ADVL1823: Larotrectinib (LOXO-101) in Children with TRK Fusion Solid Tumors and Relapsed Leukemia (CLOSED TO ACCRUAL)

Larotrectinib is a highly selective oral small molecule inhibitor of the TRK family of tyrosine kinases which are encoded by the NTRK genes (NTRK1, NTRK2, and NTRK3). Fusions of these genes occur across a wide range of pediatric and adult malignancies and are nearly pathognomonic for infantile fibrosarcoma.

Preclinical studies have shown that larotrectinib is active in cancer cell lines harboring TRK fusions, while having no activity in cell lines without these fusions. Ongoing clinical trials of larotrectinib in children and adults have shown a 75% objective response rate in patients with relapsed or refractory TRK fusion cancers across a wide range of tumor types, including a 93% objective response rate in children with TRK fusion cancers on a Phase I trial. This study also established a pediatric recommended Phase II dose.

The primary cohort for this open label Phase II trial will be patients with infantile fibrosarcoma, and patients with other TRK fusion solid tumors will be analyzed in a separate cohort. This study will also include an exploratory cohort for patients with relapsed or refractory TRK fusion acute leukemias.

• To determine the objective response rate of children with infantile fibrosarcoma treated with neoadjuvant larotrectinib prior to local control

• 21 years old or younger
• Diagnosed with one of the following:
  • Infantile fibrosarcoma with NTRK1, NTRK2 or NTRK3 fusion (Cohort A)
  • Solid tumor other than infantile fibrosarcoma, including CNS tumors but excluding high grade gliomas, with NTRK1, NTRK2 or NTRK3 fusion (Cohort B)
  • Relapsed or refractory acute leukemia with NTRK1, NTRK2 or NTRK3 fusion (Cohort C)
• No prior anti-cancer therapy, including radiotherapy, other than surgical resection (Cohorts A and B) or fully recovered from acute toxic effects of all prior anti-cancer therapy (Cohort C)
• Adequate bone marrow, liver and renal function

Exclusion criteria include:

• Pregnant or breastfeeding
• Currently receiving another investigational drug
• Currently receiving other anti-cancer agents (except leukemia patients receiving corticosteroids or hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
• High Grade Glioma

St. Jude Children’s Research Hospital
Memphis, Tennessee

Collaborating sites in the U.S.

About this study

This is a Phase II study of larotrectinib, a type of drug that works by blocking cell signal proteins that are thought to be important for tumors to grow. In a Phase II study, the goal is to find out what effects, good and/or bad, a drug or combination of drugs has on people with a type of cancer.

We are using larotrectinib in this study because it has been shown to block the growth of cancer cells with TRK fusions in children and adults who have TRK fusion cancers that have not gone away or have come back after standard therapy. In children and adults with TRK fusion cancers, larotrectinib has caused tumors to shrink in most but not all patients. This study will evaluate what the effects of larotrectinib are if given at the time cancer is first diagnosed instead of standard therapy. We do not know if it will work against your cancer.

Larotrectinib has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of children and adults with TRK fusion cancers that have spread after standard therapy, are not able to be surgically removed after standard therapy, or for whom there is no standard therapy available. Using larotrectinib to treat patients with newly diagnosed TRK fusion cancers, as is being done in this study, is still experimental.

The main goals of this study are to find out the good and/or bad effects larotrectinib has on your type of cancer. Researchers also want to learn more about the side effects of larotrectinib and how larotrectinib works against cancer cells.

• 21 years old or younger
• Newly diagnosed infantile fibrosarcoma or solid tumor with NTRK1, NTRK2 or NTRK3 fusion OR
• Relapsed/refractory acute leukemia with NTRK1, NTRK2 or NTRK3 fusion