STELLAR Trial, Historical Studies Seek to Establish Efficacy of Eflornithine in Anaplastic Astrocytoma

STELLAR (NCT02796261) is recruiting patients with AA in patients whose disease has recurred or progressed after radiation and temozolomide (Temodar) chemotherapy to determine the safety and efficacy of the novel combination of eflornithine (alpha-difluoromethylornithine) and lomustine (Gleostine).¹The primary end point is overall survival (OS) and secondary end points include progression-free survival (PFS) and objective response rate (ORR).

In the trial, the combination arm of eflornithine and lomustine will be administered orally every 8 hours on a 2-week on, 1-week off schedule and the lomustine-only arm will be dosed once every 6 weeks. Dosage for the combination arm is eflornithine at 2.8 g/m²and lomustine at 90 g/m². The dosage for the lomustine-only arm is 110 g/m². Approximately 340 patients are to be randomized 1:1 to the combination arm or lomustine-alone arm and treated with 24 months or 12 months of therapy, respectively.

Eflornithine, an inhibitor of ornithine decarboxylase, has been evaluated as a treatment for various cancers in several trials, and has been shown to be active in some leukemias and solid tumors, including breast, colon, cervical, small cell lung cancer, and melanoma.

Historically, studies involving eflornithine for the treatment of gliomas investigated the agent as a monotherapy and in combination with mitoguazone (MGBG), carmustine, and alpha-interferon.²In a literature review of the efficacy of eflornithine, Levin et al summarized findings from published studies involving eflornithine across several glioma subtypes detailed below.²

The phase I study of eflornithine and MGBG involved 45 patients with recurrent central nervous system tumors who were stratified into 2 groups. Group I received eflornithine 1 g/m²on days 1-42 every 6 hours and MGBG on days 14, 28, and 42 at 350 mg/g². Patients in group II received eflornithine on days 1-14, 21-35, and 42-56 at 1.33 g/m²every 8 hours. MGBG was administered at 200 mg/m²on days 14, 35, and 56. Thirty-three patients were evaluated for response, including 8 patients from group I and 19 patients from group II.³

These responses led to a phase II study that evaluated the agent as a monotherapy versus the combination of eflornithine and MGBG in 121 patients with recurrent malignant gliomas.⁴The combination arm was closed after 23 patients were accrued because of 2 fatalities from liver toxicity. The monotherapy arm continued to accrue patients, however, and enrolled 98 patients before the study closed. Investigators reported grade 3/4 adverse events of nausea, vomiting, diarrhea, hearing loss, thrombocytopenia, leukopenia, and granulocytopenia.

A phase II study investigating eflornithine and carmustine in 38 patients demonstrated a partial response in 10% of 21 evaluable patients with AA and anaplastic oligoastrocytoma (AOA; 2 of 21), and stable disease in 48%. Median OS for this group was 56 weeks. In patients with glioblastoma (n = 12), the median time-to-tumor progression was reported as 8 weeks and median OS was 21 weeks. In 5 patients with a brainstem glioma, 3 were alive with stable disease at 77, 93, and 220 weeks.⁵

Eflornithine and alpha-interferon were investigated in a phase II trial of 29 patients with recurrent or progressive gliomas. Investigators reported no responses in any of the patients, although stable disease exceeded 6 months in 24% (7/29) of patients and was considered due to eflornithine administration. In this trial, grade 3/4 toxicities were gastrointestinal-related, hematologic, fever, chills, and lethargy.⁶

Two parallel phase III trials stratified patients by histology into 2 strata: patients with glioblastoma (GBM) and gliosarcoma in strata 1 and patients with anaplastic gliomas (AG)—including AA, anaplastic oligodendroglioma (AO), and AOA—in strata 2. The 2 strata had different accrual goals and constituted 2 separate studies. The GBM study accrued 272 evaluable patients and the AG study accrued 228 evaluable patients.^7,8These studies led to the design of the ongoing STELLAR trial.

Patients in the combination eflornithine and PCV (procarbazine, lomustine, and vincristine) arm received eflornithine, 3 g/m²orally every 8 hours on days 1-14; lomustine, 110 mg/m²orally on day 15; procarbazine, 60 mg/m²/day orally on days 22-35; vincristine, 1.4 mg/m²intravenously (maximum 2 mg) on days 22 and 43; and eflornithine, 3 g/m²orally every 8 hours on days 29-42. The cycle was repeated at 8-week intervals, for a total of 7 cycles.

The PCV treatment arm used the following starting dose and schedule: lomustine, 110 mg/m²orally on day 1; procarbazine 60 mg/m²orally on days 8-21; and vincristine, 1.4 mg/m²intravenously (maximum 2 mg) on days 8 and 29. The cycle was repeated at 6-week intervals, for a total of 7 cycles.

For patients in strata 2, the trial was powered to detect a median OS of 54.5 months for eflornithine combined with PCV compared with 36.2 months for PCV alone.

Although accrual was stopped in June 1999, the studies were kept open until 2012. This did not change the outcome and conclusions for patients with GBM; however, it did improve statistical reliability of OS for the AG study.

Patients in the AG strata demonstrated an increase in median PFS (71.1 vs 37.5 months) and median OS (75.8 vs 61.1 months) for the combination arm versus the PCV alone arm, respectively.

Eflornithine is undergoing further investigation as a potential treatment for cancer, but earlier studies have demonstrated activity in the treatment of recurrent AA, AOA, and AO tumors. When used in combination with PCV, the agent showed an increase in OS compared with PCV alone. Given its clinical activity and its use as a monotherapy and in combination, eflornithine could be a useful treatment for patients with gliomas.

References

1. Study to evaluate eflornithine + lomustine vs lomustine in recurrent anaplastic astrocytoma (AA) patients (STELLAR). Clinical Trials website. Posted June 10, 2016. Last updated November 8, 2019. https://bit.ly/35ekCum. Accessed November 22, 2019..
2. Levin VA, Ictech SE, Hess KR. Clinical importance of eflornithine (α-difluoromethylornithine) for the treatment of malignant gliomas.CNS Oncol. 2018;7(2):CNS16. doi: 10.2217/cns-2017-003