Anaplastic Astrocytoma, Anaplastic Ependymoma, Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Glioblastoma, Gliosarcoma
Conditions
Keywords
glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, AXL1717, IGF-1 receptor inhibitor, picropodophyllin
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.
Interventions
DRUGAXL1717
IGF-1 receptor inhibitor
Sponsors
Axelar AB
Rush University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 - 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). |
| 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 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Endpoint - Determine Antitumor Effect | 4 months | To assess the ability of AXL1717 to inhibit tumor proliferation as assessed by blood IGFBP-1 through IGFBP-7, growth hormone (GH) levels, C-peptide, IGF-1 (free and total), and IGF-2 levels, insulin, and analysis of tumor tissue of patients treated with AXL1717 for 5 days before surgical re-operation by examining for the IGF-1R signal transduction pathway in the resected brain tumor tissue, and correlate with outcome. |
Countries
United States
Participant flow
Pre-assignment details
One patient was excluded from the study after screening but before treatment and is not considered in this analysis.
Participants by arm
| Arm | Count |
|---|---|
| AXL1717, 400mg Initial Dose Subjects who started and completed the study on 400mg BID | 2 |
| AXL1717, 300mg Initial Dose Subjects who started the study on 300mg BID. one subject was escalated to 400mg BID and 2 subjects were de-escalated to 215mg BID | 7 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Dose Escalation to 400mg BID | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
Baseline characteristics
| Characteristic | AXL1717, 400mg Initial Dose | AXL1717, 300mg Initial Dose | Total |
|---|---|---|---|
| Age, Continuous | 58 Years | 56.2 Years | 56.6 Years |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 0 / 7 | 0 / 2 |
| other Total, other adverse events | 0 / 3 | 1 / 7 | 1 / 2 |
| serious Total, serious adverse events | 2 / 3 | 3 / 7 | 1 / 2 |
Outcome results
Primary
Phase I - Determine Recommended Phase II Dose
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.
Time frame: 8 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | Phase I - Determine Recommended Phase II Dose | NA MG |
Primary
Phase II - To Determine if AXL1717 Has Any Antitumor Effect
To determine if AXL1717 has any antitumor effect as a single agent treatment in recurrent malignant astrocytomas by evaluating PFS at 24 weeks
Time frame: 24 Weeks
Population: Phase II of this study was never initiated and so no data was collected or analyzed for this endpoint.
Secondary
Phase II - Identify Evidence of Response on Imaging
To identify surrogate imaging evidence of response on MRI sequences (especially T2- FLAIR, DWI, Perfusion MRI and multi-voxel MRS).
Time frame: 8 Months
Population: Phase II of the study was never initiated.
Secondary
Phase II - Overall Response Rate
To assess overall response rate (ORR) in recurrent malignant astrocytomas after treatment with AXL1717
Time frame: 4 months
Population: Phase II of the study was never initiated. No data was gathered or analyzed.
Secondary
Phase II - Time-To-Progression (TTP) and Overall Survival (OS)
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.
Time frame: 4 months
Population: Phase II of this study was never initiated and so no data was collected or analyzed for this endpoint.
Secondary
Phase I - Molecular Markers of IGF (Insulin Like Growth Factor)-1R Pathway
To evaluate surrogate molecular markers of IGF-1R pathway activation/inhibition after treatment with AXL1717 in patients with malignant astrocytomas
Time frame: 8 months
Population: None of the secondary outcome measures were collected or analyzed as this study was conducted using the oral suspension of AXL1717 and there is a new formulation of AXL1717 in development (capsule). Decision was made to abandon other analysis or data collections in regards to secondary outcomes.
Secondary
Phase I - Molecular Markers of Optimum Response
To assess potential molecular markers that might predict optimum response sub-population groups
Time frame: 8 months
Population: the data for this outcome measure was not collected and/or analyzed. There is no data to report.
Secondary
Phase I - To Identify the Maximum Tolerable Dose
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.
Time frame: 8 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | Phase I - To Identify the Maximum Tolerable Dose | 300 MG |
Other Pre-specified
Exploratory Endpoint - Determine Antitumor Effect
To assess the ability of AXL1717 to inhibit tumor proliferation as assessed by blood IGFBP-1 through IGFBP-7, growth hormone (GH) levels, C-peptide, IGF-1 (free and total), and IGF-2 levels, insulin, and analysis of tumor tissue of patients treated with AXL1717 for 5 days before surgical re-operation by examining for the IGF-1R signal transduction pathway in the resected brain tumor tissue, and correlate with outcome.
Time frame: 4 months
Population: Phase II portion of this study was not initiated as the phase 1 piece was not completed fully. This endpoint was not explored and data was not collected or analyzed
Post Hoc
Phase I Subjects - Imaging Evidence of Response.
Number of Participants with Imaging Evidence of Response on MRI (magnetic resonance imaging)sequences by RANO criteria (with additional special attention to T2-FLAIR, DWI (diffusion-weighted imaging), perfusion MRI and multi-voxel MRS (magnetic resonance spectroscopy) sequences).
Time frame: 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Study Participants | Phase I Subjects - Imaging Evidence of Response. | 0 Participants |
| AXL1717, 300mg Initial Does | Phase I Subjects - Imaging Evidence of Response. | 5 Participants |