Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT03698994
Collaborator
(none)
20
109
1
54.2
0.2
0

Study Details

Study Description

Brief Summary

This phase II Pediatric MATCH trial studies how well ulixertinib works in treating patients with solid tumors that have spread to other places in the body (advanced), non-Hodgkin lymphoma, or histiocytic disorders that have a genetic alteration (mutation) in a signaling pathway called MAPK. A signaling pathway consists of a group of molecules in a cell that control one or more cell functions. Genes in the MAPK pathway are frequently mutated in many types of cancers. Ulixertinib may stop the growth of cancer cells that have mutations in the MAPK pathway.

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with BVD-523FB (ulixertinib) 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:
  1. To estimate the progression free survival in pediatric patients treated with BVD-523FB (ulixertinib) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor activating genetic alterations in the MAPK pathway.

  2. To obtain information about the tolerability of BVD-523FB (ulixertinib) in children and adolescents with relapsed or refractory cancer.

  3. To provide preliminary estimates of the pharmacokinetics of BVD-523FB (ulixertinib) in children and adolescents with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:
  1. To evaluate other biomarkers as predictors of response to BVD-523FB (ulixertinib) and specifically, whether tumors that harbor different mutations or fusions will demonstrate differential response to BVD-523FB (ulixertinib) treatment.

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

OUTLINE: This is a dose-escalation study.

Patients receive ulixertinib orally (PO) twice daily (BID). 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of BVD-523FB (Ulixertinib) in Patients With Tumors Harboring Activating MAPK Pathway Mutations
Actual Study Start Date :
Oct 1, 2018
Actual Primary Completion Date :
Mar 31, 2022
Anticipated Study Completion Date :
Apr 7, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (ulixertinib)

Patients receive ulixertinib PO BID. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Other: Pharmacokinetic Study
Ancillary studies
Other Names:
  • PHARMACOKINETIC
  • PK Study
  • Drug: Ulixertinib
    Given PO
    Other Names:
  • BVD-523
  • VRT752271
  • Outcome Measures

    Primary Outcome Measures

    1. Objective response rate (ORR = complete response [CR] + partial response [PR]) in pediatric patients treated with BVD-523FB (ulixertinib) [Up to 2 years]

      Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method

    Secondary Outcome Measures

    1. Progression free survival (PFS) in pediatric patients treated with ulixertinib [From initiation of treatment to disease progression, disease recurrence, or death from any cause assessed up to 2 years]

      PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.

    2. Percentage of patients experiencing grade 3 or 4 adverse events [From enrollment to the end of treatment, up to 2 years]

      Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Any eligible patient who receives at least one dose of protocol therapy will be considered in the evaluation of toxicity.

    3. Preliminary estimates of the pharmacokinetics of ulixertinib in children and adolescents with relapsed or refractory cancer [Pre-dose and 1, 2, 4, and 6-8 hours after dose on cycle 1, day 1; and pre-dose on cycle 1, day 2, and cycle 1, day 15]

      Will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

    Other Outcome Measures

    1. Other biomarkers as predictors of response to ulixertinib and whether tumors that harbor different mutations or fusions will demonstrate differential response to treatment [Up to 2 years]

      Will be performed and will be summarized with simple summary statistics. All of these analyses will be descriptive in nature.

    2. Profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA) [Up to 2 years]

      Will be performed and will be summarized with simple summary statistics. All of these analyses will be descriptive in nature.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Months to 21 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621J based on the presence of an actionable mutation.

    • Patients must have a body surface area >= 0.54 m^2 at the time of study enrollment.

    • Patients must have radiographically measurable disease at the time of study enrollment. Patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG)+ evaluable disease are eligible. Measurable disease in patients with central nervous system (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 relatively 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 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 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.).

    • Radiotherapy (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 brain metastases (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, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy.

    • Patients must not have received prior exposure to BVD-523FB (ulixertinib) or other ERK inhibitors.

    • For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment).

    • For patients with solid tumors without known bone marrow involvement: 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) >= 70 ml/min/1.73 m^2, or (within 7 days prior to enrollment).

    • A serum creatinine based on age/gender (within 7 days prior to enrollment).

    • 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 (within 7 days prior to enrollment).

    • Ejection fraction of >= 50% by gated radionuclide study (within 7 days prior to enrollment).

    • QTc interval =< 480 milliseconds (within 7 days prior to enrollment).

    • Patients must be able to swallow intact capsules.

    • 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 due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment and for 3 months after last dose of BVD-523FB (ulixertinib).

    • 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.

    • Patients who are currently receiving another investigational drug are not eligible.

    • Patients who are currently receiving other anti-cancer agents are not eligible.

    • 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.

    • 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. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.

    • Patients who are currently receiving drugs that are strong inducers or inhibitors of CYP1A2 and CYP2D6 are not eligible. Strong inhibitors of CYP1A2 (e.g., ciprofloxacin, enoxacin, fluvoxamine, zafirlukast) should be avoided from 14 days prior to enrollment to the end of the study. Strong inhibitors of CYP2D6 (e.g., bupropion, paroxetine, fluoxetine, quinidine, terbinafine) should also be avoided from 14 days prior to enrollment to the end of the study.

