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Clinical Trials Exploring TRK

Larotrectinib

An investigational, oral, and selective inhibitor of tropomyosin receptor kinases (TRK), a family of signaling proteins that plays an important role in cellular communication and tumor growth.

TRK Trials dna strand
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NCT02637687

Oral TRK Inhibitor Larotrectinib for Treatment of Advanced Pediatric Solid or Primary CNS Tumors

This phase 1/2 clinical trial is a global, multicenter, open-label trial in pediatric patients with advanced solid or primary CNS tumors. The trial uses a liquid formulation of larotrectinib, with dose adjusted by body surface area.

See Trial Information and Study Locations

LOXO-195

An investigational, selective TRK inhibitor under investigation to extend therapy for patients with NTRK fusion–driven cancers who develop acquired resistance after prior treatment with TRK inhibitors.

Phase Study
NCT03215511

Phase 1/2 Study of LOXO-195 in Patients
With Previously Treated NTRK Fusions or Non-Fusion NTRK Cancers

This is a phase 1/2, multicenter, open-label study designed to evaluate the safety and efficacy of LOXO-195 when administered orally to patients with NTRK fusion cancers treated with prior TRK inhibition.

See Trial Information and Study Locations

About TRK Fusions

The 3 NTRK genes each encode a separate TRK protein1:

Cell Receptor

In their normal biological context, TRK proteins are exclusively expressed in neuronal cells and play an important role in nervous system development and maintenance.7 As transmembrane proteins, these kinases function by ligand-dependent transmission of extracellular signals to the nucleus, activating cell growth, proliferation, and survival pathways, such as the MAPK/ERK and PI3/Akt pathways.1

Under normal conditions, the TRK signaling pathway is tightly regulated.1 TRK protein expression is restricted to neuronal tissue and conducts a signal cascade only upon neurotrophin binding.1 However, when DNA becomes damaged, NTRK genes occasionally fuse with another unrelated gene resulting in an NTRK fusion.1

NTRK Fusion

This hybrid gene, referred to as an NTRK fusion, can have many different fusion partners, but each typically results in an overexpressed, constitutively active TRK-fusion protein that drives cancer growth.1 TRK fusions occur in a wide range of common and less common tumor types, and when present may be the primary oncogenic driver.8-14

TRK Fusion driven cancers TRK Fusion driven cancers

TRK fusions have demonstrated the ability to acquire secondary mutations in patients treated with investigational TRK inhibitors.15 Observed mutations included TRKA G595R and G667C isolated from a patient with TRK fusion–driven colorectal cancer, as well as TRKC G623R found in a patient with ETV6-NTRK3 fusion–driven mammary analogue secretory carcinoma.16,17 These substitutions likely alter the shape of the TRK kinase domain and have demonstrated cross resistance to all tyrosine kinase inhibitors with anti-TRK activity.16

For additional information about any of the larotrectinib or LOXO-195 clinical trials, please refer to clinicaltrials.gov.

Interested physicians and patients may contact the Loxo Oncology TRK Physician and Patient Clinical Trial Hotline at +1-855-NTRK-123 or email clinicaltrials@loxooncology.com.

Policy for Access to Investigational Agents

Loxo Oncology is committed to helping patients who have not responded to available therapies and may benefit from its investigational therapies. Loxo Oncology's Policy for Access to Investigational Agents describes the principles and government regulations that the company will follow when considering a request.

    References:
  1. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023.
  2. Indo Y, Tsuruta M, Hayashida Y, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996;13(4):485-488.
  3. Yamada K, Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci. 2003;91(4):267-270.
  4. Qi XR, Zhao J, Liu J, et al. Abnormal retinoid and TrkB signaling in the prefrontal cortex in mood disorders. Cereb Cortex. 2015;25(1):75-83.
  5. Lin JC, Tsao D, Barras P, et al. Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates. PLoS One. 2008;3(4):e1900.
  6. Klein R, Silos-Santiago I, Smeyne RJ, et al. Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nature. 1994;368(6468):249-251.
  7. Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001;169(2):107-114.
  8. Yoshihara K, Wang Q, Torres-Garcia W, et al. The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene. 2015;34(37):4845-4854.
  9. Mertens F, Antonescu CR, Mitelman F. Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes. Genes Chromosomes Cancer. 2016;55(4):291-310.
  10. Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122(7):1097-1107.
  11. Haller F, Knopf J, Ackermann A, et al. Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern. J Pathol. 2016;238(5):700-710.
  12. Brenca M, Rossi S, Polano M, et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol. 2016;238(4):543-549.
  13. Bishop JA, Yonescu R, Batista D, Eisele DW, Westra WH. Most nonparotid "acinic cell carcinomas" represent mammary analogue secretory carcinomas. Am J Surg Pathol. 2013;37(7):1053-1057.
  14. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469-1472.
  15. Drilon A, Nagasubramanian R, Blake JF, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 2017;7(9):963-972.
  16. Russo M, Misale S, Wei G, et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 2016;6(1):36-44.
  17. Drilon A, Li G, Dogan S, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol. 2016;27(5):920-926.
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