TACL T2020-004: Trametinib
Protocol Title:
Risk stratified treatment for patients with newly diagnosed juvenile myelomonocytic leukemia: A Phase I/II non-randomized study of trametinib and azacitidine with or without chemotherapy IND #164058
Study Chair:
Elliot Stieglitz, MD, UCSF Benioff Children’s Hospital
Study Vice-Chair:
Mignon Loh, MD, Seattle Children’s Hospital
What is this study about:
This is a Phase I/II study of a drug called trametinib in combination with other medications. Trametinib is a type of drug called a MEK inhibitor, which stops the cell growth of various tumors that are caused by mutations in the RAS family. Trametinib is currently approved by the Food and Drug Administration (FDA) for treatment of adults with advanced melanoma with and for children with solid tumors in combination with dabrafenib. Trametinib was recently studied in a completed phase II clinical trial for patients with relapsed or refractory juvenile myelomonocytic leukemia (JMML).
You will also receive azacitidine, which is a drug that has recently been approved by the FDA for the treatment of newly diagnosed JMML. This drug is thought to work by turning on genes that limit the growth of cancer cells. Azacitidine has been given to children with JMML, and has been given in combination with other chemotherapy in both children and adults. This study is being done to find out if trametinib and azacitidine can be safely given and if it is effective in your newly diagnosed JMML.
This proposed study will be the first to test trametinib in combination with azacitidine in pediatric patients with lower-risk JMML and trametinib in combination with azacitidine, cytarabine, and fludarabine in pediatric patients with high-risk JMML. All patients will receive trametinib every day for 28 days along with azacitidine for 5 consecutive days starting on day 1. High-risk patients will also receive fludarabine and cytarabine for 5 consecutive days starting on day 6.
The main goals of this study are to determine if combining trametinib with azacitidine is safe for patients with newly diagnosed lower-risk JMML and if combining trametinib with azacitidine, cytarabine, and fludarabine is safe for patients with newly diagnosed high-risk JMML. Another goal is to see if this study can improve survival rates in children and young adults with newly diagnosed JMML.
About 64 children and young adults will participate in this study.
The goals of this study are:
Criteria that need to be met to participate in this study: (Abbreviated List)
· Patients must be ≥ 1 month and ≤21 years of age
· Patients must meet the World Health Organization criteria for diagnosis of JMML
· Adequate cardiac, pulmonary, renal, and liver function
· Patients of childbearing potential either have a negative pregnancy test or agree to use an effective method of contraception approved by the investigator
Patients cannot participate in this study if: (Abbreviated List)
· Patients have received prior leukemia directed therapy with the exception of:
· Patients have received a prior stem cell transplant
· Patients will be excluded if they have a known allergy to any of the drugs used in the study
· Patients have a clinical or molecular diagnosis of Noonan syndrome
· Patient with Down syndrome
· Systemic uncontrolled fungal, bacterial, viral or other infection with ongoing symptoms
· Patients who have had prior use of any MEK inhibitor
· Patients cannot be taking any medications for treatment of left ventricular systolic dysfunction
· Patients who are currently receiving another investigational drug or plan to receive non-protocol chemotherapy, radiation therapy, or immunotherapy during the protocol period
Treatment
Patients with newly diagnosed lower-risk JMML will be treated with daily azacitidine for 5 consecutive days (days 1-5) in combination with daily trametinib for 28 days per course for up to 12 courses. Patients with newly diagnosed high-risk JMML will be treated for 5 days with daily azacitidine (days 1-5) and fludarabine and cytarabine (days 6-10) in combination with daily trametinib for 28 days per course for up to 2 courses.
Trametinib will be administered using the following age-based dosing for both lower-risk and high-risk JMML with the starting dose as follows:
Patients will be concurrently enrolled into both the lower-risk and high-risk arm starting at Dose Level 1. The rolling 6 design will be used during Phase 1 of the study to confirm the recommended Phase 2 dose, separately for the lower-risk and high-risk arm, with one possible de-escalation.
Phase 1: Patients will initally be treated at dose level 1 with possible de-escalation to dose level -1. Patients will initially be enrolled at dose level 1. A rolling 6 design will be used.
Phase 2 –:If an RP2D is established, accrual of patients at this dose level will continue until up to 20 evaluable patients in the lower-risk cohort and 33 evaluable patients in the high-risk cohort have been enrolled, inclusive of evaluable patients enrolled during Phase I.
Click here to see a sample of the informed consent for this study which includes additional information about study requirements, treatment and side effects.
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