    • 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 who have an uncontrolled infection 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 Providence Alaska Medical Center Anchorage Alaska United States 99508
    3 Banner Children's at Desert Mesa Arizona United States 85202
    4 Banner University Medical Center - Tucson Tucson Arizona United States 85719
    5 Arkansas Children's Hospital Little Rock Arkansas United States 72202-3591
    6 Kaiser Permanente Downey Medical Center Downey California United States 90242
    7 Loma Linda University Medical Center Loma Linda California United States 92354
    8 Miller Children's and Women's Hospital Long Beach Long Beach California United States 90806
    9 Children's Hospital Los Angeles Los Angeles California United States 90027
    10 Mattel Children's Hospital UCLA Los Angeles California United States 90095
    11 Valley Children's Hospital Madera California United States 93636
    12 UCSF Benioff Children's Hospital Oakland Oakland California United States 94609
    13 Kaiser Permanente-Oakland Oakland California United States 94611
    14 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    15 Children's Hospital Colorado Aurora Colorado United States 80045
    16 Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado United States 80218
    17 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    18 Children's National Medical Center Washington District of Columbia United States 20010
    19 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    20 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    21 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    22 Nicklaus Children's Hospital Miami Florida United States 33155
    23 AdventHealth Orlando Orlando Florida United States 32803
    24 Arnold Palmer Hospital for Children Orlando Florida United States 32806
    25 Nemours Children's Hospital Orlando Florida United States 32827
    26 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    27 Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida United States 33607
    28 Saint Mary's Hospital West Palm Beach Florida United States 33407
    29 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    30 Memorial Health University Medical Center Savannah Georgia United States 31404
    31 Saint Luke's Cancer Institute - Boise Boise Idaho United States 83712
    32 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    33 Saint Jude Midwest Affiliate Peoria Illinois United States 61637
    34 Southern Illinois University School of Medicine Springfield Illinois United States 62702
    35 Riley Hospital for Children Indianapolis Indiana United States 46202
    36 Saint Vincent Hospital and Health Care Center Indianapolis Indiana United States 46260
    37 Blank Children's Hospital Des Moines Iowa United States 50309
    38 University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa United States 52242
    39 Children's Hospital New Orleans New Orleans Louisiana United States 70118
    40 Ochsner Medical Center Jefferson New Orleans Louisiana United States 70121
    41 Eastern Maine Medical Center Bangor Maine United States 04401
    42 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
    43 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    44 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 02114
    45 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    46 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    47 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    48 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    49 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    50 University of Minnesota/Masonic Cancer Center Minneapolis Minnesota United States 55455
    51 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    52 University of Mississippi Medical Center Jackson Mississippi United States 39216
    53 Children's Mercy Hospitals and Clinics Kansas City Missouri United States 64108
    54 Cardinal Glennon Children's Medical Center Saint Louis Missouri United States 63104
    55 Washington University School of Medicine Saint Louis Missouri United States 63110
    56 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    57 Children's Hospital and Medical Center of Omaha Omaha Nebraska United States 68114
    58 University of Nebraska Medical Center Omaha Nebraska United States 68198
    59 Hackensack University Medical Center Hackensack New Jersey United States 07601
    60 Morristown Medical Center Morristown New Jersey United States 07960
    61 Saint Peter's University Hospital New Brunswick New Jersey United States 08901
    62 Albany Medical Center Albany New York United States 12208
    63 Roswell Park Cancer Institute Buffalo New York United States 14263
    64 The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park New York United States 11040
    65 Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York United States 10016
    66 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    67 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    68 NYP/Weill Cornell Medical Center New York New York United States 10065
    69 University of Rochester Rochester New York United States 14642
    70 State University of New York Upstate Medical University Syracuse New York United States 13210
    71 Mission Hospital Asheville North Carolina United States 28801
    72 Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina United States 28203
    73 Duke University Medical Center Durham North Carolina United States 27710
    74 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    75 Nationwide Children's Hospital Columbus Ohio United States 43205
    76 Dayton Children's Hospital Dayton Ohio United States 45404
    77 ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital Toledo Ohio United States 43606
    78 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    79 Legacy Emanuel Children's Hospital Portland Oregon United States 97227
    80 Oregon Health and Science University Portland Oregon United States 97239
    81 Geisinger Medical Center Danville Pennsylvania United States 17822
    82 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    83 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    84 BI-LO Charities Children's Cancer Center Greenville South Carolina United States 29605
    85 Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota United States 57117-5134
    86 East Tennessee Childrens Hospital Knoxville Tennessee United States 37916
    87 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    88 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    89 Dell Children's Medical Center of Central Texas Austin Texas United States 78723
    90 Medical City Dallas Hospital Dallas Texas United States 75230
    91 UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas United States 75390
    92 Cook Children's Medical Center Fort Worth Texas United States 76104
    93 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas United States 77030
    94 M D Anderson Cancer Center Houston Texas United States 77030
    95 Children's Hospital of San Antonio San Antonio Texas United States 78207
    96 Methodist Children's Hospital of South Texas San Antonio Texas United States 78229
    97 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    98 Scott and White Memorial Hospital Temple Texas United States 76508
    99 Primary Children's Hospital Salt Lake City Utah United States 84113
    100 University of Vermont and State Agricultural College Burlington Vermont United States 05405
    101 Children's Hospital of The King's Daughters Norfolk Virginia United States 23507
    102 Virginia Commonwealth University/Massey Cancer Center Richmond Virginia United States 23298
    103 Seattle Children's Hospital Seattle Washington United States 98105
    104 Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington United States 99204
    105 Madigan Army Medical Center Tacoma Washington United States 98431
    106 University of Wisconsin Carbone Cancer Center Madison Wisconsin United States 53792
    107 Children's Hospital of Wisconsin Milwaukee Wisconsin United States 53226
    108 San Jorge Children's Hospital San Juan Puerto Rico 00912
    109 University Pediatric Hospital San Juan Puerto Rico 00926

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Kieuhoa T Vo, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03698994
    Other Study ID Numbers:
    • NCI-2018-02150
    • NCI-2018-02150
    • APEC1621J
    • APEC1621J
    • U10CA180886
    First Posted:
    Oct 9, 2018
    Last Update Posted:
    Jun 30, 2022
    Last Verified:
    Apr 1, 2022

    Study Results

    No Results Posted as of Jun 30, 2022