Myeloproliferative Neoplasms Clinical Trial

Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

Summary

This phase II trial studies how well trametinib works in treating patients with juvenile myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

View Full Description

Full Description

PRIMARY OBJECTIVE:

I. To determine the objective response rate to trametinib in children with recurrent or refractory juvenile myelomonocytic leukemia (JMML).

SECONDARY OBJECTIVES:

I. To further define and describe the toxicities of single agent trametinib in children with recurrent or refractory JMML.

II. To further characterize the pharmacokinetics of trametinib in children with recurrent or refractory JMML.

III. To prospectively evaluate mutant allele burden as a marker of disease activity in JMML.

IV. To measure the rate of complete responses in children with recurrent or refractory JMML.

V. To measure the duration of response among responders.

EXPLORATORY OBJECTIVE:

I. To describe the distribution of JMML diagnostic criteria in children with recurrent or refractory JMML.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and may undergo a bone marrow aspiration or biopsy at baseline, on day 28 of cycles 1 and 2, at all subsequent odd numbered cycles, and at end of treatment.

After completion of study treatment, patients are followed up annually for up to 5 years.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Patients must be >= 1 month and < 22 years of age at the time of study entry

Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease; the diagnosis is made based on the following criteria

JMML category 1 (all of the following): the diagnostic criteria must include all features in category 1 and EITHER (i) one of the features in category 2 OR (ii) two features from category 3 to make the diagnosis

Splenomegaly
> 1000 (1 x 10^9/uL) circulating monocytes
< 20% blasts in the bone marrow or peripheral blood
Absence of the t(9;22) or BCR/ABL fusion gene

JMML category 2 (at least one of the following if at least two category 3 criteria are not present):

Somatic mutation in RAS or PTPN11
Clinical diagnosis of NF1 or NF1 gene mutation
Homozygous mutation in CBL
Monosomy 7

JMML category 3 (at least two of the following if no category 2 criteria are met):

Circulating myeloid precursors
White blood cell count, > 10 000 (10 x 10^9/ uL)
Increased hemoglobin F for age
Clonal cytogenetic abnormality
GM-CSF hypersensitivity
Patients with refractory or relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (DNA) demethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality; frontline therapy is defined as one cycle of intravenous chemotherapy that includes any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine; frontline therapy will also include any conditioning regimen as part of a stem cell transplant; patients who transform to AML at any point with more than 20% blasts are not eligible for this trial
Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment

Myelosuppressive chemotherapy: patients must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea

Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy
Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
Biologic (anti-neoplastic agent): at least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur

Monoclonal antibodies:

At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines
At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody

Radiotherapy:

>= 2 weeks must have elapsed since local palliative external radiation therapy (XRT) (small port)
>= 6 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if traumatic brain injury (TBI) was received
>= 4 weeks must have elapsed if other substantial bone marrow irradiation was given
Stem cell transplant or rescue without TBI: no evidence of active graft versus (vs.) host disease and >= 3 months must have elapsed since transplant; >= 4 weeks must have elapsed since any donor lymphocyte infusion
Patients must not be known to be refractory to red blood cell or platelet transfusions

Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

Age: Maximum serum creatinine (mg/dL)

1 month to < 6 months: 0.4 (male) 0.4 (female)
6 months to < 1 year: 0.5 (male) 0.5 (female)
1 to < 2 years: 0.6 (male) 0.6 (female)
2 to < 6 years: 0.8 (male) 0.8 (female)
6 to < 10 years: 1 (male) 1 (female)
10 to < 13 years: 1.2 (male) 1.2 (female)
13 to < 16 years: 1.5 (male) 1.4 (female)
>= 16 years: 1.7 (male) 1.4 (female)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (=< 135 U/L) (within 7 days prior to enrollment) (for the purpose of this study, the ULN for SGPT is 45 U/L)
Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA)
Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs
Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed

Exclusion Criteria:

