Disitamab Vedotin + Pyrotinib Versus THP in the First-line Treatment for HER2+ Advanced Breast Cancer Clinical Trial

HER2-positive Metastatic Breast Cancer Clinical Trial

Official title:

Disitamab Vedotin in Combination With Pyrotinib Versus THP in the First-line Treatment for HER2-positive Advanced Breast Cancer, a Multicentre, Randomized, Double-blind Controlled, Phase III Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06278870
• Other study ID #: SYSKY-2023-431-02
• Status: Recruiting
• Phase: Phase 3
• Start date: September 6, 2023
• Est. completion date: June 30, 2031

Study information

• Verified date: February 2024
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this multicentre, randomized, double-blind controlled, phase III clinical trial is to compare the efficacy and safety of disitamab vedotin in combination with pyrotinib versus the standard first-line treatment of paclitaxel in combination with trastuzumab and pertuzumab (THP) for newly diagnosed recurrent/metastatic Human epidermal growth factor receptor 2 (HER2) positive advanced breast cancer, and to explore the impact of biomarkers on clinical efficacy and safety. The main questions it aims to answer are:

• Analyse the efficacy and safety of disitamab vedotin in combination with pyrotinib versus the standard first-line treatment of THP.

• Explore the impact of biomarkers on clinical efficacy and safety of the combination of disitamab vedotin in combination with pyrotinib treatment.

Participants in the experimental group will receive disitamab vedotin in combination with pyrotinib for 6-8 cycles (each cycle lasting 28 days), followed by maintenance treatment with trastuzumab in combination with pyrotinib. Participants in the control group will receive paclitaxel in combination with trastuzumab and pertuzumab for 6-8 cycles (each cycle lasting 21 days), followed by maintenance treatment with trastuzumab and pertuzumab.

Researchers will compare disitamab vedotin in combination with pyrotinib versus the standard first-line treatment of paclitaxel in combination with trastuzumab and pertuzumab to see if disitamab vedotin in combination with pyrotinib could be a new option for first-line treatment of HER2-positive metastatic breast cancer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 312
• Est. completion date: June 30, 2031
• Est. primary completion date: June 30, 2031
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Adult female patients (age 18-75 years) with metastatic breast cancer confirmed by pathology or imaging;

2. Pathologically confirmed HER2 positive (definition: Immunohistochemistry(IHC) 3+, or IHC 2+ and Fluorescent In Situ Hybridization(FISH) amplification);

3. No previous chemotherapy regimen for metastatic breast cancer;

4. At least one measurable lesion exists (Response Evaluation Criteria in Solid Tumors(RECIST) 1.1);

5. Eastern Cooperative Oncology Group(ECOG) performance status score = 2 and expected survival of not less than 3 months;

6. Prior treatment-related toxicity at enrollment must have resolved to National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events(CTCAE) (version 5.0) = 1 degree (except for alopecia or other toxicity that, in the judgment of the investigator, is not considered a risk to the safety of the patient);

7. Patients with adequate organ function before enrollment:

1. White Blood Cell (WBC) = 3.0 x 10^9/L;

2. Neutrophil granulocyte (ANC) =1.5 x 10^9/L;

3. Platelet (PLT) =70×10^9/L;

8. Liver, kidney, and cardiac function tests are essentially normal (based on the normal values in the laboratory of each study center):

1. Total bilirubin (TBIL) = 3 x Upper Limit of Normal (ULN);

2. Alanine aminotransferase (ALT/AST) = 2.5 x ULN (= 5 x ULN in patients with liver metastases);

3. serum creatinine = 1.5 x ULN or creatinine clearance (Ccr) = 60 ml/min;

9. . Normal cardiac function;

1. Left ventricular ejection fraction (LVEF) = 55%;

2. QT-interval corrected with Fridericia (QTcF) = 470ms;

10. Hormone receptor status is clear;

11. Female patients of childbearing potential who have a negative pregnancy test and agree to use an effective non-hormonal method of contraception during treatment and for at least 6 months after the last dose of the test drug;

12. Able to understand the study process, voluntarily participate in this study, and sign an informed consent form.

Exclusion Criteria:

1. Pathology suggestive of HER2 negativity (IHC 2+ and FISH-, or IHC 1+);

2. Patients with known hypersensitivity to the active ingredient or other components of the study drug;

3. Patients during pregnancy or lactation, patients with childbearing potential tested positive in a baseline pregnancy test, or patients unwilling to take effective contraceptive measures throughout the trial;

4. Patients not eligible for this study judged by the investigator, a pre-existing disease or condition that may interfere with participation in the study or any serious medical disorder that may interfere with the safety of the subject (e.g., uncontrolled heart disease, high blood pressure, active or uncontrolled infections, active hepatitis B virus infection).

