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Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia

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ClinicalTrials.gov Identifier: NCT03834961
Recruitment Status : Not yet recruiting
First Posted : February 8, 2019
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back. Larotrectinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Blasts 5 Percent or More of Bone Marrow Nucleated Cells Central Nervous System Neoplasm ETV6 Gene Rearrangement Infantile Fibrosarcoma NTRK1 Fusion Positive NTRK1 Gene Rearrangement NTRK2 Fusion Positive NTRK2 Gene Rearrangement NTRK3 Fusion Positive NTRK3 Gene Rearrangement Recurrent Acute Leukemia Refractory Acute Leukemia Solid Neoplasm Drug: Larotrectinib Phase 2

  Show Detailed Description

Study Type : Interventional
Estimated Enrollment : 70 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias
Estimated Study Start Date : May 22, 2019
Estimated Primary Completion Date : March 22, 2025
Estimated Study Completion Date : March 22, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia

Arm Intervention/treatment
Experimental: Treatment (larotrectinib)
Patients receive larotrectinib capsules or suspension at a dose of 100 mg/m2/dose (maximum of 100mg) PO or by NG or G-tube BID on days 1-28 for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Larotrectinib
Given PO or via NG or G tube
Other Names:
  • ARRY 470
  • LOXO 101
  • LOXO-101




Primary Outcome Measures :
  1. Objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control [ Time Frame: Up to 5 years ]
    Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.


Secondary Outcome Measures :
  1. Event-free survival (EFS) of children with IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  2. Overall survival (OS) of children with IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  3. Duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years ]
    Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.

  4. ORR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: Up to 5 years ]
    Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.

  5. EFS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  6. OS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  7. DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control [ Time Frame: From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years ]
    Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.

  8. Incidence of adverse events [ Time Frame: Up to 5 years ]
    Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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 attribution(s) to the study regimen.

  9. Percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) [ Time Frame: Baseline up to 5 years ]
    The percentage of ctDNA and frequency with which patients have detectable ctDNA prior to the start of therapy and at times during therapy when subsequent serial samples are obtained will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). In cases of treatment resistance, we will also perform exploratory deep sequencing of ctDNA to determine whether this method can detect the emergence of resistance mutations.


Other Outcome Measures:
  1. EFS of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  2. OS of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  3. DoR of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.

  4. EFS of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  5. OS of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum.

  6. DoR of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy [ Time Frame: Up to 5 years ]
    Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.

  7. Remission induction rate for patients with recurrent/refractory TRK fusion leukemia [ Time Frame: Up to 5 years ]
  8. Surgical morbidity and extent of resection of initially unresectable tumors in patients with TRK fusion solid tumors who undergo surgical resection following neoadjuvant larotrectinib [ Time Frame: Up to 5 years ]
  9. Central confirmation of TRK fusions by next generation sequencing, to evaluate for the presence and emergence of resistance mutations in the NTRK genes. [ Time Frame: Up to 5 years ]
  10. Morphologic features of TRK fusion solid tumors at time of initial biopsy to further define criteria for pathologic diagnosis of these tumors [ Time Frame: At baseline ]
  11. Immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors and in resection specimens following neoadjuvant treatment with larotrectinib [ Time Frame: Up to 5 years ]
    The pattern of immunohistochemical staining with a pan-TRK antibody will be correlated with fusion type, to evaluate use as a surrogate marker of fusion status and better define the patterns of expression as they relate to individual fusion partners and amongst various tumor types. Post-therapy specimens will be reviewed to document patterns of tumor response to therapy and provide centralized review of margin status where applicable. When possible pan-TRK immunohistochemistry will be performed to aid in evaluation of the infiltrative border of the tumor and to confirm the persistence of pan-TRK protein expression in the setting of neoadjuvant larotrectinib.

  12. Histologic response to larotrectinib in resection specimens following neoadjuvant treatment [ Time Frame: Up to 5 years ]
    A descriptive review of tumor histology will be performed. This will include central review of all cases at the time of diagnosis.

  13. Circulating tumor DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumors [ Time Frame: Up to 5 years ]
    To quantify the number of translocations and wild-type reads detected in each sample, a custom algorithm designed to realign all sequencing reads to either the reference human genome or the patient-specific translocation positive reference sequence will be used. The algorithm will report the number of reads aligned at the patient-specific translocation breakpoint and the number of wild-type reads at the equivalent genomic base-pair location within the human reference genome.

  14. Ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia [ Time Frame: Up to 5 years ]
    Will be quantified by a validated liquid chromatography?mass spectrometry (LC-MS) assay for patients with leukemia who have sampling while on study. The ratio of non-protein bound larotrectinib concentration in the plasma and CSF will be calculated. These ratios will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

  15. Change in neurocognitive/behavioral functioning over time [ Time Frame: Baseline up to 2 years post-diagnosis ]
    Neurocognitive functions will be analyzed using linear mixed-effects models with exponential covariance measures between observations within each patient. Measures to be analyzed will be the ABAS-III (General Adaptive Composite), BRIEF-P or BRIEF (Global Executive Composite Score), the BASC-3 (Internalizing, Externalizing and Behavioral Symptoms Indices) and Peds QL Total Score.



