Clinical trial NCT02097810: Study of Oral RXDX-101 in Adult Patients With Locally Advanced or Metastatic Cancer Targeting NTRK1, NTRK2, NTRK3, ROS1, or ALK Molecular Alterations.
Official title: A Phase 1, Multicenter, Open-Label Study of Oral Entrectinib (RXDX-101) in Adult Patients With Locally Advanced or Metastatic Cancer Confirmed to be Positive for NTRK1, NTRK2, NTRK3, ROS1, or ALK Molecular Alterations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Locally Advanced Solid Tumors
Metastatic Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-03-27
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Entrectinib (RXDX-101) is an orally available inhibitor of the tyrosine kinases TrkA (coded by the gene NTRK1), TrkB (coded by the gene NTRK2), TrkC (coded by the gene NTRK3), ROS1 (coded by the gene ROS1), and ALK (coded by the gene ALK). Molecular alterations to one or more of these targets are present in several different tumor types, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), prostate cancer, papillary thyroid cancer, pancreatic cancer, and neuroblastoma. Patients with locally advanced or metastatic cancer with a detectable molecular alteration in targets of interest may be eligible for enrollment.

Phase 1 will assess safety and tolerability of entrectinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and efficacy will be assessed in the dose expansion portion of the study.


Eligibility criteria: Key Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumors that have a NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alteration.
* Measurable disease according to RECIST version 1.1.
* Prior cancer therapy is allowed, including crizotinib, ceritinib, and investigational drugs.
* Prior radiotherapy is allowed
* Patients with controlled asymptomatic central nervous system involvement are allowed.
* Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
* Adult patients age 18 years or older.
* Life expectancy of at least 3 months.

Key Exclusion Criteria:

* Current participation in another therapeutic clinical trial.
* Prior treatment with entrectinib.
* History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval \> 450 milliseconds).
* History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).
* Known active infections (bacterial, fungal, viral including HIV positivity).
* Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
* Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis.
* Peripheral neuropathy ≥ Grade 2.

Primary outcomes:
measure: Dose-Limiting Toxicity (DLT)
timeFrame: 28 days following first dose of entrectinib
measure: Maximum Tolerated Dose (MTD)
timeFrame: 28 days following first dose of entrectinib
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Approx. 6 months
measure: Overall Response Rate (ORR) in Dose Expansion
timeFrame: Approx. 2 months
Secondary outcomes:
measure: Plasma Concentrations of Entrectinib
timeFrame: Cycle 1 Days 1, 7, 14, 28
measure: Disease Control
timeFrame: Approx. 2 years
measure: Duration of Response
timeFrame: Approx. 2 years
measure: Overall Survival (OS)
timeFrame: Approx. 2 years
measure: Progression-Free Survival (PFS)
timeFrame: Approx. 2 years
Other outcomes:
Locations:
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University Of Colorado
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Sarasota
country: United States
facility: Florida Cancer Specialists - Sarasota
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Drilon A, Li G, Dogan S, Gounder M, Shen R, Arcila M, Wang L, Hyman DM, Hechtman J, Wei G, Cam NR, Christiansen J, Luo D, Maneval EC, Bauer T, Patel M, Liu SV, Ou SH, Farago A, Shaw A, Shoemaker RF, Lim J, Hornby Z, Multani P, Ladanyi M, Berger M, Katabi N, Ghossein R, Ho 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 May;27(5):920-6. doi: 10.1093/annonc/mdw042. Epub 2016 Feb 15.
citation: Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, Bauer TM, Liu SV, Ou SH, Jackman D, Costa DB, Multani PS, Li GG, Hornby Z, Chow-Maneval E, Luo D, Lim JE, Iafrate AJ, Shaw AT. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol. 2015 Dec;10(12):1670-4. doi: 10.1097/01.JTO.0000473485.38553.f0.