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

NCT ID: NCT05016544

Last Updated: 2021-08-23

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-28
• Study Completion Date: 2025-02-01

Brief 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

Detailed 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.

Conditions

Non-small Cell Lung Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Inetetamab+Pyrotinib

Dose Escalation and Dose Expansion: Inetetamab in combination with Pyrotinib in HER2 mutant or amplified participants with advanced or metastatic NSCLC

Group Type: EXPERIMENTAL

inetetamab

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sun Yat-sen University

OTHER

Sponsor Role: lead

Responsible Party

Li Zhang, MD

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Li Zhang, MD.

Role: PRINCIPAL_INVESTIGATOR

Sun Yat-sen University

Locations

Sun Yat-Sen University Cancer Center

Guangzhou, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

Li Zhang, MD.

Role: CONTACT

zhangli6@mail.sysu.edu.cn

86-20-87343458

Wenfeng Fang, MD, PhD.

Role: CONTACT

fangwf@sysucc.org.cn

86-020-8734-3894

Facility Contacts

Li Zhang, professor

Role: primary

zhangli6@mail.sysu.edu.cn

86-20-8734-3458

References

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.

Reference Type: RESULT

PMID: 30951733 (View on PubMed)

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. doi: 10.1200/JCO.2005.11.478.

Reference Type: RESULT

PMID: 15886314 (View on PubMed)

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.

Reference Type: RESULT

PMID: 20087963 (View on PubMed)

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, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004 Sep 30;431(7008):525-6. doi: 10.1038/431525b.

Reference Type: RESULT

PMID: 15457249 (View on PubMed)

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 Res. 2012 Sep 15;18(18):4910-8. doi: 10.1158/1078-0432.CCR-12-0912. Epub 2012 Jul 3.

Reference Type: RESULT

PMID: 22761469 (View on PubMed)

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):19-27. doi: 10.1093/annonc/mdh031.

Reference Type: RESULT

PMID: 14679114 (View on PubMed)

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 phase II trial. Clin Lung Cancer. 2004 Jan;5(4):231-6. doi: 10.3816/clc.2004.n.004.

Reference Type: RESULT

PMID: 14967075 (View on PubMed)

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 rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):474-9. doi: 10.1073/pnas.0808930106. Epub 2009 Jan 2.

Reference Type: RESULT

PMID: 19122144 (View on PubMed)

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 growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res. 2006 Jul 1;66(13):6487-91. doi: 10.1158/0008-5472.CAN-06-0971.

Reference Type: RESULT

PMID: 16818618 (View on PubMed)

Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O'Connell J, Taylor I, Zhang H, Arcila ME, Goldberg Z, Janne PA. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015 Jul;26(7):1421-7. doi: 10.1093/annonc/mdv186. Epub 2015 Apr 21.

Reference Type: RESULT

PMID: 25899785 (View on PubMed)

Mazieres 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: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013 Jun 1;31(16):1997-2003. doi: 10.1200/JCO.2012.45.6095. Epub 2013 Apr 22.

Reference Type: RESULT

PMID: 23610105 (View on PubMed)

De Greve 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. 2012 Apr;76(1):123-7. doi: 10.1016/j.lungcan.2012.01.008. Epub 2012 Feb 10.

Reference Type: RESULT

PMID: 22325357 (View on PubMed)

Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Penuelas I, Diaz-Gonzalez JA, Calvo A. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer. 2010 May 11;10:188. doi: 10.1186/1471-2407-10-188.

Reference Type: RESULT

PMID: 20459769 (View on PubMed)

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 receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol. 2019 Mar 1;30(3):447-455. doi: 10.1093/annonc/mdy542.

Reference Type: RESULT

PMID: 30596880 (View on PubMed)

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, Phase II Study. J Clin Oncol. 2020 Aug 20;38(24):2753-2761. doi: 10.1200/JCO.20.00297. Epub 2020 Jul 2.

Reference Type: RESULT

PMID: 32614698 (View on PubMed)

Other Identifiers

2021-FXY-191

Identifier Type: -

Identifier Source: org_study_id