Celldex Therapeutics, Inc. (NASDAQ: CLDX), today announced the presentation of complete data for the primary endpoint of ACT III, a multi-center, single arm, Phase 2 clinical trial of rindopepimut (CDX-110) in patients with newly diagnosed glioblastoma multiforme (GBM). The data showed 66 percent of patients were progression-free at 8.5 months from diagnosis or 5.5 months from start of vaccination, a statistically significant increase over a predetermined progression-free rate (PFR) estimate. These data are consistent with previous studies (ACTIVATE and ACT II) with rindopepimut in GBM conducted at M.D. Anderson and Duke University. The data were presented at the Annual Meeting of The Society for Neuro-Oncology (SNO) in Montreal, Quebec, Canada. Rindopepimut is an investigational immunotherapeutic vaccine that targets the tumor-specific molecule, epidermal growth factor receptor variant III (EGFRvIII).
“This exciting data from ACT III is an important milestone in this fatal disease setting and we look forward to initiating an international, randomized, placebo-controlled Phase 3 clinical trial, which we anticipate will begin in the second half of 2011”
"These data suggest that rindopepimut is extending survival well beyond what we have seen historically in this patient population," said Rose Lai, M.D., Assistant Professor of Neurology in the Division of Neuro-Oncology, Department of Neurology, Columbia University Medical Center, and lead investigator on the ACT III study. "The consistency of data from three separate studies is impressive and clearly supports the plan to conduct a controlled pivotal study in GBM."
"This exciting data from ACT III is an important milestone in this fatal disease setting and we look forward to initiating an international, randomized, placebo-controlled Phase 3 clinical trial, which we anticipate will begin in the second half of 2011," said Anthony Marucci, President and Chief Executive Officer of Celldex Therapeutics.
The ACT III data will be discussed in a conference call and webcast presentation on Monday November 22, 2010, from 8:30 to 9:30 am Eastern Time. Lead investigator, Dr. Rose Lai, will participate in the call.
ACT III Results
The multi-center Phase 2 trial enrolled 65 patients with newly-diagnosed and optimally resected EGFRvIII-expressing GBM. Patients started vaccination with rindopepimut at approximately 3 months post-diagnosis. The results for the predefined primary endpoint (66% Progression Free Rate or "PFR" at approximately 8.5 months post-diagnosis) show a statistically significant improvement>
x Change in median PFS not statistically significant from ACTIVATE and ACT II.
* Overall survival data for ACT III are estimated and not yet final.
# Sampson, et al. J Clin Oncol. 2010 Nov 1;28(31):4722-9.
Historical controls were treated at M.D. Anderson and matched for eligibility (EGFRvIII-positive, KPS ≥ 80%, complete resection, radiation/TMZ and without progression through ~ 3 months post-diagnosis).
+ Stupp, et al. N Engl J Med 2005;352:987-96.
Importantly, rindopepimut showed a similar benefit in patients whether or not they expressed an active DNA repair gene (MGMT) that has been shown to limit the benefit from TMZ treatment. In ACT III, the number of patients who were expected to be resistant to the TMZ chemotherapy appeared to do better with vaccination than the numbers observed in the historical data. Patients who have an active DNA repair gene, MGMT, generally have a worse outcome, presumably because they do not gain much benefit from TMZ as reported in the literature. Patients with a methylated MGMT promoter in their tumor do not express MGMT and have a more favorable outcome to TMZ treatment. Patients with methylated tumors>
The ACT III Phase 2 trial studied rindopepimut in combination with maintenance TMZ in 65 patients with newly-diagnosed EGFRvIII-expressing GBM who had undergone surgical (gross total) resection followed by conformal radiation therapy with concurrent oral TMZ (75 mg/m2 per day) without tumor progression. Rindopepimut mixed with granulocyte-macrophage colony stimulating factor (GM-CSF) (~150 mcg) was administered intradermally. Patients received rindopepimut bi-weekly for three doses prior to starting maintenance TMZ and monthly thereafter on day 21 of each TMZ cycle until disease progression. The primary endpoint was PFR at 5.5 months from first vaccination/study day 0 (~ 8.5 months from diagnosis).
The ACT III Phase 2 trial began as a Phase 2b/3 randomized open-label, two-arm trial comparing rindopepimut combined with TMZ to TMZ alone in patients with newly diagnosed GBM. It was amended to a single arm design when 14 of 16 control arm patients declined further participation after notification of randomization assignment. When the patients randomized to the control arm withdrew from the study, the trial could no longer achieve the planned statistical goals due to the absence of a control arm.
Vaccination with rindopepimut was well tolerated in combination with maintenance TMZ, with local injection site reactions being the most common treatment-related adverse events. Serious treatment-related adverse events occurred in three patients, including:
- one case of toxic epidermal necrolysis (possible dapsone hypersensitivity syndrome) which resolved within 12 days of admission;
- one grade 2 hypersensitivity reaction (pruritus, erythema, flushing and mild shortness of breath), occurring within 10 minutes of dosing and fully resolved within one hour of antihistamine and corticosteroid;
- one urticarial rash (or hives)
Eighty-two percent of the evaluable vaccinated patients developed a specific anti-EGFRvIII antibody response that was maintained at a significant level in most patients.