A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors (NAVIGATE)

• ClinicalTrials.gov Identifier: NCT02576431
• Recruitment Status: Active, not recruiting
• First Posted: October 15, 2015
• Last Update Posted: May 8, 2024
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: October 12, 2015
• First Posted Date: October 15, 2015
• Last Update Posted Date: May 8, 2024
• Actual Study Start Date: September 30, 2015
• Estimated Primary Completion Date: July 20, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 26, 2023): Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independent radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type. [ Time Frame: Up to 120 months ]
• Original Primary Outcome Measures (submitted: October 13, 2015): Best Overall Response of confirmed CR or PR as measured by RECIST 1.1 or RANO criteria as appropriate to tumor type [ Time Frame: Up to 30 Months ]

Current Secondary Outcome Measures (submitted: May 26, 2023)

• Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST v1.1 or RANO criteria, as appropriate to tumor type [ Time Frame: Up to 120 months ]
• Duration of response (DOR): determined for subjects with best overall response of confirmed CR or PR by 1) an independent radiology review committee and 2) the treating Investigator [ Time Frame: Up to 120 months ]
  Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by an independent radiology committee (IRC).
• Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib [ Time Frame: Up to 120 months ]
• Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions [ Time Frame: Up to 120 months ]
• PFS: Number of months from initiation of larotrectinib to the earlier of disease progression or death due to any cause [ Time Frame: Up to 120 months ]
• Overall Survival (OS): Number of months from the initiation of larotrectinib to the date of death due to any cause. [ Time Frame: Up to 120 months ]
• Comparison of PFS following initiation of larotrectinib to that following the line of therapy immediately preceding larotrectinib in each subject who has received prior therapy [ Time Frame: Up to 120 months ]
• Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.) [ Time Frame: Up to 120 months ]
• Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 120 months ]
• Severity of safety-relevant changes in clinical parameters or vital signs after drug administration [ Time Frame: Up to 120 months ]
• Concordance coefficient [ Time Frame: Up to 120 months ]
  Concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor with the diagnostic test being evaluated by the Sponsor.

Original Secondary Outcome Measures (submitted: October 13, 2015)

• Duration of Response (DOR) [ Time Frame: Up to 30 months ]
• Progression Free Survival (PFS) [ Time Frame: Up to 30 months ]
• Overall Survival (OS) [ Time Frame: Through study completion up to 42 months ]
  Number of months from the initiation of LOXO-101 to the date of death due to any cause.
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Up to 30 months ]
  To assess the safety profile and tolerability of LOXO-101

• 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 Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors
• Official Title: A Study to Learn How Well the Drug Larotrectinib Works in Adults With Different Solid Cancers With a Change in the Genes Called NTRK Fusion
• Brief Summary: This research study is done to test how well different types of cancer respond to the drug called larotrectinib. The cancer must have a change in a particular gene (NTRK1, NTRK2 or NTRK3). Larotrectinib is a drug that blocks the actions of these NTRK genes in cancer cells and can therefore be used to treat cancer.

Detailed Description

The primary objective of this study is to investigate the efficacy of larotrectinib for the treatment of advanced solid tumors harboring a fusion of neurotrophic tyrosine receptor kinase (NTRK) of types 1-3 in children and adults.

Secondary objectives comprise the efficacy and safety of larotrectinib in different NTRK-tumor types.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors Harboring NTRK Fusion

Intervention

Drug: BAY2757556 (Larotrectinib, Vitrakvi)

Larotrectinib will be administered orally as capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-days cycles.

Other Name: LOXO-101

Study Arms

• Experimental: Arm 1_NSCLC
  Patients with solid non-small cell lung cancer (NSCLC) harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 2_Thyroid
  Patients with solid thyroid tumors harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 3_Sarcoma
  Patients with soft-tissue sarcoma harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 4_Colorectal
  Patients with solid colorectal tumors harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 5_Salivary
  Patients with solid salivary tumors harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 6_Biliary
  Patients with solid biliary tumors harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 7_Primary CNS
  Patients with solid tumors in the primary central nervous system (CNS) harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 8_Other tumors
  Patients with e.g. kidney cancer, squamous cell cancer of head or neck or ovarian solid tumors harboring NTRK fusions (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 9_Solid tumors without confirmed NTRK fusion
  Patients eligible for arms 1 to 8, but with documented NTRK fusion from a laboratory where CLIA or equivalent certification cannot be confirmed by the sponsor at the time of consent (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 10_Prospective cohort
  Patients with melanoma, non secretory breast and colorectal cancer or other tumor types harboring NTRK fusions, except soft tissue sarcoma, salivary gland and thyroid cancer (arm closed)
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)
• Experimental: Arm 11_Bone health cohort
  Patients with all tumor types harboring NTRK fusions, not eligible for the main prospective cohort, including patients with non-measurable disease
  Intervention: Drug: BAY2757556 (Larotrectinib, Vitrakvi)

