First-line Treatment With Dacomitinib Plus Anlotinib for Patients With Advanced NSCLC With EGFR 21L858R Mutations

Non-Small Cell Lung Cancer (NSCLC) Clinical Trial

Official title:

An Open Label, Multicenter, Phase I/IIB Study of Dacomitinib Plus Anlotinib for Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring Epidermal Growth Factor Receptor (EGFR) 21-L858R Mutations.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05271916
• Other study ID #: IS22001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 13, 2022
• Est. completion date: May 1, 2027

Study information

• Verified date: April 2023
• Source: Shanghai Chest Hospital
• Contact: Bo Zhang, MD
• Phone: 15800386291
• Email: zb1063253078[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, open label, Phase I/IIB study investigating the efficacy and safety of treatment with dacomitinib plus anlotinib as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) 21-L858R mutations. This study comprises two parts: 1. A dose escalation Phase I study to determine the recommended phase II dose. 2. a multi-center, open label, randomized controlled, Phase IIB study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: May 1, 2027
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. =18 years of age and =75 years;

2. Provision of a voluntarily given, personally signed and dated, written informed consent document;

3. Histologically documented, unresectable, inoperable, locally advanced, recurrent or metastatic stage IIIB or IV non-small cell lung cancer (NSCLC);

4. It is acceptable for subjects with the presence of EGFR activating mutation (exon 19 deletion and the L858R mutation in exon 21) to be included in this Phase I study; Only subjects with the L858R mutation in exon 21 to be included in this Phase IIb;

5. At least one measurable disease by RECIST criteria version 1.1;

6. Patients with controlled or stable brain metastases;

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, and life expectancy of at least 3 months;

8. No prior treatment with systemic therapy for advanced NSCLC, including TCM treatments;

9. Able to comply with required protocol procedures and able to receive oral medications;

10. Adequate organ function, including:

(1) Adequate bone marrow function Hemoglobin=90g/L, absolute neutrophil count (ANC) should be = 1.5x109/L, platelets should be = 80x109/L; (2) Adequate liver function Total bilirubin = 1.5 x upper normal limit (ULN), Aspartate Aminotransferase (AST) (SGOT) = 2.5 x ULN (= 5.0 x ULN if hepatic metastases), Alanine Aminotransferase (ALT) (SGPT) = 2.5 x ULN (= 5.0 x ULN if hepatic metastases), Creatinine= 1.5 x upper normal limit (ULN), or = 60 mL/min; (3) Cardiac function: LVEF=50% assessed by Doppler ultrasound;

Exclusion Criteria:

1. Small cell lung cancer (including mixed small cell and non-small cell lung cancer) and squamous cell carcinoma with cavitation;

2. Patients with concurrent EGFR T790M mutation or unknown mutation status or other mutation types;

3. Diagnosis of any other malignancy during the last 5 years, or with other malignancies at present;

4. Patients with pre-existing meningeal metastases;

5. Patients who have concurrent other malignant tumors;

6. Any history of hemoptysis, hematochezia, bloody sputum;

7. Tumor invasion or adjacent major vessels;

8. Patients with uncontrolled or significant systematic disease, including: active infection, thyroid dysfunction, uncontrolled hypertension, unstable angina pectoris, congestive heart failure, or myocardial infarction within 6 months, or severe arrhythmia requiring medication;

9. A history of other diseases, or metabolic dysfunction, or physical examination or laboratory results suggestive of a disease or condition that precludes the use of an investigational drug, or may affect the interpretation of the study results, or expose the patient to a high risk of treatment complications;

10. Any astrointestinal disorders resulting in inability to take medications orally, or requiring intravenous (IV) nutrition, or previous surgery impair drug absorption;

11. Pregnant or lactating females;

12. Patients allergic to any pharmaceutical ingredient.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer (NSCLC)

Intervention

Drug:
• Dacomitinib+Anlotinib
The dose of each drug in the combination Decomitinib and Anlotinib will be escalated or de-escalated until the recommended phase II dose (RP2D) is reached. Patients will then be treated with RP2D orally once a day.
• Dacomitinib
Dacomitinib orally on a continuous daily basis at a starting dose of 45 mg once a day until progressive disease.

