Study of Anlotinib in Patients With Advanced Non-small Cell Lung Cancer（ALTER0303） (ALTER0303)

• ClinicalTrials.gov Identifier: NCT02388919
• Recruitment Status: Completed
• First Posted: March 17, 2015
• Last Update Posted: September 18, 2017
• Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
• Information provided by (Responsible Party): Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Tracking Information

• First Submitted Date: February 25, 2015
• First Posted Date: March 17, 2015
• Last Update Posted Date: September 18, 2017
• Actual Study Start Date: February 26, 2015
• Actual Primary Completion Date: January 5, 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 9, 2015): Overall Survival (OS) [ Time Frame: From randomization until death (up to 24 months) ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 9, 2015)

• Progress free survival (PFS) [ Time Frame: each 42 days up to PD or death(up to 24 months) ]
• Objective Response Rate (ORR) [ Time Frame: each 42 days up to intolerance the toxicity or PD (up to 24 months) ]
• Disease Control Rate (DCR) [ Time Frame: each 42 days up to intolerance the toxicity or PD (up to 24 months) ]
• Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Until 30 day safety follow-up visit ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Anlotinib in Patients With Advanced Non-small Cell Lung Cancer（ALTER0303）
• Official Title: A Registered Randomized, Double-Blind, Placebo-Controlled (2:1), Multi-Centered Clinical Trial of Anlotinib as a Treatment for Advanced Non-Small Cell Lung Cancer
• Brief Summary: Evaluate the efficacy and safety of Anlotinib as the 3-line treatment of patients with advanced non-small lung cancer, with placebo control.
• Detailed Description: Anlotinib (AL3818) is a kind of innovative medicines approved by State Food and Drug Administration（SFDA:2011L00661） which was researched by Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd. Anlotinib is a kinase inhibitor of receptor tyrosine with multi-targets, especially for VEGFR1、VEGFR2、VEGFR3、FGFR1/2/3、PDGFRa/β c-Kit and MET.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Cancer

Intervention

• Drug: Anlotinib
  Basic dosage, take once when limosis in the morning. If patients cannot suffer from AEs, they can get declined dosage.
  Other Name: AL3818
• Drug: Placebo
  Basic dosage, take once when limosis in the morning.

Study Arms

• Experimental: Anlotinib
  Anlotinib p.o, qd and it should be continued until disease progress or toxicity cannot be tolerated or patients withdraw consent
  Intervention: Drug: Anlotinib
• Placebo Comparator: Placebo
  Placebo p.o, qd and it should be continued until disease progress or patients withdraw consent
  Intervention: Drug: Placebo

