MEK116: Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations

An Open- Label, Dose Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescent Subjects with Cancer or Plexiform Neurofibromas and Trametinib in Combination with Dabrafenib in Children and Adolescents with Cancers Harboring V600 Mutations.

Categories:

Brain Tumor

Solid Tumor

Phase I/II

Diseases Treated:

Relapsed or refractory solid tumor

Eligibility Overview:

  • Participant is at least one month old and younger than 18 years old at the time of signing the informed consent (in Part A, participants < 2 years of age are not included).
  • Participant has a histologically confirmed solid tumor
  • Participant has a disease that is relapsed or refractory to all potentially curative standard treatment regimens, or has a disease for which there is no standard treatment regimen that is potentially curative.

Description

This study will be enrolling patients who have one of the following tumors that have either comeback (recurrent) or has not responded to treatment (refractory): histologically confirmed solid tumor and primary brain tumors. People who are not in a study are usually treated with chemotherapy drugs that have been approved by the Food and Drug Administration (FDA), but there is no standard of care treatment for the type of cancer in this study. Trametinib is a new study drug used for treating patients with cancer. This study drug has been tested in adults but not children. The goal of the study is to find dose(s) of the study drug that are safe and tolerable for children and adolescents with cancer. The study also wants to find out how much of the drug gets into the blood stream and how long the body takes to get rid of it.

This study has three groups: Part A, Part B and Part C.

In Part A, the first 3 participants will receive a low dose of the study drug based on their body weight. If there are no major side effects and if the amount of drug in the body is lower than what was seen in adults the next 3 participants may receive a higher dose. If there are no major side effects and the amount of drug in the body is lower than what we see in adults in these 3 participants, another 3 participants may receive a higher dose of the study drug. Up to 6 participants may be enrolled at each dose level depending on the number of participants who have side effects at the lower dose levels. Participants under 2 years of age (at the time of signing the consent form) will not be included in these groups.

Once a dose is identified that is well-tolerated for most participants and the amount of drug in the body is similar to what we see in adults, that dose will be used for all new participants in the study. In order to make sure the best dose is chosen for children of all ages, additional participants may be enrolled in the following age group (under 2 years, 2-12 years, and over 12 years of age) and receive trametinib at a dose that is selected in Part A. In Part A, some participants may be allowed to increase their dose under special circumstances.

Part B will begin after Part A has been completed and will use the dose determined in Part A. In Part B, participants will be enrolled in one of the following four groups, depending on their type of cancer:

  • Refractory or relapsed neuroblastoma
  • Recurrent or unresectable low grade glioma
  • Neurofibromatosis Type-1 associated plexiform neurofibromas that are unresectable and medically significant 
  • Other tumors that have abnormal BRAF protein (called V600 mutation)

Part C will enroll up to 18 children and adolescents with recurrent, refractory or unresectable BRAF V600 mutated tumors. It will begin after the dose of dabrafenib and the dose of trametinib in children is established.

Objectives (among others):

  • To determine the safe and tolerable Trametinib dose(s) for chronic dosing in pediatric subjects that achieves similar exposures to the recommended adult dose.
  • To characterize the pharmacokinetics of Trametinib.
  • To characterize the safety and tolerability of Trametinib.
  • To assess any preliminary anti-tumor activity of Trametinib.

Eligibility

Inclusion Criteria (may differ depending on which part):

  • Participant is at least one month old and younger than 18 years old at the time of signing the informed consent (in Part A, participants < 2 years of age are not included).
  • Participant has a histologically confirmed solid tumor, which may include but is not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms tumor, hepatic tumors, germ cell tumors, primary brain tumors, NF-1 associated plexiform neurofibromas, and Langerhans Cell Histocytosis (LCH).
    OR
    Participant has a brain stem glioma, in which the requirement for histological confirmation can be waived, or Participant has plexiform neurofibromas, in which histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiological findings, but should be considered if malignant degeneration of a PN is clinically suspected.
  • Participant has a disease that is relapsed or refractory to all potentially curative standard treatment regimens, or has a disease for which there is no known curative therapy, or therapy proven to prolong survival with an acceptable quality of life.
  • The last dose of ALL investigational agents was at least 30 days prior to study entry.
  • Participant has recovered to < grade 1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment.

Exclusion Criteria (among others):

  • Participant has a history of another malignancy including resected non-melanomatous skin cancer.
  • Participant has NF-1 and active optic glioma.
  • Participant is a lactating or pregnant female.
  • Participant has received prior therapy with dabrafenib, trametinib, or another MEK inhibitor. Prior treatment with sorafenib is permitted. (Patients who have had prior dabrafenib therapy and had benefit from that therapy as determined by the investigator are allowed in Part C.)
  • Participant has any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with safety, obtaining informed consent, or compliance to the study procedures.
  • Participant has a history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (note: participants with laboratory evidence of cleared HBV and HCV infection are eligible).
  • Participant has presence of active GI disease or other condition that will interfere significantly with the absorption of drugs.
  • Participant has a history or evidence of cardiovascular disease.

For the current eligibility status of this clinical study, referring physicians must contact St. Jude Children's Research Hospital at 1-866-2ST-JUDE (1-866-278-5833).

Contact

Alberto Broniscer, MD

St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Phone: 901-595-2544 or 901-595-4599
Fax: 901-595-6211

OR

Tabatha E. Doyle, RN
Coordinator, Brain Tumor Program
MS 260
262 Danny Thomas Place
Memphis, TN 38105
Phone: (901) 595-2544
FAX: (901) 595-6211

The above information is intended to provide only a basic description about a research protocol that may be currently active at St. Jude. The details made available here may not be the most up-to-date information on protocols used by St. Jude. To receive full details about a protocol and its status and or use at St. Jude, a physician must contact St. Jude directly.