A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer

• ClinicalTrials.gov Identifier: NCT02122913
• Recruitment Status: Completed
• First Posted: April 25, 2014
• Last Update Posted: November 7, 2023
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: April 16, 2014
• First Posted Date: April 25, 2014
• Last Update Posted Date: November 7, 2023
• Actual Study Start Date: May 4, 2014
• Actual Primary Completion Date: February 1, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2019)

• Number of participants with adverse events [ Time Frame: 25 months ]
• Severity of adverse events [ Time Frame: 25 months ]
  The severity of adverse events will be assesssed according to the NCI CTCAE version 4.03.
• Maximum tolerated dose (MTD) [ Time Frame: 25 months ]
• Recommended dose for dose expansion [ Time Frame: 25 months ]

Original Primary Outcome Measures (submitted: April 24, 2014)

• The maximum tolerated dose (MTD) and/or the appropriate dose for further clinical investigation.[Phase 1a] [ Time Frame: 12 months [Estimated] ]
• Response Rate [Phase 1b] [ Time Frame: 12 months [Estimated] ]
  Anti-tumor activity of LOXO-101 in subjects who have an NTRK alteration.

Current Secondary Outcome Measures (submitted: March 12, 2019)

• Maximum concentration of larotrectinib in plasma (Cmax) [ Time Frame: Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 ]
• Time to maximum concentration of larotrectinib in plasma (Tmax) [ Time Frame: Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 ]
• Half-life of larotrectinib in plasma (t1/2) [ Time Frame: Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 ]
• Area under the concentration versus time curve of larotrectinib in plasma (AUC) [ Time Frame: Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 ]
• Overall Response Rate (ORR) [ Time Frame: Up to 60 months ]
  Assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate
• Duration of Response (DOR) [ Time Frame: Up to 60 months ]

Original Secondary Outcome Measures (submitted: April 24, 2014)

• Pharmacokinetic parameters of LOXO-101 including Cmax, Tmax, t1/2, and AUC following both QD and BID dosing. [Phase 1b] [ Time Frame: 12 months [Estimated] ]
• Progression Free Survival [Phase 1b] [ Time Frame: 6 and 12 months [Estimated] ]
  Progression-free survival at 6 and 12 months
• The maximum tolerated dose (MTD) [Phase 1b] [ Time Frame: 12 months [Estimated] ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer
• Official Title: A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients With Solid Tumors
• Brief Summary: This research study is done to test the safety of the drug larotrectinib in adult cancer patients. The drug may be used to treat cancer with a change in a particular gene (NTRK1, NTRK2 or NTRK3), because it blocks the action of these genes in cancer cells. The study also investigates how the drug is absorbed and processed in the human body. This is the first study to test larotrectinib in humans with cancer, for whom no other effective therapy exists.

Detailed Description

The trial will be conducted in 2 parts: an initial dose escalation phase of larotrectinib in subjects with advanced solid tumors will be followed by an expansion phase in subjects with solid tumors having a NTRK fusion.

The objectives of the study are to determine the safety, pharmacokinetic profile, recommended dose and efficacy of orally administered larotrectinib in patients with NTRK fusions.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors Harboring NTRK Fusion

Intervention

Drug: Larotrectinib (Vitrakvi, BAY2757556)

BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.

Other Name: LOXO-101

Study Arms

• Experimental: Tumor patients_Dose 1
  Adult patients with solid tumors receiving 50 mg of BAY2757556 once daily (dose escalation cohort).
  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
• Experimental: Tumor patients_Dose 2
  Adult patients with solid tumors receiving 100 mg of BAY2757556 once daily (dose escalation cohort).
  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
• Experimental: Tumor patients_Dose 3
  Adult patients with solid tumors receiving 100 mg of BAY2757556 twice daily (dose escalation cohort).
  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
• Experimental: Tumor patients_Dose 4
  Adult patients with solid tumors receiving 200 mg of BAY2757556 once daily (dose escalation cohort).
  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
• Experimental: Tumor patients_Dose 5
  Adult patients with solid tumors receiving 150 mg of BAY2757556 twice daily (dose escalation cohort).
  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
• Experimental: Tumor patients_Dose 6
  Adult patients with solid tumors receiving 200 mg of BAY2757556 twice daily (dose escalation cohort).
  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
• Experimental: Tumor patients_Expansion

  Adults patients with solid tumors and neurotrophic tyrosine kinase (NTRK) genes or proteins of types 1 - 3 (dose expansion cohort).

