Clinical trial NCT03213691: Selumetinib Sulfate in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
Official title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of Selumetinib (AZD6244 Hydrogen Sulfate) in Patients With Tumors Harboring Activating MAPK Pathway Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm
Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma
Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma
Recurrent Childhood Central Nervous System Neoplasm
Recurrent Childhood Non-Hodgkin Lymphoma
Recurrent Malignant Solid Neoplasm
Recurrent Neuroblastoma
Refractory Malignant Solid Neoplasm
Refractory Neuroblastoma
Refractory Non-Hodgkin Lymphoma
Refractory Primary Central Nervous System Neoplasm
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2017-07-11
Enrollment: 21
Sex: ALL
Minimum age (years): 12
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II Pediatric MATCH trial studies how well selumetinib sulfate works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with MAPK pathway activation mutations that have spread to other places in the body and have come back or do not respond to treatment. Selumetinib sulfate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description: PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with selumetinib (AZD6244 hydrogen sulfate) with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor activating genetic alterations in the MAPK pathway.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with selumetinib (AZD6244 hydrogen sulfate) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor MAPK activation mutations.

II. To obtain additional information about the tolerability of selumetinib (AZD6244 hydrogen sulfate) in children with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate other biomarkers as predictors of response to selumetinib (AZD6244 hydrogen sulfate) and specifically, whether tumors that harbor different mutations or fusions will demonstrate differential response to selumetinib (AZD6244 hydrogen sulfate) treatment.

II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).

OUTLINE:

Patients receive selumetinib sulfate 25 mg/m2/dose orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Eligibility criteria: Inclusion Criteria:

* Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to molecular analysis for therapy choice (MATCH) to APEC1621E based on the presence of an actionable mutation

  * Note: patients with BRAF V600 actionable mutations of interest (aMOIs) will be preferentially assigned to APEC1621G (vemurafenib) if that study is open and they are otherwise eligible for it
* Patients must have a body surface area \>= 0.5 m\^2 at enrollment
* Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have iobenguane (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice

  * Note: the following do not qualify as measurable disease:

    * Malignant fluid collections (e.g., ascites, pleural effusions)
    * Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
    * Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography \[PET\] scans) except as noted for neuroblastoma
    * Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
    * Previously radiated lesions that have not demonstrated clear progression post radiation
    * Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* Karnofsky \>= 50% for patients \> 16 years of age and Lansky \>= 50 for patients =\< 16 years of age; Note: neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; 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 anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

  * Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: \>= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
  * Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count \[ANC\] counts): \>= 7 days after the last dose of agent
  * Antibodies: \>= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =\< 1
  * Corticosteroids: if used to modify immune adverse events related to prior therapy, \>= 14 days must have elapsed since last dose of corticosteroid
  * Hematopoietic growth factors: \>= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors 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; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
  * Interleukins, interferons and cytokines (other than hematopoietic growth factors): \>= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
  * Stem cell Infusions (with or without total body irradiation \[TBI\]):

    * Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: \>= 84 days after infusion and no evidence of graft versus host disease (GVHD)
    * Autologous stem cell infusion including boost infusion: \>= 42 days
  * Cellular therapy: \>= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer \[NK\] cells, dendritic cells, etc.)
  * X-ray therapy (XRT)/external beam irradiation including protons: \>= 14 days after local XRT; \>= 150 days after TBI, craniospinal XRT or if radiation to \>= 50% of the pelvis; \>= 42 days if other substantial bone marrow (BM) radiation

    * Note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
  * Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131 metaiodobenzylguanidine \[131I-MIBG\]): \>= 42 days after systemically administered radiopharmaceutical therapy
  * Patients must not have received prior exposure to selumetinib (AZD6244 hydrogen sulfate)
* For patients with solid tumors without known bone marrow involvement:

  * Peripheral absolute neutrophil count (ANC) \>= 1000/mm\^3 within 7 days prior to enrollment
  * Platelet count \>= 100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
* Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) within 7 days prior to enrollment \>= 70 ml/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:

  * Age: 1 to \< 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
  * Age: 2 to \< 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
  * Age: 6 to \< 10 years; maximum serum creatinine (mg/dL): male 1; female 1
  * Age: 10 to \< 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
  * Age: 13 to \< 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
  * Age: \>= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
* Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age within 7 days prior to enrollment
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L) within 7 days prior to enrollment
* Serum albumin \>= 2 g/dL within 7 days prior to enrollment
* Shortening fraction of \>= 27% by echocardiogram, or ejection fraction of \>= 50% by gated radionuclide study within 7 days prior to enrollment
* A blood pressure (BP) =\< the 95th percentile for age, height, and gender measured within 7 days prior to enrollment; please note that 3 serial blood pressures should be obtained and averaged to determine baseline BP; patients with hypertension controlled on antihypertensive medications will be allowed if otherwise eligible
* Serum triglyceride level =\< 300 mg/dL within 7 days prior to enrollment
* Serum total cholesterol level =\< 300 mg/dL within 7 days prior to enrollment
* Patients must be able to swallow intact capsules whole
* All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

