Phase I/II Trial of the Safety, Tolerability, and Anti-tumor Efficacy of AXL1717 (Picropodophyllin) in the Treatment of Recurrent Malignant Astrocytomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Rush University Medical Center
Sponsor:
Collaborator:
Axelar AB
Information provided by (Responsible Party):
Robert Aiken, M.D., Rush University Medical Center
ClinicalTrials.gov Identifier:
NCT01721577
First received: October 29, 2012
Last updated: November 4, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Glioblastoma
Gliosarcoma
Anaplastic Astrocytoma
Anaplastic Oligodendroglioma
Anaplastic Oligoastrocytoma
Anaplastic Ependymoma
Drug: AXL1717
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Rush University Medical Center:

Primary Outcome Measures:
  • Phase I - Determine recommended Phase II dose. [ Time Frame: 8 months ] [ Designated as safety issue: Yes ]
    To determine the recommended phase II dose (RPTD) of AXL1717 in recurrent malignant astrocytomas

  • Phase II - Determine Antitumor effect [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    To determine if AXL1717 has any antitumor effect as a single agent treatment in recurrent malignant astrocytomas by evaluating progression-free-survival (PFS) at 6-months.

  • Phase I - Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    • physical/neurological examinations (pathological findings and quality and quantity)
    • adverse events (quality and quantity per dose level)
    • vital signs, ECG, laboratory parameters (pathological findings as quality and quantity, for laboratory parameters, descriptive statistics)


Secondary Outcome Measures:
  • Phase I - Maximum Tolerated Dose (MTD) [ Time Frame: 8 months ] [ Designated as safety issue: Yes ]
    To identify the MTD of AXL1717.

  • Phase I - Molecular markers of optimum response [ Time Frame: 8 months ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 8 months ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    To determine time-to-progression (TTP) and overall survival (OS) of patients treated with AXL1717

  • Phase II - Overall Response Rate [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    To assess overall response rate (ORR) in recurrent malignant astrocytomas after treatment with AXL1717

  • Phase II - Imaging Evidence of Response. [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    To identify surrogate 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).


Estimated Enrollment: 30
Study Start Date: December 2012
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AXL1717
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 and to assess the safety and toxicity of AXL1717. 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. 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).
Drug: AXL1717
IGF-1 receptor inhibitor
Other Name: picropodophyllin

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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. At least seven (7) days off of medications with induce CYP2C9 and CYP3A4 before administration of the first dose of AXL1717
  10. 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. Ongoing infection 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, including, but not limited to, active cardiac disease and significant dementia
  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. Post menopause is defined as: amenorrhea ≥ 12 consecutive months without another cause.
  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
  17. Patients who must take concomitant medications which induce or are potent inhibitors of CYP2C9 or sensitive substrates of CYP3A4 with narrow therapeutic range may not participate (see Appendix 7)
  18. Lack of suitability for participation in the trial, for any reason, as judged by the Investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01721577

Contacts
Contact: Robert Aiken, MD 312-563-3452 robert_aiken@rush.edu
Contact: Jeanne Sixta, RN 312-942-2388 jeanne_sixta@rush.edu

Locations
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Jeanne Sixta, RN    312-942-2388    jeanne_sixta@rush.edu   
Principal Investigator: Robert Aiken, MD         
Sponsors and Collaborators
Rush University Medical Center
Axelar AB
Investigators
Principal Investigator: Robert Aiken, MD Rush University Medical Center
  More Information

Publications:
Ekman, S., et al., Clinical Phase I study with an Insulin-like Growth Factor-1 Receptor Inhibitor: Experiences in patients with squamous non-small cell lung carcinoma. Acta Oncologica 2010.
Yin, S., et al., Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro-Oncology, 2010. 12(1): p. 19-27.

Responsible Party: Robert Aiken, M.D., Associate Professor, Neurological Sciences, Rush University Medical Center
ClinicalTrials.gov Identifier: NCT01721577     History of Changes
Other Study ID Numbers: 11090804, VABC; GCR
Study First Received: October 29, 2012
Last Updated: November 4, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Rush University Medical Center:
glioblastoma
gliosarcoma
anaplastic astrocytoma
anaplastic oligodendroglioma
anaplastic oligoastrocytoma
AXL1717
IGF-1 receptor inhibitor
picropodophyllin

Additional relevant MeSH terms:
Astrocytoma
Ependymoma
Glioblastoma
Oligodendroglioma
Gliosarcoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

ClinicalTrials.gov processed this record on July 26, 2014