Clinical Trials /

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

NCT03834961

Description:

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 with TRK fusions by blocking the TRK enzymes needed for cell growth.

Related Conditions:
  • Acute Leukemia
  • Congenital Mesoblastic Nephroma
  • Infantile Fibrosarcoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia
  • Official Title: Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias

Clinical Trial IDs

  • ORG STUDY ID: ADVL1823
  • SECONDARY ID: NCI-2019-00015
  • SECONDARY ID: ADVL1823
  • SECONDARY ID: ADVL1823
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03834961

Conditions

  • 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

Interventions

DrugSynonymsArms
LarotrectinibARRY 470, LOXO 101, LOXO-101Treatment (larotrectinib)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma
      (IFS) treated with neoadjuvant larotrectinib prior to local control.

      SECONDARY OBJECTIVES:

      I. To determine event-free survival (EFS), overall survival (OS), and duration of response
      (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.

      II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid
      tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.

      III. To describe the toxicity of larotrectinib in children with solid tumors and acute
      leukemia.

      IV. To determine the percentage of patients with TRK fusion solid tumors with detectable
      circulating tumor deoxyribonucleic acid (DNA) at baseline and after 1 week, 4 weeks, 24 weeks
      of treatment, at the time of discontinuation of larotrectinib therapy, and at progression.

      EXPLORATORY OBJECTIVES:

      I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS
      treated with adjuvant larotrectinib following upfront surgery with positive margins after
      neoadjuvant larotrectinib.

      II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience
      a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.

      III. To determine the remission induction rate for patients with recurrent/refractory TRK
      fusion leukemia when treated with larotrectinib.

      IV. To evaluate the surgical morbidity and extent of resection of initially unresectable
      tumors in patients with TRK fusion solid tumors who undergo surgical resection following
      neoadjuvant larotrectinib.

      V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK
      fusion cancers.

      VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy
      to further define criteria for pathologic diagnosis of these tumors.

      VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors
      and in resection specimens following neoadjuvant treatment with larotrectinib.

      VIII. To evaluate the histologic response to larotrectinib in resection specimens following
      neoadjuvant treatment.

      IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance
      mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.

      X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of
      larotrectinib in patients with leukemia.

      XI. To evaluate the change in neurocognitive/behavioral functioning over time between
      baseline and 2 years post-diagnosis of patients treated on this protocol using
      parent-reported adaptive functioning (Adaptive Behavior Assessment System [ABAS]-III General
      Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function
      Scales-Preschool Version [BRIEF-P] or BRIEF Global Executive Composite Score), psychosocial
      functioning (Behavior Assessment System for Children [BASC]-3 Internalizing, Externalizing
      and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory
      [PedsQL] Total score).

      OUTLINE:

      Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube)
      twice daily (BID) on days 1-28 for up to 26 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36,
      and 48 months and annually thereafter for up to 5 years from the date of study entry.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (larotrectinib)ExperimentalPatients receive larotrectinib 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.
  • Larotrectinib

Eligibility 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.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control
Time Frame:Up to 5 years
Safety Issue:
Description: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

Measure:Event-free survival (EFS) of children with IFS treated with neoadjuvant larotrectinib prior to local control
Time Frame:Up to 5 years
Safety Issue:
Description:Will be computed one year after the last enrollment in a stratum.
Measure:Overall survival (OS) of children with IFS treated with neoadjuvant larotrectinib prior to local control
Time Frame:Up to 5 years
Safety Issue:
Description:Will be computed one year after the last enrollment in a stratum.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Will be computed one year after the last enrollment in a stratum.
Measure: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
Safety Issue:
Description:Will be computed one year after the last enrollment in a stratum.
Measure: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
Safety Issue:
Description: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.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA)
Time Frame:Baseline up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

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