Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Recruiting
CT.gov ID
NCT03213704
Collaborator
(none)
49
124
1
86.2
0.4
0

Study Details

Study Description

Brief Summary

This phase II Pediatric MATCH trial studies how well larotrectinib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with NTRK fusions that have spread to other places in the body and have come back or do not respond to treatment. Larotrectinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVE:
  1. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with larotrectinib sulfate (LOXO-101 [larotrectinib]) with advanced solid tumors (including central nervous system [CNS] tumors), non-Hodgkin lymphomas or histiocytic disorders harboring NTRK 1/2/3 fusions.
SECONDARY OBJECTIVES:
  1. To estimate the progression free survival in pediatric patients treated with LOXO-101 (larotrectinib) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders with NTRK 1/2/3 fusions.

  2. To obtain additional information about the tolerability of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer.

  3. To provide preliminary estimates of the pharmacokinetics of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer.

EXPLORATORY OBJECTIVE:
  1. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).
OUTLINE:

Patients receive larotrectinib sulfate orally (PO) or via nasogastric (NG)- or gastric (G)-tube twice per day (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 at 30 days, then periodically thereafter.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
49 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 LOXO-101 (Larotrectinib) in Patients With Tumors Harboring Actionable NTRK Fusions
Actual Study Start Date :
Jul 24, 2017
Anticipated Primary Completion Date :
Sep 30, 2024
Anticipated Study Completion Date :
Sep 30, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (larotrectinib sulfate)

Patients receive larotrectinib sulfate PO or via NG- or G-tube twice per day (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Larotrectinib Sulfate
Given PO or via nasogastric- or gastric-tube
Other Names:
  • ARRY 470 Sulfate
  • LOXO 101 Sulfate
  • LOXO-101 Sulfate
  • Vitrakvi
  • Outcome Measures

    Primary Outcome Measures

    1. Objective response rate [Up to 5 years]

      Will be determined by Response Evaluation Criteria in Solid Tumors.

    Secondary Outcome Measures

    1. Progression free survival [The time 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]

      Progression free survival along with the confidence intervals will be estimated using the Kaplan-Meier method. Patients with local calls of disease progression (i.e. calls made by the treating institution), will be counted as having had an event, even if the central review does not declare progression. Progression free survival will be reported based on central radiology review as a secondary analysis, if adequate number of disagreements in progressions exist between the treating institutions and the central radiology review to make such an analysis meaningful.

    Other Outcome Measures

    1. Incidence of adverse events [Up to 5 years]

      Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.

    2. Pharmacokinetics of larotrectinib [Pre-dose, 1, 2, 4, and 6-8 hours after morning dose of day 1 cycle 1 and pre-dose of day 1 cycle 2]

      A descriptive analysis of pharmacokinetic parameters of LOXO-101 (larotrectinib) will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The pharmacokinetic parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). All these analyses will be descriptive and exploratory and hypotheses generating in nature.

    3. Ability to detect NTRK fusions in circulating cell-free tumor deoxyribonucleic acid in plasma [Up to 5 years]

      A descriptive analysis of the exploratory aims 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:
    • APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621A based on the presence of an actionable mutation as defined in APEC1621SC

    • 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)+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT); 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 time frame, 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; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment

    • = 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 [ANC] counts): >= 7 days after the last dose of agent; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment

    • 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 leukocyte 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, NK cells, dendritic cells, etc.)

    • Radiation 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 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 other NTRK inhibitors including but not limited to LOXO-101 (larotrectinib), entrectinib (RXDX-101), DS6051, PLX7486

    • For patients with solid tumors without known bone marrow involvement:

    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

    • 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

    • 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

    • 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)

    • Serum albumin >= 2 g/dL

    • Patients with seizure disorder may be enrolled if on anti-convulsants and well controlled

    • Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflect (DTR); any grade of DTR is eligible