Publications *

• Qin T, Liu Z, Wang J, Xia J, Liu S, Jia Y, Liu H, Li K. Anlotinib suppresses lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma through a process potentially involving VEGFR-3 signaling. Cancer Biol Med. 2020 Aug 15;17(3):753-767. doi: 10.20892/j.issn.2095-3941.2020.0024.
• Jiang S, Liang H, Liu Z, Zhao S, Liu J, Xie Z, Wang W, Zhang Y, Han B, He J, Liang W. The Impact of Anlotinib on Brain Metastases of Non-Small Cell Lung Cancer: Post Hoc Analysis of a Phase III Randomized Control Trial (ALTER0303). Oncologist. 2020 May;25(5):e870-e874. doi: 10.1634/theoncologist.2019-0838. Epub 2020 Feb 20.
• Zhang PL, Liu ZJ. Esophago-tracheobronchial fistula following treatment of anlotinib in advanced squamous cell lung cancer: Two case reports. Medicine (Baltimore). 2019 Nov;98(44):e17700. doi: 10.1097/MD.0000000000017700.
• Si XY, Wang HP, Zhang XT, Wang MZ, Zhang L. [Efficacy and safety of anlotinib in 16 patients with advanced non-small cell lung cancer]. Zhonghua Nei Ke Za Zhi. 2018 Nov 1;57(11):830-834. doi: 10.3760/cma.j.issn.0578-1426.2018.11.007. Chinese.
• Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, Yu H, Zhao Y, Chen W, Luo Y, Wu L, Wang X, Pirker R, Nan K, Jin F, Dong J, Li B, Sun Y. Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2018 Nov 1;4(11):1569-1575. doi: 10.1001/jamaoncol.2018.3039. Erratum In: JAMA Oncol. 2018 Nov 1;4(11):1625.
• Si X, Zhang L, Wang H, Zhang X, Wang M, Han B, Li K, Wang Q, Shi J, Wang Z, Cheng Y, He J, Shi Y, Chen W, Wang X, Luo Y, Nan K, Jin F, Li B, Chen Y, Zhou J, Wang D. Quality of life results from a randomized, double-blinded, placebo-controlled, multi-center phase III trial of anlotinib in patients with advanced non-small cell lung cancer. Lung Cancer. 2018 Aug;122:32-37. doi: 10.1016/j.lungcan.2018.05.013. Epub 2018 May 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 20, 2017): 439
• Original Estimated Enrollment (submitted: March 9, 2015): 450
• Actual Study Completion Date: January 6, 2017
• Actual Primary Completion Date: January 5, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Signed and dated informed consent
2. Diagnosed with advanced NSCLC (phase IIIB/IV) through pathology, with measurable nidus(using RECIST 1.1)
3. at least two systematic chemotherapy with upwards of 3-line treatments or cannot suffer
4. Patients must provide detectable specimen (from tumor tissue or hydrothorax) before participating, who negative in EGFR&ALK can participate or who positive in EGFR&ALK, have or have not drug tolerance after the treatment with relative targeted drugs
5. ECOG PS：0-1,Expected Survival Time: Over 3 months
6. main organs function is normal
7. The woman patients of childbearing age who must agree to take contraceptive methods (e.g. intrauterine device, contraceptive pill or condom) during the research and within another 6 months after it; who are not in the lactation period and examined as negative in blood serum test or urine pregnancy test within 7 days before the research; The man patients who must agree to take contraceptive methods during the research and within another 6 months after it

Exclusion Criteria:

1. have used Anlotinib before
2. Small Cell Lung Cancer (including small cell cancer and other kinds of cancer mixed with non-small cell cancer)
3. examined as positive in EGFR&ALK mutation detection and never take the treatment of TKIs
4. central lung squamous carcinoma along with cavum, or non-small cell lung cancer along with hemoptysis (>50ml/day)
5. other kinds of malignancies within 5 years or for now
6. plan to take systemic anti-tumor therapy within 4 weeks before grouping or during the medicine-taking period of this research, including Cytotoxic Therapy, Signal Transduction Inhibitor, and Immunotherapy (or who use Mitomycin C within 6 weeks before taking the treatment with experimental drug); The patients who have already taken Extended Field Radiotherapy (EF-RT) within 4 weeks before grouping or Limited Field Radiotherapy with proposed assessment of nidus within 2 weeks before grouping
7. have got non remissive toxic reactions derived from previous therapies, which is over level 1 in CTC AE (4.0), alopecia NOT included
8. with kinds of factors which affect oral medicine (e.g. failing to swallow, gastrointestinal tract getting resected, chronic diarrhea and ileus)
9. pleural effusion or ascites, resulting in respiratory syndrome (≥CTC AE level 2)
10. symptoms of brain metastases cannot be controlled and treated within less than 2 months
11. get any severe diseases or the ones that cannot be controlled
12. take major surgical treatments, open biopsy, or get overt traumatic injury within 28 days before grouping
13. have any habitus or medical history of hemorrhage, however severe it is; the patients who have non healing wounds, ulcer or fracture after any events with hemorrhage or bleeding (≥CTCAE level 3)
14. get arterial/venous thrombosis within 6 months, such as cerebrovascular accidents (including temporary ischemic stoke), deevenous thrombosis, and pulmonary embolism
15. ever abuse psychiatric drugs and cannot abstain or who are diagnosed with mental disorder
16. have participated in other clinical trials of anti-tumor medicine within 4 weeks
17. diagnosed with disease which will severely endanger the security of patients or influence the completion of this research.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT02388919
• Other Study ID Numbers: ALTN-03-IIB
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Baohui Han, professor; Chest hospital affiliated to Shanghai jiaotong university
• Study Director: Kai Lee, professor; Tianjin Medical University Cancer Hospital

• PRS Account: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
• Verification Date: January 2017