Inetetamab in Combination With Pyrotinib in HER2 Mutant or Amplified Advanced Non-small Cell Lung Cancer

Non-small Cell Lung Cancer Clinical Trial

Official title:

A Phase Ib Clinical Study Evaluating the Safety and Efficacy of Inetetamab in Combination With Pyrotinib in HER2 Mutant or Amplified Patients With Advanced Non-small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05016544
• Other study ID #: 2021-FXY-191
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: July 28, 2021
• Est. completion date: February 1, 2025

Study information

• Verified date: August 2021
• Source: Sun Yat-sen University
• Contact: Li Zhang, MD.
• Phone: 86-20-87343458
• Email: zhangli6[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1, open-label study to evaluate the safety and the efficacy of inetetamab in combination with pyrotinib in patients in HER2 mutant or amplified patients with advanced non-small cell lung cancer

Description:

This study is a multi-center, opening, dose-escalating phase Ib clinical trial. The aim of the study is to evaluate the safety and efficacy of inetetamab combined with pyrotinib in the treatment of patients in HER2 mutant or amplified patients with advanced non-small cell lung cancer .Primary endpoint of the study is dose-limiting toxicity dosage and safety. Efficacy indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) are as Secondary endpoint. Up to 48 NSCLC patients will be enrolled the treatment will be performed 3+3 dose-escalation phase I design and expanded to phase II study. A treatment cycle lasts 3 weeks,and the combined medication will be continued until the occurrence of toxicity intolerance,disease progression,or death,or patients refuse to continue participating in this clinical study,or the investigators determine that the medication must be terminated. The recommended initial consistent dose of inetetamab in groups 1-3 are 8 mg/kg, intravenous infusion for more than 90 minutes, and the maintenance dose is 6 mg/kg. The oral doses of pyrotinib in groups 1-3 were 240 mg, 320 mg, or 400 mg, respectively. Safety evaluation will be taken according to hematological toxicity, non-hematological toxicity and National Cancer Institute (NCI)-Common Terminology Criteria (CTC) For Adverse Events (AE) V5.0.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: February 1, 2025
• Est. primary completion date: August 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age over 18;

2. Histologically or cytologically documented metastatic NSCLC, HER2 activation amplification or mutation stage IIIB-IV NSCLC patient;

3. At least 1 measurable lesion according to RECIST 1.1;

4. ECOG score 0 or 1;

5. Life expectancy of at least 3 months;

6. Within one week before admission, blood routine examination was basically normal:

1. hemoglobin =90g/L or =5.6mmol/L;

2. neutrophil count (ANC) = 1.5 × 10 ^ 9 / L;

3. platelet count (PLT) = 100 × 10 ^ 9 / L;

4. Liver and kidney function tests were basically normal within one week before enrollment;

5. total bilirubin (TBIL) = 1.5 × upper limit of normal value (ULN);

6. alanine aminotransferase (ALT / AST) = 2.5 × ULN (liver metastasis patients = 5xuln);

7. serum creatinine = 1.5 × ULN;

8. Partially activated thrombin time(APTT)= 1.5 × ULN;

7. For fertile women had negative blood pregnancy tests 7 days before screening;

8. willing to participate and sign the informed consent in person.

Exclusion Criteria:

1. Patients who have received anti-HER2 monoclonal antibody therapy;

2. Have received chemotherapy, biotherapy, targeted therapy, immunotherapy and other anti-tumor therapies within 4 weeks prior to the first use of the study drug including: oral small molecule targeted drugs within 2 weeks prior to the first use of the study drug or within 5 half-lives of known drugs (depending on the time);Radiotherapy was performed within 2 weeks prior to the first administration of the study drug;

3. Have received other clinical study drugs within 4 weeks prior to the first study drug administration;

4. Patients who underwent major surgery within 4 weeks prior to the first dosing of the study drug(except needle biopsy or significant trauma);

5. Those who have been known to have allergic history to the drug components of this regimen;

6. Study drugs that had used a CYP3A4 inhibitor, inducer, or a narrow therapeutic window with a CYP3A4-sensitive substrate ,P-ep strong inducer and inhibitor within 14 days before first administration;

7. The adverse reactions of previous antitumor therapy have not recovered to CTCAE 5.0 grade 1(Hair loss and other toxicities were excluded for which the researchers judged no safety risk);

8. Patients with central nervous system metastasis and clinical symptoms;

9. History of immunodeficiency, including positive HIV test, or suffering from other acquired, congenital immunodeficiency diseases, or history of organ transplantation;

10. Active hepatitis B (HBV virus titer 1000 copies /ml or 200IU/ml);Hepatitis C virus, syphilis infection;

11. Severe heart disease or discomfort, including, but not limited to, the following:

complete left bundle branch block or degree atrioventricular block, history of myocardial infarction, angioplasty, coronary artery bridging, patients with prolonged QT/QTc interval at baseline (QTcF men >450 ms, women >480ms), significant ventricular arrhythmias (such as ventricular tachycardia), history of heart failure or systolic dysfunction (LVEF < 50%), cardiac failure, New York College of Cardiology (NYHA) grade II or higher, uncontrolled hypertension (systolic blood pressure > 180 mmHg ), history or current history of cardiomyopathy that the investigator judged to have an impact on the study;