    • 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

    • 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 (GVHD) 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 have received prior therapy with a specific inhibitor of TRK (including but not limited to entrectinib [RXDX-101], DS-6051b, and PLX7486) 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 Valley Children's Hospital Madera California United States 93636
    11 UCSF Benioff Children's Hospital Oakland Oakland California United States 94609
    12 Kaiser Permanente-Oakland Oakland California United States 94611
    13 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    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 Yale University New Haven Connecticut United States 06520
    18 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    19 Children's National Medical Center Washington District of Columbia United States 20010
    20 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    21 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    22 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    23 Nicklaus Children's Hospital Miami Florida United States 33155
    24 AdventHealth Orlando Orlando Florida United States 32803
    25 Arnold Palmer Hospital for Children Orlando Florida United States 32806
    26 Nemours Children's Hospital Orlando Florida United States 32827
    27 Nemours Children's Clinic - Pensacola Pensacola Florida United States 32504
    28 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    29 Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida United States 33607
    30 Saint Mary's Hospital West Palm Beach Florida United States 33407
    31 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    32 Saint Luke's Cancer Institute - Boise Boise Idaho United States 83712
    33 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    34 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    35 Saint Jude Midwest Affiliate Peoria Illinois United States 61637
    36 Southern Illinois University School of Medicine Springfield Illinois United States 62702
    37 Riley Hospital for Children Indianapolis Indiana United States 46202
    38 Saint Vincent Hospital and Health Care Center Indianapolis Indiana United States 46260
    39 Blank Children's Hospital Des Moines Iowa United States 50309
    40 University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa United States 52242
    41 Norton Children's Hospital Louisville Kentucky United States 40202
    42 Children's Hospital New Orleans New Orleans Louisiana United States 70118
    43 Ochsner Medical Center Jefferson New Orleans Louisiana United States 70121
    44 Eastern Maine Medical Center Bangor Maine United States 04401
    45 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
    46 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    47 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    48 Michigan State University Clinical Center East Lansing Michigan United States 48824-7016
    49 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    50 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    51 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    52 University of Minnesota/Masonic Cancer Center Minneapolis Minnesota United States 55455
    53 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    54 University of Mississippi Medical Center Jackson Mississippi United States 39216
    55 Children's Mercy Hospitals and Clinics Kansas City Missouri United States 64108
    56 Cardinal Glennon Children's Medical Center Saint Louis Missouri United States 63104
    57 Washington University School of Medicine Saint Louis Missouri United States 63110
    58 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    59 Children's Hospital and Medical Center of Omaha Omaha Nebraska United States 68114
    60 University of Nebraska Medical Center Omaha Nebraska United States 68198
    61 University Medical Center of Southern Nevada Las Vegas Nevada United States 89102
    62 Sunrise Hospital and Medical Center Las Vegas Nevada United States 89109
    63 Alliance for Childhood Diseases/Cure 4 the Kids Foundation Las Vegas Nevada United States 89135
    64 Summerlin Hospital Medical Center Las Vegas Nevada United States 89144
    65 Hackensack University Medical Center Hackensack New Jersey United States 07601
    66 Morristown Medical Center Morristown New Jersey United States 07960
    67 Saint Peter's University Hospital New Brunswick New Jersey United States 08901
    68 Albany Medical Center Albany New York United States 12208
    69 Montefiore Medical Center - Moses Campus Bronx New York United States 10467
    70 Roswell Park Cancer Institute Buffalo New York United States 14263
    71 The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park New York United States 11040
    72 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    73 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    74 NYP/Weill Cornell Medical Center New York New York United States 10065
    75 University of Rochester Rochester New York United States 14642
    76 Stony Brook University Medical Center Stony Brook New York United States 11794
    77 State University of New York Upstate Medical University Syracuse New York United States 13210
    78 New York Medical College Valhalla New York United States 10595
    79 Mission Hospital Asheville North Carolina United States 28801
    80 Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina United States 28203
    81 Novant Health Presbyterian Medical Center Charlotte North Carolina United States 28204
    82 Duke University Medical Center Durham North Carolina United States 27710
    83 Sanford Broadway Medical Center Fargo North Dakota United States 58122
    84 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    85 Rainbow Babies and Childrens Hospital Cleveland Ohio United States 44106
    86 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    87 Nationwide Children's Hospital Columbus Ohio United States 43205
    88 Dayton Children's Hospital Dayton Ohio United States 45404
    89 ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital Toledo Ohio United States 43606
    90 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    91 Legacy Emanuel Children's Hospital Portland Oregon United States 97227
    92 Oregon Health and Science University Portland Oregon United States 97239
    93 Geisinger Medical Center Danville Pennsylvania United States 17822
    94 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    95 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    96 Prisma Health Richland Hospital Columbia South Carolina United States 29203
    97 BI-LO Charities Children's Cancer Center Greenville South Carolina United States 29605
    98 Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota United States 57117-5134
    99 East Tennessee Childrens Hospital Knoxville Tennessee United States 37916
    100 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    101 The Children's Hospital at TriStar Centennial Nashville Tennessee United States 37203
    102 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    103 Dell Children's Medical Center of Central Texas Austin Texas United States 78723
    104 Driscoll Children's Hospital Corpus Christi Texas United States 78411
    105 Medical City Dallas Hospital Dallas Texas United States 75230
    106 UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas United States 75390
    107 Cook Children's Medical Center Fort Worth Texas United States 76104
    108 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas United States 77030
    109 M D Anderson Cancer Center Houston Texas United States 77030
    110 Children's Hospital of San Antonio San Antonio Texas United States 78207
    111 Methodist Children's Hospital of South Texas San Antonio Texas United States 78229
    112 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    113 Scott and White Memorial Hospital Temple Texas United States 76508
    114 Primary Children's Hospital Salt Lake City Utah United States 84113
    115 Children's Hospital of The King's Daughters Norfolk Virginia United States 23507
    116 Virginia Commonwealth University/Massey Cancer Center Richmond Virginia United States 23298
    117 Seattle Children's Hospital Seattle Washington United States 98105
    118 Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington United States 99204
    119 Madigan Army Medical Center Tacoma Washington United States 98431
    120 West Virginia University Healthcare Morgantown West Virginia United States 26506
    121 University of Wisconsin Carbone Cancer Center Madison Wisconsin United States 53792
    122 Children's Hospital of Wisconsin Milwaukee Wisconsin United States 53226
    123 San Jorge Children's Hospital San Juan Puerto Rico 00912
    124 University Pediatric Hospital San Juan Puerto Rico 00926

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Katherine A Janeway, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03213704
    Other Study ID Numbers:
    • NCI-2017-01264
    • NCI-2017-01264
    • APEC1621A
    • APEC1621A
    • APEC1621A
    • U10CA180886
    First Posted:
    Jul 11, 2017
    Last Update Posted:
    Aug 24, 2022
    Last Verified:
    Jul 1, 2022

    Study Results

    No Results Posted as of Aug 24, 2022