Clinical Trial: Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Efficacy and Safety of AP 12009 in Adult Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma as Compared to Standard Chemotherapy Treatm

Brief Summary: In this multinational Phase III study the efficacy and safety of 10 µM AP 12009 is compared to standard chemotherapy (temozolomide or BCNU or CCNU) in adult patients with confirmed recurrent or refractory anaplastic astrocytoma (WHO grade III) or secondary glioblastoma (WHO grade IV).

Detailed Summary:

The purpose of this study is to compare the safety and efficacy of the 10 µM concentration of AP 12009 and standard chemotherapy (temozolomide, BCNU, CCNU) in adult patients with recurrent or refractory anaplastic astrocytoma (AA, WHO grade III) or secondary glioblastoma (GBM, WHO grade IV). AP 12009 (trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human Transforming Growth Factor beta 2 (TGF-beta-2), which is applied intratumorally. The growth factor TGF-beta plays a key role in malignant progression of various tumors by inducing proliferation, invasion, metastasis, angiogenesis, and escape from immunosurveillance. In patients with high-grade glioma, the TGF-beta-2 overexpression is associated with disease stage, clinical prognosis, and the immunodeficient state of the patients. Main objective of the study is to determine survival (rate) and tumor response.

Important note: Due to early trial termination, resulting in limited data availability, all analyses remain descriptive by nature, only. No conclusive endpoint analysis can be performed.


Sponsor: Isarna Therapeutics GmbH

Current Primary Outcome:

  • Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only) [ Time Frame: 24 months ]
    Survival rate was defined as the proportion of participants known to be alive at 24 months from randomization. If a participant's status was unknown and there was no follow-up information available, they were categorized as 'Died' for the purposes of the analysis.
  • Survival at 24 Months in the Intent-to-treat Population - Number of Participants [ Time Frame: 24 months ]
    Survival status was assessed at 24 months from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to / insufficient follow-up" includes participants who were alive at last data collection point but did not yet have enough follow-up time to reach the 24 month time point.


Original Primary Outcome: Survival rate [ Time Frame: 24 months ]

Current Secondary Outcome:

  • Survival Rate at 12, 18, and 21 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only) [ Time Frame: 12, 18, and 21 months ]
    Survival rate was defined as the proportion of participants known to be alive at each time-point from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead.
  • Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants [ Time Frame: 12, 18, and 21 months ]
    Survival status was assessed at each time-point from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to follow-up" for each time-point includes participants who were alive at the last data collection point but did not yet have enough follow-up time to reach the time point.
  • Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only) [ Time Frame: Up to 24 months ]
    Median overall survival was defined as the date of randomization to the date of death. If a participant's status was unknown and there was no follow-up information available, they were categorized as 'Died' for the purposes of the analysis. Analysis was by Kaplan-Meier estimation.
  • Response Category by Independent Review in the Intent-to-treat Population - Number of Participants [ Time Frame: Up to 24 months ]

    Tumor response was classified based on the (neuro-)radiologist's evaluation according to the Macdonald Response Criteria for bidimensionally measurable disease as outlined below:

    • Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.
    • Partial Response (PR): ≥50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.
    • Progressive Disease (PD): ≥25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.
    • Stable Disease (SD): all other situations.

    Two qualified neuro-radiologists reviewed scans at each MRI time point, with adjudication of discrepancies by a third reviewer. Their findings and clinical information were independently reviewed by a neuro-oncologist, who made the assessment of overall response.

  • Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only) [ Time Frame: Up to 24 months ]
    Overall response rate was the proportion of participants with a best response of Complete Response (CR) or Partial Response (PR) observed from the start of treatment until disease progression.
  • Tumor Control Rate (CR+PR+SD) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only) [ Time Frame: Up to 24 months ]
    Tumor control rate was defined as the proportion of participants assessed as having Complete Response (CR), Partial Response (PR), or Stable Disease (SD). Participants with unknown or missing response were treated as non-responders.
  • Median Duration of Response (Days) by Independent Review (Descriptive Analysis, Only) [ Time Frame: Up to 24 months ]

    Duration of response was defined as the time from the first documentation of confirmed response (Complete Response, CR, or Partial Response, PR) to the first signs of Progressive Disease (PD), as assessed by the study neuro-oncologist. Median Duration of Response was calculated by Kaplan-Meier estimate.

    Censoring rules were:

    • at the date of randomization -- participants without baseline assessments, or for those with no post-baseline timor assessments who were discontinued for other than progressive disease or death.
    • at the date of last tumor assessment -- discontinuation other than PD or death, or if a new treatment was started prior to disease progression
    • at the date of death or last tumor assessment -- death or PD after one missed tumor assessment
    • at the date of last tumor assessment -- death or PD after more than one missed tumor assessment
    • at the date of last tumor assessment -- participants on ongoing treatment at data cut-off
  • Disease Progression at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Number of Participants [ Time Frame: 10, 12, 14, 16, 18, 21, and 24 months ]

  • Progression rate [ Time Frame: 10, 12, 14, 16, 18, 21, and 24 months ]
  • Time to death (months)
  • Overall response rate
  • Tumor control rate
  • Duration of response
  • Time to progression (months)
  • Survival rate [ Time Frame: 12, 18, 21, 27, and 30 months; 3 and 4 years ]
  • Quality of Life (EORTC QLQ-C30, Independent Living Score [ILS])


Information By: Isarna Therapeutics GmbH

Dates:
Date Received: September 26, 2008
Date Started: December 2008
Date Completion:
Last Updated: November 4, 2014
Last Verified: November 2014