Summary

for people ages 12 months to 21 years (full criteria)
at UCSF
study started
estimated completion
Carla B. Golden (ucsf) Robert E. Goldsby (ucsf)

Description

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.

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

Details

PRIMARY OBJECTIVES:

  1. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with 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.

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

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

TERTIARY OBJECTIVES:

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

OUTLINE:

Patients receive larotrectinib orally (PO) or via nasogastric- or gastric-tube twice per day (BID) on days 1-28. Courses 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.

Keywords

Advanced Malignant Solid NeoplasmAnn Arbor Stage III Childhood Non-Hodgkin LymphomaAnn Arbor Stage IV Childhood Non-Hodgkin LymphomaMalignant GliomaNTRK1 Fusion PositiveNTRK2 Fusion PositiveNTRK3 Fusion PositiveRecurrent Central Nervous System NeoplasmRecurrent Childhood EpendymomaRecurrent Childhood Malignant Germ Cell TumorRecurrent Childhood MedulloblastomaRecurrent Childhood Non-Hodgkin LymphomaRecurrent Childhood RhabdomyosarcomaRecurrent Childhood Soft Tissue SarcomaRecurrent Ewing SarcomaRecurrent GliomaRecurrent HepatoblastomaRecurrent Langerhans Cell HistiocytosisRecurrent Malignant Solid NeoplasmRecurrent NeuroblastomaRecurrent OsteosarcomaRecurrent Peripheral Primitive Neuroectodermal TumorRefractory Central Nervous System NeoplasmRefractory Childhood Malignant Germ Cell TumorRefractory Langerhans Cell HistiocytosisRefractory Malignant Solid NeoplasmRefractory NeuroblastomaRefractory Non-Hodgkin LymphomaRhabdoid TumorStage III Osteosarcoma AJCC v7Stage III Soft Tissue Sarcoma AJCC v7Stage IV Osteosarcoma AJCC v7Stage IV Soft Tissue Sarcoma AJCC v7Stage IVA Osteosarcoma AJCC v7Stage IVB Osteosarcoma AJCC v7Wilms TumorLymphomaNeoplasmsSarcomaLymphoma, Non-HodgkinGliomaNeuroblastomaNeoplasms, Germ Cell and EmbryonalOsteosarcomaRhabdomyosarcomaEpendymomaSarcoma, EwingMedulloblastomaNeuroectodermal TumorsNeuroectodermal Tumors, PrimitiveRhabdomyosarcoma, EmbryonalNeuroectodermal Tumors, Primitive, PeripheralHistiocytosisHistiocytosis, Langerhans-CellNervous System NeoplasmsCentral Nervous System NeoplasmsHepatoblastomaLaboratory Biomarker AnalysisLarotrectinibPharmacological Study

Eligibility

You can join if…

Open to people ages 12 months to 21 years

  • 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
  • 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 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 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 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/mm3

  • Platelet count >= 100,000/mm3 (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 m2 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] 4) resulting from prior therapy must be =< grade 2
  • 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

You CAN'T join if...

  • Pregnant or breast-feeding women will not be entered on this study; 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

Locations

  • Children's Hospital and Research Center at Oakland accepting new patients
    OaklandCalifornia94609-1809United States
  • UCSF Medical Center-Mission Bay accepting new patients
    San FranciscoCalifornia94158United States
  • Children's Hospital Los Angeles accepting new patients
    Los AngelesCalifornia90027United States

Lead Scientists

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
National Cancer Institute (NCI)
ID
NCT03213704
Phase
Phase 2
Study Type
Interventional
Last Updated