell skin cancer
6. Other active malignancy during the previous 3 years
7. Major surgical procedure within 4 weeks
8. Prior stereotactic or gamma knife radiosurgery or proton radiation, unless unequivocal progression by functional neuro-imaging (PET, dynamic MRI, MRS, SPECT) or by re-operation with documented histologic confirmation of recurrence.
9. Prior anti-tumor therapy, as follows: at least 12-weeks from radiation therapy; at least 4-weeks from prior treatment with temozolomide or bevacizumab, 6-weeks from BCNU or CCNU.
10. Women of child bearing potential (WOCBP) who do not consent to using acceptable methods of birth control (oral contraceptives, IUD). For purposes of this study, WOCBP include any female who has experienced menarche, who has not undergone tubal ligation, and who is not postmenopausal.
11. Medically uncontrolled Type 1 or Type 2 diabetes mellitus
12. Pregnancy or lactation
13. Current participation in any other investigational clinical trial within 4-weeks.
14. Eastern Cooperative Oncology Group (ECOG) performance status \> 2 after optimization of medications (See Appendix 4) or KPS \< 60
15. Anticipated Life expectancy less than 3 months
16. Contraindications to the investigational product or known or suspected hypersensitivity