Clinical Trials /

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)

NCT03213704

Description:

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.

Related Conditions:
  • Histiocytic and Dendritic Cell Neoplasm
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pediatric MATCH: Trk Inhibitor LOXO-101 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01264
  • SECONDARY ID: NCI-2017-01264
  • SECONDARY ID: APEC1621A
  • SECONDARY ID: APEC1621A
  • SECONDARY ID: APEC1621A
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03213704

Conditions

  • Advanced Malignant Solid Neoplasm
  • Malignant Glioma
  • NTRK1 Fusion Positive
  • NTRK2 Fusion Positive
  • NTRK3 Fusion Positive
  • Recurrent Central Nervous System Neoplasm
  • Recurrent Childhood Ependymoma
  • Recurrent Childhood Malignant Germ Cell Tumor
  • Recurrent Childhood Medulloblastoma
  • Recurrent Childhood Non-Hodgkin Lymphoma
  • Recurrent Childhood Rhabdomyosarcoma
  • Recurrent Childhood Soft Tissue Sarcoma
  • Recurrent Ewing Sarcoma
  • Recurrent Glioma
  • Recurrent Hepatoblastoma
  • Recurrent Langerhans Cell Histiocytosis
  • Recurrent Malignant Solid Neoplasm
  • Recurrent Neuroblastoma
  • Recurrent Osteosarcoma
  • Recurrent Peripheral Primitive Neuroectodermal Tumor
  • Refractory Central Nervous System Neoplasm
  • Refractory Childhood Malignant Germ Cell Tumor
  • Refractory Langerhans Cell Histiocytosis
  • Refractory Malignant Solid Neoplasm
  • Refractory Neuroblastoma
  • Refractory Non-Hodgkin Lymphoma
  • Rhabdoid Tumor
  • Stage III Childhood Non-Hodgkin Lymphoma
  • Stage III Osteosarcoma AJCC v7
  • Stage III Soft Tissue Sarcoma AJCC v7
  • Stage IV Childhood Non-Hodgkin Lymphoma
  • Stage IV Osteosarcoma AJCC v7
  • Stage IV Soft Tissue Sarcoma AJCC v7
  • Stage IVA Osteosarcoma AJCC v7
  • Stage IVB Osteosarcoma AJCC v7
  • Wilms Tumor

Interventions

DrugSynonymsArms
LarotrectinibARRY 470, LOXO 101, LOXO-101Treatment (Trk inhibitor LOXO-101)

Purpose

This phase II trial studies Trk inhibitor LOXO-101 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. Trk inhibitor LOXO-101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the objective response rate (ORR; complete response + partial response) in
      pediatric patients treated with Trk inhibitor LOXO-101 (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:

      I. 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:

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

      OUTLINE:

      Patients receive Trk inhibitor LOXO-101 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (Trk inhibitor LOXO-101)ExperimentalPatients receive Trk inhibitor LOXO-101 PO or via nasogastric- or gastric-tube BID on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Larotrectinib

Eligibility Criteria

        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

          -  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/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] 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

        Exclusion Criteria:

          -  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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 5 years
Safety Issue:
Description:Will be determined by Response Evaluation Criteria in Solid Tumors.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 4, 2017