Locations

Country	Name	City	State
China	Shanghai Chest Hospital	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Chest Hospital

Country where clinical trial is conducted

China, 

References & Publications (12)

Cheng Y, Mok TS, Zhou X, Lu S, Zhou Q, Zhou J, Du Y, Yu P, Liu X, Hu C, Lu Y, Zhang Y, Lee KH, Nakagawa K, Linke R, Wong CH, Tang Y, Zhu F, Wilner KD, Wu YL. Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050). Lung Cancer. 2021 Apr;154:176-185. doi: 10.1016/j.lungcan.2021.02.025. Epub 2021 Feb 23. — View Citation

Corral J, Mok TS, Nakagawa K, Rosell R, Lee KH, Migliorino MR, Pluzanski A, Linke R, Devgan G, Tan W, Quinn S, Wang T, Wu YL. Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer. Future Oncol. 2019 Aug;15(24):2795-2805. doi: 10.2217/fon-2019-0299. Epub 2019 Jul 17. — View Citation

De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D, Pinto A, Normanno N. The role of the EGFR signaling in tumor microenvironment. J Cell Physiol. 2008 Mar;214(3):559-67. doi: 10.1002/jcp.21260. — View Citation

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. — View Citation

Lin B, Song X, Yang D, Bai D, Yao Y, Lu N. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRbeta and FGFR1. Gene. 2018 May 15;654:77-86. doi: 10.1016/j.gene.2018.02.026. Epub 2018 Feb 14. Erratum In: Gene. 2020 Jan 10;723:144119. — View Citation

Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Lee M, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Wu YL. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol. 2018 Aug 1;36(22):2244-2250. doi: 10.1200/JCO.2018.78.7994. Epub 2018 Jun 4. Erratum In: J Clin Oncol. 2020 Nov 1;38(31):3725. — View Citation

Perdrizet K, Leighl NB. The Role of Angiogenesis Inhibitors in the Era of Immune Checkpoint Inhibitors and Targeted Therapy in Metastatic Non-Small Cell Lung Cancer. Curr Treat Options Oncol. 2019 Feb 18;20(3):21. doi: 10.1007/s11864-019-0617-6. — View Citation

Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Gemma A, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):625-635. doi: 10.1016/S1470-2045(19)30035-X. Epub 2019 Apr 8. — View Citation

Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, Zhao F, Ahmad R, Zhao J. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. 2018 Sep 19;11(1):120. doi: 10.1186/s13045-018-0664-7. — View Citation

Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res. 2007 Mar;5(3):203-20. doi: 10.1158/1541-7786.MCR-06-0404. — View Citation

Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3. Epub 2017 Sep 25. — View Citation

Zhou Q, Xu CR, Cheng Y, Liu YP, Chen GY, Cui JW, Yang N, Song Y, Li XL, Lu S, Zhou JY, Ma ZY, Yu SY, Huang C, Shu YQ, Wang Z, Yang JJ, Tu HY, Zhong WZ, Wu YL. Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study. Cancer Cell. 2021 Sep 13;39(9):1279-1291.e3. doi: 10.1016/j.ccell.2021.07.005. Epub 2021 Aug 12. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall safety profile	Overall safety profile of combined Dacomitinib plus Anlotinib in Escalation Phase, including adverse events (AE), as defined and graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE 4.03], and first cycle Dose Limiting Toxicities (DLTs).	Day 21 of Cycle 1, every 6 weeks until disease progression or death due to any cause, whichever occurred first (up to 22 months)
Primary	Progression Free Survival (PFS)	Progression Free Survival (PFS) is defined as the time from start of treatment to the date of disease progression as defined by RECIST v1.1 per investigator review or death due to any cause, whichever occurred first.	Day 21 of Cycle 1, every 6 weeks until disease progression or death due to any cause, whichever occurred first (up to 22 months)
Secondary	Overall Survival (OS)	Overall Survival is defined as the time from start of treatment to the date of death for any cause. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive.	48 months
Secondary	Best Overall Response (BOR)	Best overall response is best response from start of treatment until disease progression, and will calculated as the percentage of participants with an objective response (CR or PR) or stable disease, based on the RECIST v1.1, relative to the total number of participants enrolled in the cohort.	From baseline until disease progression, up to 48 months