Phase I/II Clinical Trial of the Safety, Tolerability, and Anti-tumor Efficacy of the IGF-1R Inhibitor, AXL1717 (Picropodophyllin), in the Treatment of Recurrent Malignant Astrocytomas
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I - Determine recommended Phase II dose.
To determine the recommended phase II dose (RPTD) of AXL1717 in recurrent malignant astrocytomas
Robert Aiken, MD
Rush University Medical Center
United States: Food and Drug Administration
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