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.
• Doz F, van Tilburg CM, Geoerger B, Hojgaard M, Ora I, Boni V, Capra M, Chisholm J, Chung HC, DuBois SG, Gallego-Melcon S, Gerber NU, Goto H, Grilley-Olson JE, Hansford JR, Hong DS, Italiano A, Kang HJ, Nysom K, Thorwarth A, Stefanowicz J, Tahara M, Ziegler DS, Gavrilovic IT, Norenberg R, Dima L, De La Cuesta E, Laetsch TW, Drilon A, Perreault S. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol. 2022 Jun 1;24(6):997-1007. doi: 10.1093/neuonc/noab274.
• Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, Won JK, Jung KC, Kwon D, Chung EJ, Hah JH, Paeng JC, Kim JH, Choi J, Kim OH, Oh JM, Ahn BC, Wirth LJ, Shin CH, Kim JI, Park YJ. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest. 2021 Sep 15;131(18):e144847. doi: 10.1172/JCI144847.
• 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.
• O'Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii36-viii40. doi: 10.1093/annonc/mdz385. Epub 2019 Dec 24.
• 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.
• Shi E, Chmielecki J, Tang CM, Wang K, Heinrich MC, Kang G, Corless CL, Hong D, Fero KE, Murphy JD, Fanta PT, Ali SM, De Siena M, Burgoyne AM, Movva S, Madlensky L, Heestand GM, Trent JC, Kurzrock R, Morosini D, Ross JS, Harismendy O, Sicklick JK. FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. J Transl Med. 2016 Dec 14;14(1):339. doi: 10.1186/s12967-016-1075-6.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 16, 2024): 215
• Original Estimated Enrollment (submitted: October 13, 2015): 151
• Estimated Study Completion Date: October 31, 2025
• Estimated Primary Completion Date: July 20, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. Subjects who have an NTRK gene fusion identified in a lab where CLIA or equivalent certification cannot be confirmed by the Sponsor at the time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0. From protocol version 9.0: CLIA or similar certification of the lab performing the fusion assay is required. However, patients may be included after discussion with the sponsor if the lab performing the fusion assay is not CLIA or similar certified.
• Subjects who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments and in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

• Subjects must have at least one measurable lesion as defined by RECIST v1.1 (Eisenhauer et al. 2009). Subjects with solid tumors without RECIST v1.1 measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type. Subjects with primary CNS tumors should meet the following criteria:

  1. Have received prior treatment including radiation and/or chemotherapy, with radiation completed > 12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type.
  2. Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions ≥ 1 cm in each dimension and noted on more than one imaging slice.
  3. Imaging study performed within 28 days before enrollment. If on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study.

  4. Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.

     For subjects eligible for enrollment to bone health cohort, inclusion criterion 3 is modified as the following:

  5. Subjects must have at least one lesion at baseline (measurable or non-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type).
  6. Subjects with primary CNS tumors must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.
• At least 18 years of age
• Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3. If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥ 50%.
• Tumor tissue before treatment (mandatory). If neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.

• Adequate organ function as defined by the following criteria:

  1. Serum AST and serum ALT < 2.5 x upper limit of normal (ULN), or AST and ALT < 5 x ULN if liver function abnormalities are due to underlying malignancy
  2. Total bilirubin < 2.5 x ULN, except in the setting of biliary obstruction. Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible
  3. Serum creatinine < 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30 mL/minute using the Cockcroft-Gault formula: (140- age) x body weight (kg) x 0.85 (if female)/serum creatinine (mg/dL) x 72 with either result acceptable for enrollment.
• Ability to comply (or for guardian to ensure compliance) with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
• Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his/her partner, for the duration of treatment and for 1 month following study completion.
• For subjects eligible for enrollment to bone health cohort only: life expectancy of at least 6 months, based on investigator assessment.

Exclusion Criteria:

• Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute and/or clinically significant toxicities from that therapy.
• Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK. Subjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.
• Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brain metastases are eligible to participate in the study.) Subjects with primary CNS tumors are eligible.
• Uncontrolled concurrent malignancy that would limit assessment of efficacy of larotrectinib. Allowed conditions may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin.

• Active uncontrolled systemic bacterial, viral, or fungal infection CTCAE grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures. Unstable cardiovascular disease is defined as:

  1. In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive therapy.
  2. Myocardial infarction within 3 months of screening.
  3. Stroke within 3 months of screening.
• Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer
• Currently recovering from AEs/ ADRs due to previous treatments (excluding alopecia). Inclusion is only advised once the AE/ADR resolves or recovers to baseline or at least to CTCAE grade 1.
• Known or suspected hypersensitivity against the active substance or any of the ingredients of the IMP.
• Known history of HIV infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
• HBV or HCV infection. All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBVDNA. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.

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: Argentina, Brazil, China, Czechia, Denmark, France, Germany, India, Ireland, Japan, Korea, Republic of, Portugal, Singapore, Spain, Sweden, Taiwan, Turkey, United States
• Removed Location Countries: Australia, Belgium, Canada, Colombia, Greece, Hungary, Italy, New Zealand, Norway, Poland, Russian Federation, Slovakia, Ukraine, United Kingdom

Administrative Information

• NCT Number: NCT02576431
• Other Study ID Numbers: 20289; LOXO-TRK-15002 ( Other Identifier: Loxo Oncology, Inc ); 2022-502667-38-00 ( Other Identifier: CTIS (EU) ); 2015-003582-28 ( EudraCT Number )
• 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: No

Plan Description

Availability of this study's data will later 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.vivli.org 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 member 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: May 2024