SJELIOT: Phase I Study of a CHK1/2 Inhibitor Therapy in Combination with Chemotherapy for Children and Adolescents with Refractory or Recurrent Medulloblastoma Brain Tumors (CLOSED TO ACCRUAL)

Brief Summary

This Phase I, multinational clinical trial explores the combination of prexasertib (LY2606368) with established DNA-damaging agents in children and adolescents with recurrent or refractory medulloblastoma.

Prexasertib is a small molecule inhibitor of checkpoint kinase 1 and 2 (CHK1/2) that has shown promise in preclinical medulloblastoma studies when administered in combination with other agents. In this study, participants will receive prexasertib with either cyclophosphamide or gemcitabine.

Patients 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) in absence of disease progression or unacceptable toxicity.

Each stratum will contain 8 dose levels, two of which (dose level 0 and dose level -1) are below the starting dose level and will be studied only if the starting dose level is too toxic. The Rolling 6 design will be used separately in each stratum to estimate the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D).

Primary Objectives

Stratum A - Prexasertib and Cyclophosphamide

• To determine the safety and tolerability and estimate the MTD/RP2D of combination treatment with prexasertib and cyclophosphamide in participants with recurrent/refractory Group 3 and Group 4 medulloblastoma and recurrent/refractory SHH medulloblastoma
• To characterize the pharmacokinetics of prexasertib in combination with cyclophosphamide

Stratum B - Prexasertib and Gemcitabine

• To determine the safety and tolerability and estimate the MTD/RP2D of combination treatment with prexasertib and gemcitabine in participants with recurrent/refractory Group 3 and Group 4 medulloblastoma
• To characterize the pharmacokinetics of prexasertib in combination with gemcitabine

Eligibility Criteria

Inclusion criteria include:

• Recurrent, refractory or progressive Group 3, Group 4 or Sonic Hedgehog (SHH) medulloblastoma
• At least 1 year old and younger than 25 years old
• Last dose of chemotherapy at least 3 weeks prior to enrollment
• Last fraction of radiation at least 4 weeks prior to enrollment
• Adequate bone marrow and organ function

Exclusion Criteria include:

• Previous exposure to any CHK-1 inhibitor
• Uncontrolled heart disease and/or repolarization abnormalities
• History of QTc prolongation
• Pregnant or breastfeeding

Study Sites

St. Jude Children’s Research Hospital, Memphis, Tennessee
Collaborating sites outside the U.S.

About this study

Medulloblastoma is the most common brain cancer in children. While most children with medulloblastoma get better with standard treatments like surgery, radiation or medication, some children do not respond to treatment. Other children may get better at first, but the cancer comes back later.

This clinical trial will test an experimental drug treatment for children and adolescents with medulloblastoma tumors that did not get better with treatment or came back after treatment. The experimental drug is called prexasertib. Research in the lab suggests prexasertib may help fight certain kinds of medulloblastoma tumors. However, prexasertib has not been proven to work in people with these types of tumors.

Before you can participate in this study, we need to find out what type of medulloblastoma tumor you have. We will do this by looking at a sample of your tumor. This is called the screening part of the study.

You may be eligible for the treatment part of the study if the screening shows your tumor is one of four medulloblastoma subtypes: Group 3, Group 4, Sonic Hedgehog (SHH) or Indeterminate.

If you qualify for the treatment part of the trial, you will be given prexasertib along with one of two standard chemotherapy drugs: cyclophosphamide  or gemcitabine. Chemotherapy is strong anti-cancer medicine. These drugs will be given through a vein in the arm. You may continue to receive this medicine for up to 2 years unless you develop serious side effects or your tumor worsens.

Throughout the study, you will have tests and procedures to check for side effects, and to see how your tumor is responding to the treatment.

You may or may not benefit from taking part in this study. However, information learned from this study may help future patients with cancer.

Purpose of this clinical trial

The main goal of this study is to find the highest, safe dose of prexasertib that can be given with chemotherapy without causing severe side effects. Researchers also want to find out if prexasertib combined with chemotherapy is a helpful treatment for medulloblastoma tumors.

Eligibility overview

• Recurrent, refractory or progressive medulloblastoma
• At least 1 year old and younger than 25 years old