  Patients receive either the recommended or maximum tolerated dose of BAY2757556 as determined in the dose escalation part.

  Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)

Publications *

• Waguespack SG, Drilon A, Lin JJ, Brose MS, McDermott R, Almubarak M, Bauman J, Casanova M, Krishnamurthy A, Kummar S, Leyvraz S, Oh DY, Park K, Sohal D, Sherman E, Norenberg R, Silvertown JD, Brega N, Hong DS, Cabanillas ME. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022 Apr 29;186(6):631-643. doi: 10.1530/EJE-21-1259.
• Le X, Baik C, Bauman J, Gilbert J, Brose MS, Grilley-Olson JE, Patil T, McDermott R, Raez LE, Johnson JM, Shen L, Tahara M, Ho AL, Norenberg R, Dima L, Brega N, Drilon A, Hong DS. Larotrectinib Treatment for Patients With TRK Fusion-Positive Salivary Gland Cancers. Oncologist. 2022 May 10:oyac080. doi: 10.1093/oncolo/oyac080. Online ahead of print.
• Drilon A, Tan DSW, Lassen UN, Leyvraz S, Liu Y, Patel JD, Rosen L, Solomon B, Norenberg R, Dima L, Brega N, Shen L, Moreno V, Kummar S, Lin JJ. Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers. JCO Precis Oncol. 2022 Jan;6:e2100418. doi: 10.1200/PO.21.00418.
• Bebb DG, Banerji S, Blais N, Desmeules P, Gill S, Grin A, Feilotter H, Hansen AR, Hyrcza M, Krzyzanowska M, Melosky B, Noujaim J, Purgina B, Ruether D, Simmons CE, Soulieres D, Torlakovic EE, Tsao MS. Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults. Curr Oncol. 2021 Jan 15;28(1):523-548. doi: 10.3390/curroncol28010053.
• Perreault S, Chami R, Deyell RJ, El Demellawy D, Ellezam B, Jabado N, Morgenstern DA, Narendran A, Sorensen PHB, Wasserman JD, Yip S. Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients. Curr Oncol. 2021 Jan 9;28(1):346-366. doi: 10.3390/curroncol28010038.
• Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3. Epub 2020 Feb 24.
• Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA 3rd, Doebele RC. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539.
• Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448.
• Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57. doi: 10.1158/2159-8290.CD-15-0443. Epub 2015 Jul 27.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 5, 2019): 75
• Original Estimated Enrollment (submitted: April 24, 2014): 146
• Actual Study Completion Date: April 9, 2021
• Actual Primary Completion Date: February 1, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adult patients with a locally advanced or metastatic solid tumor that has progressed or was nonresponsive to available therapies, are unfit for standard chemotherapy or for which no standard or available curative therapy exists
• Proof of a malignancy harboring a NTRK fusion
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2 and a life expectancy of at least 3 months
• Adequate hematologic, hepatic, and renal function

Exclusion Criteria:

• Patients with unstable primary central-nervous-system tumors or metastasis, exceptions possible
• Clinically significant active cardiovascular disease or history of myocardial infarction
• Active uncontrolled systemic bacterial, viral, or fungal infection
• Current treatment with a strong CYP3A4 inhibitor or inducer
• Pregnancy or lactation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02122913
• Other Study ID Numbers: 20288; LOXO-TRK-14001 ( Other Identifier: Loxo Inc. )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Loxo Oncology, Inc.
• Current Study Sponsor: Bayer
• Original Study Sponsor: Loxo Oncology, Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: November 2023