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

This is a single-center, open-label, non-randomized, Phase I/IIa study to investigate the safety, tolerability, and antitumor efficacy of AXL1717 (picropodophyllin as active agent formulated in an oral suspension; PPP) in patients with recurrent malignant astrocytomas (glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, and anaplastic ependymoma). Patients will be treated for up to 5 cycles. A treatment cycle is defined as 28 days+7 days rest (28+7 days during cycle 1 to 4, and 28 days during cycle 5). The following cycle will not be started until the treatment continuation criteria are fulfilled. Concomitant supportive therapies will be allowed.

AXL1717, as a ready-to-use suspension of picropodophyllin for oral administration, will be distributed in bottles for single use at a concentration of 25 mg/mL. Fixed doses will be used, i.e. there are no adjustments for weight or body surface. There will be no randomization or blinding in the study.

The trial will be divided in two phases. In the first phase, 10-20 patients will be enrolled and treated with 300-520 mg BID of AXL1717 for 28 days. The primary endpoint of the first phase is to determine the recommended Phase 2 dose (RP2D) of AXL1717 in patients with recurrent or progressive glioblastoma and to assess the safety and toxicity of AXL1717 in this patient population. The study has a 3+3 design and the first cohort will be treated with 400 mg AXL1717 BID for 28 days repeated in up to 5 cycles. If dose-limiting toxicity (DLT) such as neutropenia occurs, dosing will be interrupted and the individual patient will, following normalization, be restarted on the same or a lower dose level according to standardized procedure. If two or three of the first 3 patients on a specific dose level experience a DLT during the first 28 days of treatment with AXL1717, the following patients will be treated with a lower dose level. If one DLT occurs during the first 28 days of dosing in the first 3 three patients another 3 patients will be treated with the same dose level. If 2 of the 6 patients display DLT, the next patients will be treated with a lower dose level. The highest dose level without DLT or with maximally one DLT out of 6 patients will be the RPTD. All assessments with respect to dose adjustments for subsequent cohorts will be done during the first 28 days of treatment. Non-progressing patients may be treated for a total of five 28-day cycles (24 weeks).

In the second phase, 12 patients will be enrolled and treated with the identified RP2D of AXL1717 for 28 days repeated in five cycles. The primary endpoints of phase II is to assess the proportion of patients who are progression-free at 24 weeks and to assess safety, tolerability, and adverse event profile of AXL1717.

Eligibility Criteria:
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