Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) (STARTRK-2)

• ClinicalTrials.gov Identifier: NCT02568267
• Recruitment Status: Active, not recruiting
• First Posted: October 5, 2015
• Last Update Posted: March 28, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: October 2, 2015
• First Posted Date: October 5, 2015
• Last Update Posted Date: March 28, 2024
• Actual Study Start Date: November 19, 2015
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2015)

Objective Response Rate [ Time Frame: Approximately 24 months ]

Assessed by blinded independent central review (BICR) using RECIST v1.1

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 20, 2020)

• Duration of Response [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RECIST v1.1
• Time to Response [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RECIST v1.1
• Clinical Benefit Rate [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RECIST v1.1
• Intracranial Tumor Response [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RANO or RANO-BM, as applicable
• CNS Progression-free Survival [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RANO or RANO-BM, as applicable
• Progression-free Survival [ Time Frame: Approximately 30 months ]
  Assessed by Kaplan-Meier method
• Overall Survival [ Time Frame: Approximately 36 months ]
  Assessed by Kaplan-Meier method
• Population PK [ Time Frame: Approximately 24 months ]
  Assessed by Kaplan-Meier method
• Adverse Events [ Time Frame: Approximately 36 months ]
  Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities, graded by the NCI CTCAE
• Quality of Life [ Time Frame: Approximately 24 months ]
  Assessed with the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the Euro-QoL Group EQ-5D. NSCLC and mCRC patients will complete the lung cancer and colorectal cancer specific modules, QLQ-LC13 and QLQ-CR29, respectively
• Bone Growth and Bone Mineral Density [ Time Frame: Approximately 30 months ]
  Assessed with DHA scans
• Bone Biomarkers [ Time Frame: Approximately 30 months ]
  Measured by blood

Original Secondary Outcome Measures (submitted: October 2, 2015)

• Duration of Response [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RECIST v1.1
• Time to Response [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RECIST v1.1
• Clinical Benefit Rate [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RECIST v1.1
• Intracranial Tumor Response [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RANO-BM
• CNS Progression-free Survival [ Time Frame: Approximately 24 months ]
  Assessed by blinded independent central review (BICR) using RANO-BM
• Progression-free Survival [ Time Frame: Approximately 36 months ]
  Assessed by Kaplan-Meier method
• Overall Survival [ Time Frame: Approximately 36 months ]
  Assessed by Kaplan-Meier method

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

Descriptive Information

• Brief Title: Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)
• Official Title: An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients With Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements
• Brief Summary: This is an open-label, multicenter, global Phase 2 basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion. Patients will be assigned to different baskets according to tumor type and gene fusion.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Breast Cancer
• Cholangiocarcinoma
• Colorectal Cancer
• Head and Neck Neoplasms
• Lymphoma, Large-Cell, Anaplastic
• Melanoma
• Neuroendocrine Tumors
• Non-Small Cell Lung Cancer
• Ovarian Cancer
• Pancreatic Cancer
• Papillary Thyroid Cancer
• Primary Brain Tumors
• Renal Cell Carcinoma
• Sarcomas
• Salivary Gland Cancers
• Adult Solid Tumor

Intervention

Drug: Entrectinib

TrkA/B/C, ROS1, and ALK inhibitor

Other Name: RXDX-101

Study Arms

• Experimental: NTRK1/2/3-rearranged NSCLC
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: ROS1-rearranged NSCLC
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: ALK- or ROS1-rearranged NSCLC

  with CNS-only progression previously treated with crizotinib (NOTE: The ALK-rearranged portion of this arm is now closed to enrollment.)

