Novel Combo Explored for Rare Brain Tumor

Investigators are seeking to determine whether the combination of eflornithine (alpha-difluoromethylornithine) with lomustine can improve survival for patients with recurrent anaplastic astrocytoma (AA), a rare form of brain tumor. AA occurs most often in adults aged 30 to 50 years and accounts for 17% of primary malignant brain tumors.¹ Of note, this tumor type is even more rare when it recurs, according to Victor A. Levin, MD, emeritus professor of neuro-oncology at The University of Texas MD Anderson Cancer Center in Houston and a clinical professor at the University of California, San Francisco, School of Medicine.

RATIONALE

Eflornithine is an irreversible inhibitor of ornithine decarboxylase, a key enzyme in polyamine biosynthesis; polyamines help create a chromatin environment that stimulates neoplastic transformation of cells. Inhibiting ornithine decarboxylase can affect DNA and mRNA stabilization, translation, and transcription, thereby inhibiting cell growth and proliferation.

According to Levin, eflornithine also has an inhibitory impact on cancer cells invading surrounding tissues and metastasizing to other sites, and it might even have an impact on the mutation rate of tumor cells. “There is some experimental evidence that if [eflornithine] is given in combination with a nitrosourea, such as lomustine, then it can have additive activity, more than predicted from the single agent alone,” said Levin.

Currently, treatment for patients with AA is often ineffective; the 5-year survival rate is 27%. In the recurrent setting, treatment options are even more limited. The National Comprehensive Cancer Network guidelines suggest that eligible patients be enrolled in clinical trials, receive palliative care, or repeat systemic therapy, with lomustine being one of the options.²

TRIAL DESIGN

The phase III, randomized STELLAR trial (NCT02796261), which is currently enrolling, seeks to address the recurrent setting by adding eflornithine to lomustine compared with standard-of-care lomustine monotherapy.

WHO IS ELIGIBLE?

Eligible patients will have AA that recurred or progressed after completing radiation therapy and adjuvant temozolomide. Patients who received treatment for a grade 2 tumor who have recurrence of a grade 3 tumor will be included, as will patients who originally had a grade 3 tumor, provided it is their first recurrence. The primary endpoint is overall survival.

“If this [combination with eflornithine] is successful and is subsequently approved, it will be the first new proven targeted therapy to get approved for the treatment of gliomas,” Levin said. “I believe that it will be critical because it can effectively be used for lower-grade tumors and for pediatric patients.”

REFERENCES

• Glioblastoma and malignant astrocytoma. American Brain Tumor Association website. abta.org/secure/glioblastoma-brochure.pdf. Published 2017. Accessed February 15, 2018.
• Nabors LB, Portnow J, Ammirati M, Baehring J, Brem H, Butowski N, et al. Central nervous system cancers: version I.2017. NCCN clinical practice guidelines in oncology. Natl Compr Canc Netw. 2017;15:1331-1345. doi:10.6004/jnccn.2017.0166J.