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 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-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:
- 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.
- 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.
- 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]):
- 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)
- 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 (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)
- 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 (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.
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. Female patients of
reproductive potential may not participate unless they have agreed to use a highly
effective contraceptive method for the duration of study therapy and for at least one
month after the final dose of larotrectinib. Males of reproductive potential with a
non-pregnant female partner of child-bearing potential must use a highly effective
contraception for the duration of the study and for at least one month after the final
dose of larotrectinib. Because of the unknown risk of larotrectinib in nursing
infants, nursing women should discontinue breastfeeding during treatment with
larotrectinib and for 3 days following the final dose.
- 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.
- 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.
