PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR; complete response + partial response) in
pediatric patients treated with 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.
EXPLORATORY OBJECTIVE:
I. To explore approaches to profiling changes in tumor genomics over time through evaluation
of circulating tumor deoxyribonucleic acid (DNA).
OUTLINE:
Patients receive larotrectinib sulfate orally (PO) or via nasogastric (NG)- or gastric
(G)-tube twice per day (BID) on days 1-28. Cycles 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 at 30 days, then periodically
thereafter.
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 absolute neutrophil [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] 5.0) resulting from prior therapy must be =< grade 2, with the exception
of decreased tendon reflect (DTR); any grade of DTR is eligible
- 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 due to risks of
fetal and teratogenic adverse events as seen in animal/human studies; 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
