Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias
Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias
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.
PRIMARY OBJECTIVE:
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 2 weeks, 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 5 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-2 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. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients whose tumors shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumor while on study.
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.
Inclusion Criteria:
Patients must be =< 30 years of age at the time of study entry
COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with an NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement Act/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.
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.
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.
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.
Anti-cancer agents that are 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]):
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).
For patients with solid tumors without known bone marrow involvement: Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
For patients with solid tumors without known bone marrow involvement: Hemoglobin >= 8.0 g/dL at baseline (within 7 days prior to enrollment) (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 above (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 (within 7 days prior to enrollment) (may receive platelet transfusions; must not be known to be refractory to red cell or platelet transfusion).
For patients with leukemia: Hemoglobin >= 8.0 g/dL at baseline (within 7 days prior to enrollment) (may receive RBC transfusions; must not be known to be refractory to red cell or platelet transfusion).
For patients with leukemia: 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)
Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment). 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.
Patients with solid tumors: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L.
Patients with solid tumors: 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).
Patients with leukemias: SGPT (ALT) =< 225 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L.
Patients with leukemias: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
Patients with seizure disorder may be enrolled if on a stable antiepileptic regimen for >= 14 days 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.
All patients and/or their parents or legal guardians must sign a written informed consent.
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
Exclusion Criteria:
Denver, Colorado 80218, United States
Miami, Florida 33136, United States
Grand Rapids, Michigan 49503, United States
Lebanon, New Hampshire 03756, United States
New York, New York 10032, United States
Houston, Texas 77030, United States
Spokane, Washington 99204, United States
Madison, Wisconsin 53792, United States