  Oral entrectinib (RXDX-101)

  Intervention: Drug: Entrectinib
• Experimental: NTRK/1/2/3-rearranged mCRC
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: ROS1-rearranged mCRC
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: ALK-rearranged mCRC
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: NTRK1/2/3-rearranged other solid tumor
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: ROS1-rearranged other solid tumor
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib
• Experimental: ALK-rearranged other solid tumor
  Oral entrectinib (RXDX-101)
  Intervention: Drug: Entrectinib

Publications *

• Sullivan WG, Hatswell AJ. Letter re: 'Intrapatient comparisons of efficacy in a single-arm trial of entrectinib in tumour-agnostic indications'. ESMO Open. 2021 Dec;6(6):100282. doi: 10.1016/j.esmoop.2021.100282. Epub 2021 Oct 28. No abstract available.
• Doebele RC, Perez L, Trinh H, Martinec M, Martina R, Riehl T, Krebs MG, Meropol NJ, Wong WB, Crane G. Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data in ROS1+ NSCLC. J Comp Eff Res. 2021 Dec;10(17):1271-1282. doi: 10.2217/cer-2021-0131. Epub 2021 Aug 24. Erratum In: J Comp Eff Res. 2022 May;11(7):545-548.
• Dziadziuszko R, Krebs MG, De Braud F, Siena S, Drilon A, Doebele RC, Patel MR, Cho BC, Liu SV, Ahn MJ, Chiu CH, Farago AF, Lin CC, Karapetis CS, Li YC, Day BM, Chen D, Wilson TR, Barlesi F. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. doi: 10.1200/JCO.20.03025. Epub 2021 Mar 1.
• Drilon A, Siena S, Dziadziuszko R, Barlesi F, Krebs MG, Shaw AT, de Braud F, Rolfo C, Ahn MJ, Wolf J, Seto T, Cho BC, Patel MR, Chiu CH, John T, Goto K, Karapetis CS, Arkenau HT, Kim SW, Ohe Y, Li YC, Chae YK, Chung CH, Otterson GA, Murakami H, Lin CC, Tan DSW, Prenen H, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Doebele RC; trial investigators. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):261-270. doi: 10.1016/S1470-2045(19)30690-4. Epub 2019 Dec 11. Erratum In: Lancet Oncol. 2020 Feb;21(2):e70. Lancet Oncol. 2020 Jul;21(7):e341.
• Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-282. doi: 10.1016/S1470-2045(19)30691-6. Epub 2019 Dec 11. Erratum In: Lancet Oncol. 2020 Feb;21(2):e70. Lancet Oncol. 2020 Jul;21(7):e341. Lancet Oncol. 2020 Aug;21(8):e372. Lancet Oncol. 2021 Oct;22(10):e428.
• Sigal D, Tartar M, Xavier M, Bao F, Foley P, Luo D, Christiansen J, Hornby Z, Maneval EC, Multani P. Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer. J Natl Compr Canc Netw. 2017 Nov;15(11):1317-1322. doi: 10.6004/jnccn.2017.7029.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 6, 2023): 534
• Original Estimated Enrollment (submitted: October 2, 2015): 300
• Estimated Study Completion Date: April 1, 2025
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically- or cytologically-confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement
• For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Ignyta's CLIA laboratory post-enrollment
• Measurable or evaluable disease
• Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed

• Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements)

  - Note: prior treatment with crizotinib is permitted only in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK inhibitors are prohibited.

• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy
• At least 4 weeks must have elapsed since completion of antibody-directed therapy
• Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of 4 weeks
• Adequate organ function as defined per protocol
• Ability to swallow entrectinib intact
• Other protocol specified criteria

Exclusion Criteria:

• Current participation in another therapeutic clinical trial

• Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements

  - Note: prior treatment with crizotinib is permitted only in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK inhibitors are prohibited.

• History of other previous cancer that would interfere with the determination of safety or efficacy
• Familial or personal history of congenital bone disorders, or bone metabolism alterations
• Incomplete recovery from any surgery
• History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤50% observed during screening for the study
• History of non-pharmacologically induced prolonged QTc interval
• History of additional risk factors for torsades de pointes
• Peripheral neuropathy Grade ≥ 2
• Known active infections
• Active gastrointestinal disease or other malabsorption syndromes
• Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
• Other protocol specified criteria

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: Australia, Belgium, China, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Netherlands, Poland, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02568267
• Other Study ID Numbers: RXDX-101-02; 2015-003385-84 ( EudraCT Number ); GO40782 ( Other Identifier: Hoffman-La Roche )
• Has Data Monitoring Committee: Not Provided

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: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: March 2024