PHASE II TRIAL OF SINGLE-AGENT BEVACIZUMAB FOLLOWED BY BEVACIZUMAB PLUS IRINOTECAN AT TUMOR PROGRESSION IN RECURRENT GLIOBLASTOMA

BACKGROUND

Background
  • Patients with glioblastoma generally have poor prognoses, with median survival times of approximately 14 months.
  • Because glioblastoma cells express high levels of vascular endothelial growth factor (VEGF), antiangiogenic agents such as bevacizumab may prove useful in combating this malignancy.
  • Research has indicated that combination therapy with bevacizumab and irinotecan has shown significant antitumor activity, when compared with other regimens used to treat glioblastoma.
  • Studies of single-agent irinotecan for recurrent glioma have not shown promising results, thus the value of irinotecan is unknown.

 

Objective

  • This study was conducted to evaluate the single-agent activity of bevacizumab in patients with recurrent glioblastoma.
  • A companion trial evaluated the efficacy of adding irinotecan to bevacizumab therapy following tumor progression on bevacizumab.

 
GENERAL STUDY OVERVIEW

Title/Citation

Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740-745. Epub 2008 Dec 29.

 

Funding

No financial support was received in conjunction with this publication.

 

Trial design

This was a prospective, phase II, single-agent, single-arm clinical trial conducted at the Clinical Center of the National Institutes of Health between July 2006 and November 2007.

 

Enrollment

48 patients with recurrent glioblastoma following radiation and temozolomide were treated with bevacizumab monotherapy. Subsequently, 19 patients experiencing tumor progression received combination therapy with bevacizumab and irinotecan.

 
METHODS

Inclusion criteria

The study included patients with:

  • Histologically confirmed recurrent glioblastoma following standard therapy
  • Age greater than 18 years
  • Karnofsky performance status (KPS) ≥60%
  • Normal metabolic and end-organ function
  • Estimated survival of at least 2 months

 

Exclusion criteria

The study excluded patients with:

  • Acute intracranial hemorrhage
  • Anticoagulation therapy
  • Prior irinotecan therapy (for patients enrolled in companion study with combination therapy)

 

Study groups
  • The study consisted of a single arm, in which patients were treated with bevacizumab 10 mg/kg every 14 days on a 28-day cycle.
  • Patients with progressive tumor growth participated in a companion trial, in which their next scheduled dose of bevacizumab was given with irinotecan 340 mg/m2/ or 125 mg/m2, depending on use of enzyme-inducing antiepileptic drugs.

 

End points
  • Primary end point: progression-free survival at 6 months (PFS6)
  • Secondary end points: magnetic resonance imaging (MRI) and positron emission tomography (PET) response rates and their correlations with PFS
  • MRI scans were assessed using subjective Levin criteria (gadolinium enhancement, edema, and mass effect compared with baseline) and objective Macdonald criteria (linear measurements of target lesion cross-sectional diameters).
  • Levin criteria responses were scored as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).

 

Statistical analyses

  • Kaplan-Meier methodology was used to estimate PFS6; 32 patients were required to distinguish between a 15% and 35% PFS6.
  • 20 patients were required for the companion study. If ≥3 patients responded to combination therapy, the addition of irinotecan would be considered potentially effective.
  • In evaluating secondary end points, 2-sided log-rank tests were used to assess how radiographic responses were related to PFS.

 
RESULTS

Baseline characteristics
  • 20 females and 28 males were enrolled in the study.
  • The median age was 53 years, and the median KPS was 90%.

 

End points

Efficacy/Survival:

  • The median PFS was 16 weeks (95% confidence interval [CI], 12–26 weeks), and PFS6 was 29% (95% CI, 18%–48%).
  • The 6-month survival rate was 57% (95% CI, 44%–75%).
  • The median overall survival was 31 weeks (95% CI, 21–54 weeks).
  • Age had a major effect on clinical outcome: older patients had a PFS of 30 weeks, whereas younger ones had a PFS of 11 weeks (P <.001).
  • In the companion trial, 12 patients demonstrated tumor progression after 1 cycle of bevacizumab and irinotecan, with a median time to tumor progression of 30 days. Thus, accrual to the companion trial was terminated early.

