FCF Funded Projects

Everolimus clinical trial

Status: Completed

Timeframe: 2010 – 2014

Goal: Assess potential of everolimus (RAD001) as a treatment option for FLC

Principal Investigator: Ghassan Abou-Alfa, MD

Study background and overview: At the time of this trial, the molecular drive of fibrolamellar, the DNAJB1-PRKACA fusion gene, had not been identified. However, several factors suggested that estrogen and estrogen-dependent pathways may play a role in FLC’s pathogenesis, including:

  • Case reports of gynecomastia as a presenting feature of FLC in young males
  • Documentation of aromatase overexpression in FLC tumors
  • The association of hyperestrogenic states including pregnancy and oral contraceptive use with FLC
  • Demonstration of increased mammalian target of rapamycin (mTOR) activity in FLC tumors by immunohistochemical staining.

Consequently, on the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, the team hypothesized that suppression of estrogen and mTOR signaling could stop FLC tumor cells from growing and dividing. The combination of letrozole, a drug that prevents estrogen production, and everolimus (RAD001), a drug that controls the cancer cell signals had previously been shown to be active and safe in breast cancer patients. The team therefore proposed a study testing the effectiveness of estrogen deprivation therapy and mTOR inhibition in patients with advanced FLC.

The resulting phase II trial randomized patients into the following three arms:

  • Arm A (everolimus),
  • Arm B (letrozole/leuprolide) – estrogen deprivation therapy, or
  • Arm C (everolimus/letrozole/leuprolide).

Upon disease progression, patients in arm A or B could transition to the everolimus/letrozole/leuprolide treatment.

Through this effort, FCF funded the first clinical trial of drugs aimed specifically at fibrolamellar carcinoma.  The trial was conducted Memorial Sloan Kettering, along with several other consortium members, including the University of California San Francisco, Johns Hopkins, and Dana Farber. Two major pharmaceutical companies donated the drugs investigated.  

Key findings: In total, 28 FLC patients were enrolled in this phase II trial. The study concluded that estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. Neither approach improved patient outcomes.

The results of the clinical trial were published in The Oncologist in May 2020. Click here to read the published results of the study.