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

NCT01721577 | Terminated Phase 1 Results DMC

• 2 other identifiers: 11090804VABC; GCR
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma; Anaplastic Ependymoma

Keywords

glioblastoma; gliosarcoma; anaplastic astrocytoma; anaplastic oligodendroglioma; anaplastic oligoastrocytoma; AXL1717; IGF-1 receptor inhibitor; picropodophyllin

Outcome Measures

Primary Outcomes (2)

• 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.

  8 months

• 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

  24 Weeks

Secondary Outcomes (6)

• Phase I - To Identify the Maximum Tolerable Dose

  8 Months

• Phase I - Molecular Markers of Optimum Response

  8 months

• Phase I - Molecular Markers of IGF (Insulin Like Growth Factor)-1R Pathway

  8 months

• Phase II - Time-To-Progression (TTP) and Overall Survival (OS)

  4 months

• Phase II - Overall Response Rate

  4 months

Other Outcomes (1)

• Exploratory Endpoint - Determine Antitumor Effect

  4 months

Study Arms (1)

Phase 1: AXL1717, 300mg

EXPERIMENTAL

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).

Drug: AXL1717

Interventions

AXL1717 DRUG

IGF-1 receptor inhibitor

Also known as: picropodophyllin

Phase 1: AXL1717, 300mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be informed of the nature of the study and have provided written informed consent
• At least 18 years of age
• ECOG performance of 0, 1, or 2, or KPS (Karnofsky performance status) ≥ 60.
• Pathological verification of a WHO grade 4 astrocytoma (glioblastoma or gliosarcoma), or WHO Grade 3 anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplastic ependymoma.
• Documented recurrent glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplastic ependymoma after at least one failed treatment of chemotherapy and radiation
• Expected survival of at least 3 months
• 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.
• Ability to undergo MRI scanning without and with imaging dye on a periodic basis as defined in the protocol
• 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

You may not qualify if:

• Any or other major recent or ongoing disease that, according to the Investigator, poses an unacceptable risk to the patient
• 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.)
• Coexisting uncontrolled medical condition.
• Hepatitis B or Hepatitis C, or HIV infection requiring anti-retroviral therapy
• Active malignancy other than basal cell skin cancer
• Other active malignancy during the previous 3 years
• Major surgical procedure within 4 weeks
• 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.
• 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.
• 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.
• Medically uncontrolled Type 1 or Type 2 diabetes mellitus
• Pregnancy or lactation
• Current participation in any other investigational clinical trial within 4-weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status \> 2 after optimization of medications (See Appendix 4) or KPS \< 60
• Anticipated Life expectancy less than 3 months

Sponsors & Collaborators

• Rush University Medical Center: lead
• Axelar AB: collaborator

Study Sites (1)

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Related Publications (4)

• Andrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G, Aiken RD. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol. 2001 Apr 15;19(8):2189-200. doi: 10.1200/JCO.2001.19.8.2189.

  PMID: 11304771 BACKGROUND

• Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 2004 Jan 1;64(1):236-42. doi: 10.1158/0008-5472.can-03-2522.

  PMID: 14729630 BACKGROUND

• Ekman S, Frodin JE, Harmenberg J, Bergman A, Hedlund A, Dahg P, Alvfors C, Stahl B, Bergstrom S, Bergqvist M. Clinical Phase I study with an Insulin-like Growth Factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma. Acta Oncol. 2011 Apr;50(3):441-7. doi: 10.3109/0284186X.2010.499370. Epub 2010 Aug 11.

  PMID: 20698809 BACKGROUND

• Yin S, Girnita A, Stromberg T, Khan Z, Andersson S, Zheng H, Ericsson C, Axelson M, Nister M, Larsson O, Ekstrom TJ, Girnita L. Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro Oncol. 2010 Jan;12(1):19-27. doi: 10.1093/neuonc/nop008. Epub 2009 Oct 20.

  PMID: 20150364 BACKGROUND

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Astrocytoma; Oligodendroglioma; Ependymoma

Interventions

picropodophyllin

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Results Point of Contact

• Title: Crista Brawley
• Organization: Rush University Medical Center

crista_brawley@rush.edu

312-563-2312

Study Officials

• Robert Aiken, MD

  Rush University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2012
• First Posted: November 5, 2012
• Study Start: December 1, 2012
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: May 22, 2023
• Results First Posted: May 22, 2023

Record last verified: 2023-04

Locations

US (1)