SJELIOT clinical trial explores a new approach for recurring and unresponsive medulloblastoma tumors

A new St. Jude Children’s Research Hospital clinical trial, SJELIOT, is evaluating an adult cancer drug that shows potential for improved treatment of high-risk pediatric brain tumors. This phase I investigation is evaluating the combination of a kinase inhibitor (prexasertib) with established anti-cancer agents in children and adolescents who have recurrent or refractory (unresponsive) medulloblastoma, the most common malignant brain tumor in childhood.

Leading SJELIOT is neuro-oncologist Giles Robinson, MD, who is also running the SJDAWN clinical trial.

“We are very excited to launch this clinical trial,” Robinson said, “since it translates years of very promising laboratory work by esteemed medulloblastoma researchers around the world, especially Dr. Nick Gottardo, this trial’s co-principal investigator, whose research in Perth, Australia, contributed to and launched the interest in this therapy.”

Why some brain tumors are more dangerous than others

Most pediatric patients with medulloblastoma survive after undergoing combinations of surgery, radiation and chemotherapy. Chemotherapy attacks medulloblastoma, in part, by disrupting tumor cell reproduction. Such cell damage normally triggers apoptosis, which is normal cell death. But some tumor cells promptly repair the damage inflicted on their DNA, enabling the disease to persist or rebound.

This unwanted repair process is powered by a type of enzyme called checkpoint kinase 1 and 2 (CHK1/2). In non-cancerous cells CHK1/2 perform beneficial tasks within the cellular life-cycle. In cancer cells, they pose a menace.

How to solve the problem

A molecular-scale inhibitor for CHK1/2 could offer clinicians two breaks for high risk cases:

• Chemo-damaged medulloblastoma cells will remain genetically unstable and eventually self-destruct without multiplying.
• Since the chemotherapy won’t have to overpower the meddlesome CHK1/2, clinicians can administer lower concentrations of chemo to kill medulloblastoma.

That’s where prexasertib, the primary drug under evaluation in SJELIOT, may be able to help, when combined with a standard chemotherapy drug (either cyclophosphamide or gemcitabine). Prexasertib is an inhibitor of CHK1/2, designed to prevent the enzyme from reversing the good work done by chemotherapy. It has shown promise in preclinical medulloblastoma studies, but it has not yet been proven to work in people with these types of tumors.

Clinical trial structure

Patients participating in the study will be assigned to one of two strata, based on the biologic characteristics of their tumors. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) as long as there is no disease progression or unacceptable toxicity.

In addition to learning if a prexasertib/chemo combination therapy will work against medulloblastoma tumors, the SJELIOT team intends to find the highest, safe dose (MTD/RP2D) without causing severe side effects.

“This is exactly the type of scientifically-sound trial that we aspire to produce and are very optimistic and eager to see the outcome from this therapy,” Robinson said.

Plans are in place to also launch the trial in Germany and Australia.