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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with an NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement Amendments/College of American Pathologists (CLIA/CAP) certified laboratory. Fusions may be identified by fluorescence in situ hybridization (FISH) or molecular techniques (reverse transcriptase-polymerase chain reaction [RT-PCR] using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, an ETV6 rearrangement is sufficient for eligibility in Cohort A. Identification of the upstream TRK fusion partner is not required.
  • COHORT B: Patients must have a histologic diagnosis of any solid tumor other than infantile fibrosarcoma, including central nervous system (CNS) tumors but excluding high grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility) unless the patient has a diagnosis of congenital mesoblastic nephroma in which case an ETV6 rearrangement is sufficient for eligibility. Identification of the upstream TRK fusion partner is not required.
  • COHORT C: Patients must have a histologic diagnosis of relapsed or refractory acute leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility). Identification of the upstream TRK fusion partner is not required.
  • SOLID TUMORS (COHORTS A AND B): Patients must have measurable disease. Patients must have disease that cannot be completely resected without a predicted functional, neurologic, or significant cosmetic deficit in the opinion of the investigator.
  • LEUKEMIA (COHORT C): Patients must have >= 5% blasts in the bone marrow. Extramedullary disease is permitted.
  • Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky 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.
  • COHORTS A AND B: No prior anti-cancer therapy, including radiotherapy, other than surgical resection is permitted.

    • Patients who experience recurrence after surgery alone and no other anti-cancer therapy will be eligible.
    • If not eligible due to prior anticancer therapy, patients may be eligible for the larotrectinib arm of Pediatric MATCH (APEC1621A) or treatment with commercial larotrectinib off study.
  • COHORT C: Patients with relapsed leukemia (Cohort C) 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. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.

      • A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, thioguanine [6MP], and/or methotrexate).
      • A waiting period is not required for patients receiving a single dose of intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior to enrollment
      • >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.

        • Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy.
    • 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. 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. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
    • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. A waiting period prior to enrollment is not required for patients receiving corticosteroid for leukemia therapy/cytoreduction.
    • 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 agents 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.)
    • 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 BM radiation.
    • Radiopharmaceutical therapy (e.g., radiolabeled antibody): >= 42 days after systemically administered radiopharmaceutical therapy.
    • Patients must not have received prior exposure to TRK inhibitors (including larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, or lestaurtinib).
  • 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)
    • Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions).
  • Patients with solid tumors 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.
  • For patients with leukemia:

    • Platelet count >= 20,000/mm^3 (may receive platelet transfusions) (within 7 days prior to enrollment).
    • Hemoglobin >= 8.0 g/dL at baseline (may receive RBC transfusions)
    • These patients must not be known to be refractory to red cell or platelet transfusion.
  • 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 (within 7 days prior to enrollment):

    • 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)
    • 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)
    • 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
    • 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
    • 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
    • 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
    • 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)
    • >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL)

      • For patients < 1 month of age, serum creatinine levels must be < 1.5 x the treating institution?s creatinine upper limit of normal (ULN) for patients < 1 month of age or the creatinine clearance or radioisotope GFR must be > 70 mL/min/1.73 m^2.
  • Patients with solid tumors:

    • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age. After approval of the study chair or designee, infants with a higher total bilirubin due to physiologic or breast milk jaundice are eligible if the conjugated (direct) bilirubin is =< 2 mg/dL (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).
  • Patients with leukemias:

    • Conjugated (direct) bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment).
    • SGPT (ALT) =< 225 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).
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
  • Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5) except tendon reflex decreased resulting from prior therapy must be =< grade 2.

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, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy. This criterion does not exclude infants who are breast fed.
  • Patients with solid tumors, including CNS tumors, requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Patients with leukemia may receive systemic corticosteroids for cytoreduction up to 24 hours prior to the start of protocol therapy. 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 [except leukemia patients receiving corticosteroids or hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Patients with leukemia should receive a single dose of intrathecal cytarabine, hydrocortisone, and/or methotrexate within 7 days prior to Day 1 of Cycle 1 at the time of the baseline lumbar puncture.
  • 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 currently receiving a strong CYP3A4 inducer or inhibitor 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 with malabsorption syndrome or other conditions that significantly limit enteral absorption are not eligible.
  • Patients who are unable to swallow capsules or liquid and do not have gastric access via a nasogastric or gastrostomy tube are not eligible.
  • Patients who have an uncontrolled infection are not eligible.
  • Patients who have received 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.
  • Patients with high grade gliomas (HGG) are not eligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03834961


Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Theodore W Laetsch Children's Oncology Group

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT03834961     History of Changes
Other Study ID Numbers: ADVL1823
NCI-2019-00015 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1823 ( Other Identifier: Childrens Oncology Group )
ADVL1823 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: February 8, 2019    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: January 2019

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Leukemia
Neoplasms
Acute Disease
Nervous System Neoplasms
Central Nervous System Neoplasms
Fibrosarcoma
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Neoplasms by Site
Nervous System Diseases
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma