SJDAWN: Molecular-Based Therapy for Aggressive Brain and Spinal Cord Tumors in Children and Young Adults

Molecularly-Driven Doublet Therapy for All Children with Refractory or Recurrent CNS Malignant Neoplasms and Young Adults with Refractory or Recurrent SHH Medulloblastoma

Category:

Brain Tumor

Diseases Treated:

Brain tumor, medulloblastoma, ependymoma

Eligibility Overview:

Ages for Study Enrollment

  • Stratum A (ribociclib and gemcitabine):  Between 1 and 24 years old with recurrent, progressive or refractory non-WNT,  non-sonic hedgehog (SHH) (NWNS) medulloblastoma or ependymoma
  • Stratum B (ribociclib and trametinib):  Between 1 and 24 years old with recurrent, progressive, or refractory central nervous system (CNS) tumors, including:
    • High-grade glioma
    • Atypical teratoid rhabdoid tumor (ATRT)
    • SHH and WNT medulloblastoma
    • CNS embryonal tumors [previously called PNET])
  • Stratum C (ribociclib and sonidegib):  Between 10 and 39 years old with recurrent, progressive, or refractory SHH medulloblastoma and copy number loss of 9q or PTCH1 mutation. (This stratum is only open to patients with SHH medulloblastoma who are fully grown.  Patients younger than 18 years old will have bone age to determine if fully grown)

Screening Phase Eligibility

Inclusion Criteria:

  • Participants with recurrent, progressive, or refractory brain tumors
  • At least 1 year old and younger than 25 years old at the time of screening. Exception: Participants with recurrent, progressive or refractory medulloblastoma who are at least 1 year old and younger than 40 years of age at the time of study screening are eligible for screening.
  • Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.

Exclusion Criteria:

  • Recurrent, progressive or refractory low grade glioma (LGG)
  • Prior exposure to a CDK4/6 inhibitor
  • History of clinically significant, uncontrolled heart disease and/or repolarization abnormalities
  • History of QTc prolongation
  1. Brief Summary

    This is a Phase I, dose escalation study of ribociclib given in combination with gemcitabine, trametinib or sonidegib in patients with refractory or recurrent brain tumors. This study aims to evaluate the safety and tolerability of these combinations, followed by a small expansion cohort to detect preliminary efficacy.­

    Research Stratum

    • Stratum A:  Ribociclib and gemcitabine in patients with recurrent NWNS (i.e. Group 3 and Group 4) medulloblastoma and recurrent ependymoma
    • Stratum B:  Ribociclib and trametinib in patients with recurrent or refractory CNS tumors, excluding low-grade glioma and diffuse intrinsic pontine glioma (DIPG)
    • Stratum C:  Ribociclib and sonidegib in skeletally mature patients up to 39 years old with recurrent SHH medulloblastoma

    Primary Objectives

    • To determine the safety and tolerability of the proposed doublet therapies for each research stratum, and to estimate the Maximum Tolerated Dose/Recommended Phase II Dose (MTD/RP2D) for each research stratum
    • To determine the pharmacokinetic of the doublet therapies used in each research stratum

    Study Sites

    St. Jude Children’s Research Hospital, Memphis, Tennessee

  2. About this Study

    Doctors want to find new treatments for brain tumors that come back after treatment or do not get better with treatment.  They know tumors disrupt the natural “checks and balances” of the body’s cells. This disruption forces cells to grow and divide. Doctors refer to this process as “cell cycle activation.” The drugs that inhibit these molecular signals are known as “cell cycle inhibitors.”

    Doctors have also identified some drugs that have potential to kill particular brain tumors. However, these drugs need an extra boost to be more effective. Researchers in this study want to find out if giving a combination of cell cycle inhibitors with specific drugs tailored to a particular tumor type can treat these kinds of aggressive tumors.

    This study will test a combination drug therapy in children and young adults with tumors of the brain and spinal cord. This study is called a Phase I study because the goal is to find the highest doses of these drugs that can be given together safely.

    The first part of the study is a screening phase. In this phase, doctors will test a sample of your tumor to see if it is a good target for one of three treatments in this clinical trial. If the test shows you are eligible, St. Jude will assign you to one of three treatment groups. These treatment groups are called Stratum A, Stratum B and Stratum C.

    All study participants will receive a drug called ribociclib, a cell cycle inhibitor. This drug will be given in combination with one of these three additional drugs: gemcitabine, trametinib, or sonidegib. In Stratum A, participants will receive ribociclib and gemcitabine. In Stratum B, participants will receive ribociclib and trametinib. In Stratum C, participants will receive ribociclib and sonidegib. Your specific treatment will depend on your tumor type and the treatment group you are in.

    Ribociclib has been approved by the U.S. Food and Drug Administration (FDA) for treating adults with breast cancer. Gemcitabine has been approved by the FDA for treating adults with ovarian, breast, lung and pancreatic cancer. Trametinib and sonidegib have been approved by the FDA to treat adults with certain types of skin cancer. None of these drugs have been approved to treat brain tumors or to treat children with any type of cancer. However, our research suggests that these drugs may have a good effect against brain tumors.

    Purpose of this Clinical Trial

    The main goal of this study is to find out the highest dose of the combination medicine that is safe to give children and young adults with these brain tumors. Researchers also want to learn about the good and bad effects of these drug combinations, as well as learn more about how your body absorbs, processes and removes these drugs from your body (pharmacokinetics).

    Participants will also have the option to participate in additional studies. These may include additional blood tests and tests on the already removed tumor. These studies will help researchers better understand the molecular makeup of your type of brain tumor and better inform research about your tumor’s response to therapy. You will not get a direct health benefit from these optional studies. However, the results may help people with the same type of tumor in the future. The goal of this research is to eventually improve the ability to match therapy with your type of tumor.  

  3. SJDAWN Quick VIew
    Sponsors St. Jude Children's Research Hospital
    ClinicalTrials.gov identifier NCT02808650
    Trial Start Date April 2018
    Estimated Enrollment 108
    Study Type Interventional
    Study Phase Phase I
    Conditions Brain tumors
    Ages Please see above for specific strata ages.
    Principal investigator Giles Robinson, MD 
    Study Sites St. Jude Children's Research Hospital and collaborating sites in the U.S.
    For a consultation or to discuss SJDAWN St. Jude Physician/Patient Referral Office
    1-888-226-4343
    referralinfo@stjude.org

St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Voice: 1-888-226-4343 or 901-595-4055
24-Hour Emergency Access Pager: 1-800-349-4334
Email: referralinfo@stjude.org

OR

Central Contact
Tabatha Doyle
262 Danny Thomas Place
Memphis, TN 38105
Phone: (901) 595-2544
Fax: (901) 595-6211