* Pregnant or breast-feeding women will not be entered on this study because there is currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in girls who are post-menarchal; females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment; males with sexual partners who are pregnant or who could become pregnant (ie, women of child-bearing potential) should use effective methods of contraception for 12 weeks after completing the study to avoid pregnancy and/or potential adverse effects on the developing embryo
* Concomitant medications

  * Corticosteroids: patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 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
  * 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
  * Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
  * CYP3A4 agents: patients who are currently receiving drugs that are strong inducers or inhibitors of CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study
  * CYP2C19 agents: patients who are currently receiving drugs that are strong CYP2C19 inducers (e.g., rifampin, ritonavir) or inhibitors (e.g.., fluoxetine, fluvoxamine, ticlopidine) are not eligible
* Patients who have an uncontrolled infection are not eligible
* Patients with known significant ophthalmologic conditions (uncontrolled glaucoma, history of retinal vein occlusion or retinal detachment, excluding patients with longstanding findings secondary to existing conditions) are not eligible
* Patients with low grade glioma are not eligible
* Patients who have received a prior solid organ transplantation 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

Primary outcomes:
measure: Response Rate
timeFrame: From enrollment to the end of treatment, up to 2 years
Secondary outcomes:
measure: Percentage of Participants With Treatment-related Adverse Events as Accessed by Common Terminology Criteria for Adverse Events (CTCAE) Version (v) 5.0
timeFrame: From enrollment to the end of treatment, up to 2 years
measure: Progression Free Survival (PFS)
timeFrame: From the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 5 years
Other outcomes:
measure: Biomarker Analysis as Predictors of Response to Selumetinib
timeFrame: Up to 4.5 years
measure: Changes in Tumor Genomic Profile
timeFrame: Up to 4.5 years
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Mesa
country: United States
facility: Banner Children's at Desert
state: Arizona
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Downey
country: United States
facility: Kaiser Permanente Downey Medical Center
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Long Beach
country: United States
facility: Miller Children's and Women's Hospital Long Beach
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital UCLA
state: California
city: Madera
country: United States
facility: Valley Children's Hospital
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Oakland
country: United States
facility: Kaiser Permanente-Oakland
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Saint Joseph's Hospital/Children's Hospital-Tampa
state: Florida
city: West Palm Beach
country: United States
facility: Saint Mary's Medical Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Arthur M Blank Hospital
state: Georgia
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Boise
country: United States
facility: Saint Luke's Cancer Institute - Boise
state: Idaho
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Peoria
country: United States
facility: Saint Jude Midwest Affiliate
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Children's Hospital New Orleans
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center of Omaha
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Alliance for Childhood Diseases/Cure 4 the Kids Foundation
state: Nevada
city: Las Vegas
country: United States
facility: Summerlin Hospital Medical Center
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Saint Peter's University Hospital
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New Hyde Park
country: United States
facility: The Steven and Alexandra Cohen Children's Medical Center of New York
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
city: Toledo
country: United States
facility: ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Legacy Emanuel Children's Hospital
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Greenville
country: United States
facility: BI-LO Charities Children's Cancer Center
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Knoxville
country: United States
facility: East Tennessee Childrens Hospital
state: Tennessee
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Children's Hospital of San Antonio
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Burlington
country: United States
facility: University of Vermont and State Agricultural College
state: Vermont
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: San Jorge Children's Hospital
city: San Juan
country: Puerto Rico
facility: University Pediatric Hospital
Study officials:
affiliation: Children's Oncology Group
name: Carl E Allen
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eckstein OS, Allen CE, Williams PM, Roy-Chowdhuri S, Patton DR, Coffey B, Reid JM, Piao J, Saguilig L, Alonzo TA, Berg SL, Ramirez NC, Jaju A, Mhlanga J, Fox E, Hawkins DS, Mooney MM, Takebe N, Tricoli JV, Janeway KA, Seibel NL, Parsons DW. Phase II Study of Selumetinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic Alterations: Arm E of the NCI-COG Pediatric MATCH Trial. J Clin Oncol. 2022 Jul 10;40(20):2235-2245. doi: 10.1200/JCO.21.02840. Epub 2022 Apr 1.