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Inhibiting EGFR in Glioblastoma

Ralph Weissleder, MD, PhD; Andrew Chi, MD, PhD; and Tracy Batchelor, MD (members of the MGH Brain Tumor Lab) are evaluating non-invasive methods for following dynamic markers of anti-tumor response in a phase 2 trial of a new BRCA inhibitor in glioblastoma.

Glioblastomas are the most aggressive primary brain tumors in adults, with a median survival of only 9 to 15 months. Standard therapy includes surgery if possible, radiation and chemotherapy, and sometimes Avastin (bevacizumab), an angiogenesis inhibitor. Despite aggressive treatment, glioblastoma almost always recurs and second-line treatments are largely ineffective. Many drugs do not enter the brain, limiting treatment options.

An ongoing Phase 2 clinical trial for recurrent glioblastoma is testing a new EGFR inhibitor, dacomitinib (PF-00299804). The investigators are also conducting correlative studies to determine whether the drug is reaching the target and affecting underlying pathways, and whether that activity correlates with the patient’s clinical response to the drug.  “In neuro-oncology, we are especially restricted in our ability to answer these crucial questions because we cannot take serial biopsies,” said Tracy Batchelor, MD (MGH), the principal investigator. To overcome that limitation, the trial is evaluating new clinical tools for non-invasively following a patient’s tumor response over time.

Prior Evidence and Rationale

Genetic analysis of glioblastoma tumors suggested epidermal growth factor receptor (EGFR) as a compelling target for drug therapy. About 40 percent of the tumors have extra copies of the gene, amplifying EGFR’s growth signal and potentially making tumors more aggressive. However, clinical trials testing the first generation EGFR inhibitors Iressa (gefitinib) and Tarceva (erlotinib), were negative. Notably, these studies did not restrict enrollment to glioblastoma patients with EGFR amplification, and these drugs may not cross the blood brain barrier. Dacomitinib is a potent, irreversible EGFR inhibitor demonstrated to cross the blood brain barrier in preclinical models. “We wanted to test this targeted therapy in genetically defined patients,” says Batchelor. “Participants are prospectively selected based on the presence of the drug’s target in their tumors.” The trial is open and accruing participants.

Study Objectives and Design

Recurrent glioblastoma patients eligible for enrollment in this 3-arm trial must have EGFR amplification in their tumors and have failed standard therapy. The objective is to determine how well dacomitinib kills tumor cells. The primary endpoint is no evidence of tumor progression at six months. Secondary endpoints include tumor response or shrinkage as measured by MRI, overall survival, and tolerability.

Arm 1 is enrolling ten patients eligible to undergo surgery for a recurrent tumor. For one week prior to surgery, participants take a daily oral dose of dacomitinib. Immediately following surgery, researchers analyze the tumor tissue to determine whether the drug penetrated the brain tumor and whether the EGFR pathway is inhibited. Participants resume taking the drug after recovering from surgery.

In Arm 2, 30 participants who do not require surgery will receive dacomitinib. In Arm 3, patients who have failed prior standard therapy and bevacizumab will receive dacomitinib.  

Novel Correlative Science

The investigators will use two new, non-invasive methods for following anti-tumor drug activity and resistance from markers in the patients’ blood samples collected before and during treatment. These methods involve circulating exosomes, which are membrane-bound particles containing tumor-specific RNA and DNA that are released by tumor cells into the bloodstream. The investigators want to determine whether that tumor-derived genetic material is associated with response or resistance to therapy. In one method, the researchers will isolate the circulating exosomes and extract the genetic material for quantification and sequencing. “If the patient’s tumor shows a response on magnetic resonance imaging (MRI), do the RNA levels of EGFR decrease? If the tumor progresses, do the levels increase and are there new mutations that are associated with progression?” explained Andrew Chi, MD/PhD (MGH), who with Xandra Breakefield, PhD (MGH), oversees these investigations.

They will also test a hand-held dynamic magnetic resonance (DMR) device developed by Ralph Weissleder, MD/PhD (MGH), to rapidly detect and quantify levels of glioma-specific proteins on exosomes in the blood samples. The device provides readings in real time and, if validated, could help predict a patient’s response to the drug.

Said Batchelor, “We hope that these techniques may give us a dynamic window into what is happening in a brain tumor over time when using targeted therapies. We expect these tools could benefit other cancers too.”

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Phase 2 Trial

Title:
PF-00299804 in Adult Patients With Relapsed/Recurrent Glioblastoma

Principal Investigator:
Tracy Batchelor, MD (MGH)

Protocol:
09-468

ClinicalTrials.gov Identifier:
NCT01112527

Support
Research detailed in this article was funded in part by NIH grants, including CA065164, CA125440, CA156009, and private funding from Pfizer, Inc., the Ben and Catherine Ivy Foundation, and Voices Against Brain Cancer.