Patients who are pregnant or breast-feeding are not eligible for this study as there is yet no available information regarding human fetal or teratogenic toxicities; negative pregnancy tests must be obtained in girls who are post-menarchal; patients of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; women of childbearing potential should be advised to use effective contraception for 4 months after the last dose of trametinib; trametinib may also potentially be secreted in milk and therefore breastfeeding women are excluded; female patients should not breastfeed during treatment with trametinib, and for 4 months following the last dose; male patients must use a condom during intercourse and agree not to father a child during therapy and for 4 months following discontinuation of trametinib to avoid unnecessary exposure of trametinib to the fetus

Concomitant Medications

Corticosteroids: patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid

Note: hydrocortisone used as a pre-medication to prevent transfusion related reactions is not considered a concomitant corticosteroid
Investigational drugs: patients who are currently receiving another investigational drug are not eligible
Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible (except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
Anti-graft versus host disease (GVHD) or agents to prevent organ rejection post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
Cardiac medications: any medications for treatment of left ventricular systolic dysfunction
Patients who have an uncontrolled infection are not eligible
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Patients with a history of hepatic sinusoid obstructive syndrome (veno-occlusive disease) within the prior 3 months are not eligible
Patients with a history of or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible
Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension
Patients with uncontrolled systemic disease(s) such as hypertension or diabetes mellitus are not eligible; blood pressure must be =< the 95th percentile for age, height, and gender
Patients with a history of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib are not eligible
Patients with a clinical diagnosis of Noonan syndrome are not eligible; Note: patients with Casitas B-lineage lymphoma (CBL) syndrome, also known as Noonan-like syndrome, are eligible to enroll

Study is for people with:

Myeloproliferative Neoplasms

Phase:

Phase 2

Estimated Enrollment:

24

Study ID:

NCT03190915

Recruitment Status:

Recruiting

Sponsor:

National Cancer Institute (NCI)

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There are 57 Locations for this study

