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

Summary

Objectives

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.