12. Inability to swallow medications orally, or that the investigator determines severely affect gastrointestinal absorption;

13. Other malignant tumors in the past 5 years, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma or in situ cervical cancer and/or breast cancer;

14. Any history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonia requiring steroid treatment, or evidence of clinically active interstitial lung disease;

15. Patients with a history of other serious systemic diseases who were judged by the investigator to be unsuitable for clinical trials;

16. Alcohol or drug dependence;

17. Have a clear history of neurological or mental disorders, including epilepsy or dementia;

18. Pregnant and/or breastfeeding;

19. Any other reason the investigator considers the patient is not suitable to participate in the study.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• inetetamab
All dose levels will receive 8 mg/kg loading dose for cycle 1, followed by 6 mg/kg in subsequent cycles, every 3 weeks.
• Pytotinib
Starting pytotinib Dose of 240mg: Cohort 1: pyrotinib 240mg p.o. d1 to d21, q3w; Cohort 2: pyrotinib 320mg p.o. d1 to d21, q3w; Cohort 3: pyrotinib 400mg p.o. d1 to d21, q3w.

Locations

Country	Name	City	State
China	Sun Yat-Sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (15)

Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, Paik PK, Zakowski MF, Kris MG, Ladanyi M. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer R — View Citation

Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. Cancer. 2010 Mar 1;116(5):1155-64. doi: 10.1002/cncr.24815. Review. — View Citation

Cocco E, Lopez S, Santin AD, Scaltriti M. Prevalence and role of HER2 mutations in cancer. Pharmacol Ther. 2019 Jul;199:188-196. doi: 10.1016/j.pharmthera.2019.03.010. Epub 2019 Apr 2. Review. — View Citation

De Grève J, Teugels E, Geers C, Decoster L, Galdermans D, De Mey J, Everaert H, Umelo I, In't Veld P, Schallier D. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. — View Citation

Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Peñuelas I, Díaz-González JA, Calvo A. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. — View Citation

Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F, Ardizzoni A, Barton C, Ghahramani P, Hirsh V. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004 Jan;15(1) — View Citation

Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O'Connell J, Taylor I, Zhang H, Arcila ME, Goldberg Z, Jänne PA. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patie — View Citation

Lara PN Jr, Laptalo L, Longmate J, Lau DH, Gandour-Edwards R, Gumerlock PH, Doroshow JH, Gandara DR; California Cancer Consortium. Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and pha — View Citation

Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, Besse B, Blons H, Mansuet-Lupo A, Urban T, Moro-Sibilot D, Dansin E, Chouaid C, Wislez M, Diebold J, Felip E, Rouquette I, Milia JD, Gautschi O. Lung cancer that harbors an HER2 mutation — View Citation

Perera SA, Li D, Shimamura T, Raso MG, Ji H, Chen L, Borgman CL, Zaghlul S, Brandstetter KA, Kubo S, Takahashi M, Chirieac LR, Padera RF, Bronson RT, Shapiro GI, Greulich H, Meyerson M, Guertler U, Chesa PG, Solca F, Wistuba II, Wong KK. HER2YVMA drives r — View Citation

Pisters KM, Le Chevalier T. Adjuvant chemotherapy in completely resected non-small-cell lung cancer. J Clin Oncol. 2005 May 10;23(14):3270-8. Review. Erratum in: J Clin Oncol. 2008 May 1;26(13):2238. — View Citation

Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, Greulich H, Glatt KA, Meyerson M, Shapiro GI, Wong KK. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal — View Citation

Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K — View Citation

Wang Y, Jiang T, Qin Z, Jiang J, Wang Q, Yang S, Rivard C, Gao G, Ng TL, Tu MM, Yu H, Ji H, Zhou C, Ren S, Zhang J, Bunn P, Doebele RC, Camidge DR, Hirsch FR. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER — View Citation

Zhou C, Li X, Wang Q, Gao G, Zhang Y, Chen J, Shu Y, Hu Y, Fan Y, Fang J, Chen G, Zhao J, He J, Wu F, Zou J, Zhu X, Lin X. Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phas — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose escalation	Number of Participants with a Dose-Limiting Toxicity (DLT)	Up to 21 days after the first dose
Primary	Incidence of adverse events	Incidence, severity, and serious adverse events (SAEs) based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0	Up to 30 days after the last dose of inetetamab or pyrotinib
Secondary	Objective response rate	Per RECIST v1.1 criteria, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients.	up to12 months
Secondary	Disease Control Rate	Per RECIST v1.1 criteria, the proportion of patients whose best remission was CR , PR and SD accounted for the total number of evaluable patients.	up to12 months
Secondary	Progression free survival	PFS is defined as the time from the date of first dosing till the first documentation of disease progression (per RECIST v1.1 criteria) assessed by the investigator or death due to any cause (whichever occurs first).	24 months
Secondary	Overall survival	Overall survival (OS) is defined as the time from the date of first dosing till death due to any cause.	36 months
Secondary	Investigation on molecular markers associated with the clinical efficacy and the mechanism of drug resistance	Using next generation sequencing (NGS) method to detect 22 genes from circulating free DNA (cf-DNA) in patients, periphereal blood sample were collected at baseline, first time tumor efficacy evaluation, and withdrawn study due to disease progression.	36 months