Radiographic Responses and Correlation to PFS:

  • The overall response rate based on Levin criteria was 71% (34 PRs).
  • The overall response rate based on Macdonald criteria was 35% (1 CR and 16 PRs).
  • MRI responses at 96 hours:
    • Patients who had a PR by Levin criteria had a statistically significant improvement in PFS compared with those with SD (P <.001); PFS6 was 32% and 0% for PR and SD, respectively.
    • There were not enough PRs at 96 hours by Macdonald criteria to conduct a statistical analysis
  • MRI responses at 4 weeks:
    • Patients who had a PR by Levin criteria had a statistically significant improvement in PFS compared with patients with SD (P = .03).
    • Patients who had a PR by Macdonald criteria showed a trend toward improved PFS compared with those with SD, but this was not statistically significant (P = .07).
  • Based on PET scan responses at 4 weeks, there was no significant difference in PFS for patients who had diminished fluorodeoxyglucose  uptake compared with those with no change.

Toxicity:

  • Overall, bevacizumab treatment was well-tolerated.
  • 6 patients (12.5%) experienced thromboembolic events that were possibly or probably related to bevacizumab.
  • Hypertension was the second most frequent drug-related adverse event.
  • No patients experienced an intracranial hemorrhage.
  • In the companion study, irinotecan was well-tolerated, with hypophosphatemia, neutropenia, and lymphopenia being the most commonly seen toxicities.

 
CONCLUSIONS

Conclusions
  • Single-agent bevacizumab is well-tolerated and has significant activity in patients with recurrent glioblastoma; the observed PFS6 of 29% compares favorably with historical controls of other regimens.
  • Although data indicate that the addition of irinotecan to bevacizumab is futile in the treatment of recurrent glioblastoma, a contribution cannot be ruled out if both agents had been used simultaneously as initial treatment.
  • The predictive value of Levin criteria is more valuable than that of Macdonald criteria in patients with glioblastoma; gliomas consist of asymmetrically infiltrating tumor cells, thus spatial measurements of enhancement are questionable in this setting.

 
DISCUSSION

Study strengths/ limitations

Strengths:

  • Authors provided thorough and comprehensive background information, as well as good rationale for studying single-agent bevacizumab for the treatment of glioblastoma.
  • Drug doses were appropriately selected based on a previous trial evaluating bevacizumab and irinotecan therapy.
  • Investigators chose an appropriate primary end point (PFS6) because the North American Brain Tumor Consortium uses this as the efficacy end point for recurrent high-grade glioma therapy trials, and other studies have shown that PFS6 correlates well with 12-month overall survival.
  • The lack of financial support from drug manufacturers reduced potential bias.

Limitations:

  • The study had no comparator group, so findings had to be compared with historical controls.
  • The study excluded patients with a poor performance status, which may have reduced external validity.
  • The finding that older patients had a significantly longer PFS than younger ones may reflect statistical variance caused by small sample size; however, the primary study did meet the target accrual necessary to ensure adequate power of statistical tests.
  • Investigators assessed drug toxicity, but did not list it as a study end point.
  • Although MRI images reflected a decrease in gadolinium enhancement, this is not an accurate marker of tumor mass in the face of VEGF inhibition.

 

Future implications
  • Bevacizumab may be indicated for the treatment of recurrent glioblastoma.
  • Randomized phase III trials must be done to determine whether irinotecan adds any clinical benefit to bevacizumab treatment.
  • Future clinical studies should assess the simultaneous administration of bevacizumab and irinotecan for initial treatment of recurrent glioma.
  • Studies should be conducted to identify whether bevacizumab has greater activity in the biologic subtype of gliomas more commonly found in older patients.
  • Future studies should investigate the role of bevacizumab in combination with other cytotoxic therapies.

 

 

 

 

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