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

Titre officiel

Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumours and TRK Fusion Relapsed Pediatric Acute Leukemias

Sommaire:

Cet essai de phase II porte sur les effets secondaires et l’efficacité du larotrectinib dans le traitement des tumeurs solides porteuses d’une fusion du gène TRK qui n’ont jamais été traitées et de la leucémie aiguë récidivante associée à une fusion du gène TRK. Le larotrectinib peut stopper la croissance des cellules cancéreuses porteuses d’une fusion du gène TRK en bloquant certaines enzymes nécessaires à la croissance cellulaire.

Description de l'essai

Primary Outcome:

  • Objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control
Secondary Outcome:
  • Event-free survival (EFS) of children with IFS treated with neoadjuvant larotrectinib prior to local control
  • Overall survival (OS) of children with IFS treated with neoadjuvant larotrectinib prior to local control
  • Duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control
  • ORR of children with newly diagnosed TRK fusion solid tumours other than IFS treated with neoadjuvant larotrectinib prior to local control
  • EFS of children with newly diagnosed TRK fusion solid tumours other than IFS treated with neoadjuvant larotrectinib prior to local control
  • OS of children with newly diagnosed TRK fusion solid tumours other than IFS treated with neoadjuvant larotrectinib prior to local control
  • DoR of children with newly diagnosed TRK fusion solid tumours other than IFS treated with neoadjuvant larotrectinib prior to local control
  • Incidence of adverse events
  • Percentage of patients with TRK fusion solid tumours with detectable circulating tumour deoxyribonucleic acid (DNA)
PRIMARY OBJECTIVE:
  • To determine the objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control.
SECONDARY OBJECTIVES:
  • 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.
  • To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid tumours other than IFS treated with neoadjuvant larotrectinib prior to local control.
  • To describe the toxicity of larotrectinib in children with solid tumours and acute leukemia.
  • To determine the percentage of patients with TRK fusion solid tumours with detectable circulating tumour 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:
  • To determine the EFS, OS, and DoR of children with TRK fusion solid tumours other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib.
  • To determine the EFS, OS, and DoR of children with TRK fusion solid tumours who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.
  • To determine the remission induction rate for patients with recurrent/refractory TRK fusion leukemia when treated with larotrectinib.
  • To evaluate the surgical morbidity and extent of resection of initially unresectable tumours in patients with TRK fusion solid tumours who undergo surgical resection following neoadjuvant larotrectinib.
  • To evaluate mechanisms of response and resistance to larotrectinib in children with TRK fusion cancers.
  • To evaluate the morphologic features of TRK fusion solid tumours at time of initial biopsy to further define criteria for pathologic diagnosis of these tumours.
  • To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumours and in resection specimens following neoadjuvant treatment with larotrectinib.
  • To evaluate the histologic response to larotrectinib in resection specimens following neoadjuvant treatment.
  • To evaluate circulating tumour DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumours treated with larotrectinib.
  • To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia.
  • 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 Behaviour 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 Behavioural 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 tumours shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumour 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.

Voir cet essai sur ClinicalTrials.gov

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