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Children's Hospital of Alabama
Birmingham Alabama, 35233, United States More Info
Site Public Contact
Contact
205-638-9285
[email protected]
Matthew A. Kutny
Principal Investigator
Phoenix Childrens Hospital
Phoenix Arizona, 85016, United States More Info
Site Public Contact
Contact
602-546-0920
Dana B. Salzberg
Principal Investigator
Arkansas Children's Hospital
Little Rock Arkansas, 72202, United States More Info
Site Public Contact
Contact
501-364-7373
David L. Becton
Principal Investigator
Kaiser Permanente Downey Medical Center
Downey California, 90242, United States More Info
Site Public Contact
Contact
626-564-3455
Robert M. Cooper
Principal Investigator
Loma Linda University Medical Center
Loma Linda California, 92354, United States
Kaiser Permanente-Oakland
Oakland California, 94611, United States More Info
Site Public Contact
Contact
877-642-4691
[email protected]
Aarati V. Rao
Principal Investigator
Children's Hospital of Orange County
Orange California, 92868, United States More Info
Site Public Contact
Contact
714-509-8646
[email protected]
Elyssa M. Rubin
Principal Investigator
Lucile Packard Children's Hospital Stanford University
Palo Alto California, 94304, United States More Info
Site Public Contact
Contact
800-694-0012
[email protected]
Jay Michael S. Balagtas
Principal Investigator
UCSF Medical Center-Mission Bay
San Francisco California, 94158, United States More Info
Site Public Contact
Contact
877-827-3222
[email protected]
Elliot Stieglitz
Principal Investigator
Children's Hospital Colorado
Aurora Colorado, 80045, United States More Info
Site Public Contact
Contact
303-764-5056
[email protected]
Kelly W. Maloney
Principal Investigator
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver Colorado, 80218, United States More Info
Site Public Contact
Contact
303-839-6000
Jennifer J. Clark
Principal Investigator
Connecticut Children's Medical Center
Hartford Connecticut, 06106, United States More Info
Site Public Contact
Contact
860-545-9981
Michael S. Isakoff
Principal Investigator
Alfred I duPont Hospital for Children
Wilmington Delaware, 19803, United States More Info
Site Public Contact
Contact
302-651-5572
[email protected]
Scott M. Bradfield
Principal Investigator
MedStar Georgetown University Hospital
Washington District of Columbia, 20007, United States
Children's National Medical Center
Washington District of Columbia, 20010, United States More Info
Site Public Contact
Contact
202-884-2549
AeRang Kim
Principal Investigator
Nemours Children's Clinic-Jacksonville
Jacksonville Florida, 32207, United States More Info
Site Public Contact
Contact
302-651-5572
[email protected]
Scott M. Bradfield
Principal Investigator
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami Florida, 33136, United States More Info
Site Public Contact
Contact
305-243-2647
Julio C. Barredo
Principal Investigator
Nicklaus Children's Hospital
Miami Florida, 33155, United States More Info
Site Public Contact
Contact
888-624-2778
Ziad A. Khatib
Principal Investigator
Arnold Palmer Hospital for Children
Orlando Florida, 32806, United States More Info
Site Public Contact
Contact
321-841-5357
[email protected]
Amy A. Smith
Principal Investigator
Nemours Children's Hospital
Orlando Florida, 32827, United States More Info
Site Public Contact
Contact
302-651-5572
[email protected]
Scott M. Bradfield
Principal Investigator
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa Florida, 33607, United States More Info
Site Public Contact
Contact
813-357-0849
[email protected]
Don E. Eslin
Principal Investigator
Children's Healthcare of Atlanta - Egleston
Atlanta Georgia, 30322, United States More Info
Site Public Contact
Contact
404-785-2025
[email protected]
Himalee S. Sabnis
Principal Investigator
Lurie Children's Hospital-Chicago
Chicago Illinois, 60611, United States More Info
Site Public Contact
Contact
773-880-4562
Elizabeth A. Sokol
Principal Investigator
Saint Jude Midwest Affiliate
Peoria Illinois, 61637, United States More Info
Site Public Contact
Contact
888-226-4343
Jaime M. Libes
Principal Investigator
Riley Hospital for Children
Indianapolis Indiana, 46202, United States More Info
Site Public Contact
Contact
800-248-1199
Sandeep Batra
Principal Investigator
University of Iowa/Holden Comprehensive Cancer Center
Iowa City Iowa, 52242, United States More Info
Site Public Contact
Contact
800-237-1225
David S. Dickens
Principal Investigator
University of Kentucky/Markey Cancer Center
Lexington Kentucky, 40536, United States More Info
Site Public Contact
Contact
859-257-3379
James T. Badgett
Principal Investigator
National Institutes of Health Clinical Center
Bethesda Maryland, 20892, United States More Info
Site Public Contact
Contact
800-411-1222
Srivandana Akshintala
Principal Investigator
Dana-Farber Cancer Institute
Boston Massachusetts, 02215, United States
C S Mott Children's Hospital
Ann Arbor Michigan, 48109, United States More Info
Site Public Contact
Contact
800-865-1125
Rajen Mody
Principal Investigator
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis Minnesota, 55404, United States More Info
