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: May 12, 2021
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors Harboring NTRK Fusion	Drug: Larotrectinib (Vitrakvi, BAY2757556)	Phase 1

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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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients With Solid Tumors
• Actual Study Start Date: May 4, 2014
• Actual Primary Completion Date: February 1, 2017
• Actual Study Completion Date: April 9, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tumor patients_Dose 1; Adult patients with solid tumors receiving 50 mg of BAY2757556 once daily (dose escalation cohort).	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101
Experimental: Tumor patients_Dose 2; Adult patients with solid tumors receiving 100 mg of BAY2757556 once daily (dose escalation cohort).	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101
Experimental: Tumor patients_Dose 3; Adult patients with solid tumors receiving 100 mg of BAY2757556 twice daily (dose escalation cohort).	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101
Experimental: Tumor patients_Dose 4; Adult patients with solid tumors receiving 200 mg of BAY2757556 once daily (dose escalation cohort).	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101
Experimental: Tumor patients_Dose 5; Adult patients with solid tumors receiving 150 mg of BAY2757556 twice daily (dose escalation cohort).	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101
Experimental: Tumor patients_Dose 6; Adult patients with solid tumors receiving 200 mg of BAY2757556 twice daily (dose escalation cohort).	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101
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.	Drug: Larotrectinib (Vitrakvi, BAY2757556); BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.; Other Name: LOXO-101

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. 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 ]
2. 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 ]
3. 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 ]
4. 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 ]
5. 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
6. Duration of Response (DOR) [ Time Frame: Up to 60 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Colorado

University of Colorado

Aurora, Colorado, United States, 80045

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Ohio

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States, 44106

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15232

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

United States, Texas

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Bayer

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02122913
• Other Study ID Numbers: 20288; LOXO-TRK-14001 ( Other Identifier: Loxo Inc. )
• First Posted: April 25, 2014
• Last Update Posted: May 12, 2021
• Last Verified: April 2021

Individual Participant Data (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.

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

Keywords provided by Bayer:

Advanced solid tumors; Neurotrophic tyrosine receptor kinase (NTRK); NTRK1; NTRK2; NTRK3; Fusion Positive; TRK fusion; TRKA; TRKB; TRKC; ETV6