Phase I/II Trial of AXL1717 in the Treatment of Recurrent Malignant Astrocytomas
- Conditions
- GliosarcomaGlioblastomaAnaplastic AstrocytomaAnaplastic OligoastrocytomaAnaplastic EpendymomaAnaplastic Oligodendroglioma
- Interventions
- Registration Number
- NCT01721577
- Lead Sponsor
- Rush University Medical Center
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 10
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Phase 1: AXL1717, 300mg AXL1717 In the first phase, 10-20 patients will be enrolled and treated with 300mg (original range of starting dose was 300-520mg) BID of AXL1717 for 28 days. The primary endpoint of the first phase is to determine the recommended Phase 2 dose (RP2D) of AXL1717 and to assess the safety and toxicity of AXL1717. The study has a 3+3 design and the first cohort will be treated with 300 mg AXL1717 BID for 28 days repeated in up to 5 cycles. The highest dose level without DLT or with maximally one DLT out of 6 patients will be the RP2D. Non-progressing patients may be treated for a total of five 28-day cycles (24 weeks).
- Primary Outcome Measures
Name Time Method Phase I - Determine Recommended Phase II Dose 8 months To determine the recommended phase II dose (RPTD) of AXL1717 in recurrent malignant astrocytomas defined as the highest dose level without DLT (Dose Limiting Toxicity) or with maximally one DLT out of 6 patients will be the RPTD.
Phase II - To Determine if AXL1717 Has Any Antitumor Effect 24 Weeks To determine if AXL1717 has any antitumor effect as a single agent treatment in recurrent malignant astrocytomas by evaluating PFS at 24 weeks
- Secondary Outcome Measures
Name Time Method Phase I - To Identify the Maximum Tolerable Dose 8 Months To identify the Maximum Tolerated Dose (MTD) of AXL1717 in the Phase I subject population. MTD is the highest dose of AXL1717 with the lowest average per subject cases of DLT.
Phase I - Molecular Markers of Optimum Response 8 months To assess potential molecular markers that might predict optimum response sub-population groups
Phase I - Molecular Markers of IGF (Insulin Like Growth Factor)-1R Pathway 8 months To evaluate surrogate molecular markers of IGF-1R pathway activation/inhibition after treatment with AXL1717 in patients with malignant astrocytomas
Phase II - Time-To-Progression (TTP) and Overall Survival (OS) 4 months To determine time-to-progression (TTP) and overall survival (OS) of patients treated with AXL1717. Only overall survival for subjects is prolonged stable disease was analyzed.
Phase II - Overall Response Rate 4 months To assess overall response rate (ORR) in recurrent malignant astrocytomas after treatment with AXL1717
Phase II - Identify Evidence of Response on Imaging 8 Months To identify surrogate imaging evidence of response on MRI sequences (especially T2- FLAIR, DWI, Perfusion MRI and multi-voxel MRS).
Trial Locations
- Locations (1)
Rush University Medical Center
🇺🇸Chicago, Illinois, United States