Site Public Contact
Contact
612-813-5193
Michael K. Richards
Principal Investigator
University of Minnesota/Masonic Cancer Center
Minneapolis Minnesota, 55455, United States More Info
Site Public Contact
Contact
612-624-2620
Emily G. Greengard
Principal Investigator
Children's Mercy Hospitals and Clinics
Kansas City Missouri, 64108, United States More Info
Site Public Contact
Contact
816-302-6808
[email protected]
Kevin F. Ginn
Principal Investigator
Washington University School of Medicine
Saint Louis Missouri, 63110, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Robert J. Hayashi
Principal Investigator
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park New York, 11040, United States More Info
Site Public Contact
Contact
718-470-3460
Julie I. Krystal
Principal Investigator
Mount Sinai Hospital
New York New York, 10029, United States More Info
Site Public Contact
Contact
212-824-7309
[email protected]
Gary D. Crouch
Principal Investigator
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York New York, 10032, United States More Info
Site Public Contact
Contact
212-305-6361
[email protected]
Luca Szalontay
Principal Investigator
Carolinas Medical Center/Levine Cancer Institute
Charlotte North Carolina, 28203, United States More Info
Site Public Contact
Contact
800-804-9376
Joel A. Kaplan
Principal Investigator
Duke University Medical Center
Durham North Carolina, 27710, United States More Info
Site Public Contact
Contact
888-275-3853
Lars M. Wagner
Principal Investigator
Cincinnati Children's Hospital Medical Center
Cincinnati Ohio, 45229, United States More Info
Site Public Contact
Contact
513-636-2799
[email protected]g
Joseph G. Pressey
Principal Investigator
Nationwide Children's Hospital
Columbus Ohio, 43205, United States More Info
Site Public Contact
Contact
614-722-6039
[email protected]
Mark A. Ranalli
Principal Investigator
Dayton Children's Hospital
Dayton Ohio, 45404, United States More Info
Site Public Contact
Contact
800-228-4055
Mukund G. Dole
Principal Investigator
University of Oklahoma Health Sciences Center
Oklahoma City Oklahoma, 73104, United States More Info
Site Public Contact
Contact
405-271-8777
[email protected]
Rene Y. McNall-Knapp
Principal Investigator
Oregon Health and Science University
Portland Oregon, 97239, United States More Info
Site Public Contact
Contact
503-494-1080
[email protected]
Bill H. Chang
Principal Investigator
Children's Hospital of Philadelphia
Philadelphia Pennsylvania, 19104, United States More Info
Site Public Contact
Contact
267-425-5544
[email protected]
Theodore W. Laetsch
Principal Investigator
Children's Hospital of Pittsburgh of UPMC
Pittsburgh Pennsylvania, 15224, United States More Info
Site Public Contact
Contact
412-692-8570
[email protected]
Jean M. Tersak
Principal Investigator
BI-LO Charities Children's Cancer Center
Greenville South Carolina, 29605, United States More Info
Site Public Contact
Contact
864-241-6251
Aniket Saha
Principal Investigator
Saint Jude Children's Research Hospital
Memphis Tennessee, 38105, United States More Info
Site Public Contact
Contact
888-226-4343
[email protected]
Jeffrey E. Rubnitz
Principal Investigator
The Children's Hospital at TriStar Centennial
Nashville Tennessee, 37203, United States More Info
Site Public Contact
Contact
615-342-1919
Jennifer A. Domm
Principal Investigator
Vanderbilt University/Ingram Cancer Center
Nashville Tennessee, 37232, United States More Info
Site Public Contact
Contact
800-811-8480
Scott C. Borinstein
Principal Investigator
Dell Children's Medical Center of Central Texas
Austin Texas, 78723, United States More Info
Site Public Contact
Contact
512-628-1902
[email protected]
Shannon M. Cohn
Principal Investigator
UT Southwestern/Simmons Cancer Center-Dallas
Dallas Texas, 75390, United States More Info
Site Public Contact
Contact
214-648-7097
[email protected]
Kathleen (Wiertel) Ludwig
Principal Investigator
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston Texas, 77030, United States More Info
Site Public Contact
Contact
713-798-1354
[email protected]
Rachel E. Rau
Principal Investigator
Methodist Children's Hospital of South Texas
San Antonio Texas, 78229, United States More Info
Site Public Contact
Contact
210-575-6240
[email protected]
Jose M. Esquilin
Principal Investigator
Primary Children's Hospital
Salt Lake City Utah, 84113, United States More Info
Site Public Contact
Contact
801-585-5270
Luke D. Maese
Principal Investigator
Seattle Children's Hospital
Seattle Washington, 98105, United States More Info
Site Public Contact
Contact
866-987-2000
Navin R. Pinto
Principal Investigator
Children's Hospital of Wisconsin
Milwaukee Wisconsin, 53226, United States More Info
Site Public Contact
Contact
414-955-4727
[email protected]
Michael J. Burke
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Myeloproliferative Neoplasms

Phase:

Phase 2

Estimated Enrollment:

24

Study ID:

NCT03190915

Recruitment Status:

Recruiting

Sponsor:


National Cancer Institute (NCI)

How clear is this clinincal trial information?

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