Related Conditions & MeSH terms

• Breast Neoplasms
• First-line Treatment
• HER2-positive Metastatic Breast Cancer

Intervention

Drug:
• disitamab vedotin
disitamab vedotin 2mg/kg iv q2w
• Pyrotinib
pyrotinib 400mg po q28d
• trastuzumab
trastuzumab 8mg/kg for the first cycle, 6mg/kg for subsequent treatments iv q21d
• Pertuzumab
pertuzumab 840mg for the first cycle, 420mg for subsequent treatments iv q21d
• taxane drug
Docetaxel/paclitaxel/albumin paclitaxel/liposomal paclitaxel, dosage and administration are determined according to the latest version of the NCCN and CSCO breast cancer guideline recommendations

Locations

Country	Name	City	State
China	Sun Yat-sen Memorial Hospital,Sun Yat-sen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Country where clinical trial is conducted

China, 

References & Publications (13)

Brunelli M, Manfrin E, Martignoni G, Miller K, Remo A, Reghellin D, Bersani S, Gobbo S, Eccher A, Chilosi M, Bonetti F. Genotypic intratumoral heterogeneity in breast carcinoma with HER2/neu amplification: evaluation according to ASCO/CAP criteria. Am J Clin Pathol. 2009 May;131(5):678-82. doi: 10.1309/AJCP09VUTZWZXBMJ. — View Citation

Cortes J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Huang CS, Kim JH, Chiu JWY, Pedrini JL, Lee C, Liu Y, Cathcart J, Bako E, Verma S, Hurvitz SA; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022. — View Citation

Glockner S, Buurman H, Kleeberger W, Lehmann U, Kreipe H. Marked intratumoral heterogeneity of c-myc and cyclinD1 but not of c-erbB2 amplification in breast cancer. Lab Invest. 2002 Oct;82(10):1419-26. doi: 10.1097/01.lab.0000032371.16521.40. — View Citation

Koleva-Kolarova RG, Oktora MP, Robijn AL, Greuter MJW, Reyners AKL, Buskens E, de Bock GH. Increased life expectancy as a result of non-hormonal targeted therapies for HER2 or hormone receptor positive metastatic breast cancer: A systematic review and meta-analysis. Cancer Treat Rev. 2017 Apr;55:16-25. doi: 10.1016/j.ctrv.2017.01.001. Epub 2017 Feb 20. — View Citation

Li BT, Michelini F, Misale S, Cocco E, Baldino L, Cai Y, Shifman S, Tu HY, Myers ML, Xu C, Mattar M, Khodos I, Little M, Qeriqi B, Weitsman G, Wilhem CJ, Lalani AS, Diala I, Freedman RA, Lin NU, Solit DB, Berger MF, Barber PR, Ng T, Offin M, Isbell JM, Jones DR, Yu HA, Thyparambil S, Liao WL, Bhalkikar A, Cecchi F, Hyman DM, Lewis JS, Buonocore DJ, Ho AL, Makker V, Reis-Filho JS, Razavi P, Arcila ME, Kris MG, Poirier JT, Shen R, Tsurutani J, Ulaner GA, de Stanchina E, Rosen N, Rudin CM, Scaltriti M. HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers. Cancer Discov. 2020 May;10(5):674-687. doi: 10.1158/2159-8290.CD-20-0215. Epub 2020 Mar 25. — View Citation

Mendes D, Alves C, Afonso N, Cardoso F, Passos-Coelho JL, Costa L, Andrade S, Batel-Marques F. The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer--a systematic review. Breast Cancer Res. 2015 Nov 17;17:140. doi: 10.1186/s13058-015-0648-2. — View Citation

Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. — View Citation

Ocana A, Amir E, Pandiella A. HER2 heterogeneity and resistance to anti-HER2 antibody-drug conjugates. Breast Cancer Res. 2020 Jan 31;22(1):15. doi: 10.1186/s13058-020-1252-7. — View Citation

Rios-Doria J, Harper J, Rothstein R, Wetzel L, Chesebrough J, Marrero A, Chen C, Strout P, Mulgrew K, McGlinchey K, Fleming R, Bezabeh B, Meekin J, Stewart D, Kennedy M, Martin P, Buchanan A, Dimasi N, Michelotti E, Hollingsworth R. Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies. Cancer Res. 2017 May 15;77(10):2686-2698. doi: 10.1158/0008-5472.CAN-16-2854. Epub 2017 Mar 10. — View Citation

Shin SJ, Hyjek E, Early E, Knowles DM. Intratumoral heterogeneity of her-2/neu in invasive mammary carcinomas using fluorescence in-situ hybridization and tissue microarray. Int J Surg Pathol. 2006 Oct;14(4):279-84. doi: 10.1177/1066896906293055. — View Citation

Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortes J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. doi: 10.1016/S1470-2045(19)30863-0. Epub 2020 Mar 12. — View Citation

Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018 Jul 10;36(20):2105-2122. doi: 10.1200/JCO.2018.77.8738. Epub 2018 May 30. — View Citation

Yao X, Jiang J, Wang X, Huang C, Li D, Xie K, Xu Q, Li H, Li Z, Lou L, Fang J. A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity. Breast Cancer Res Treat. 2015 Aug;153(1):123-33. doi: 10.1007/s10549-015-3503-3. Epub 2015 Aug 8. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	From enrollment to progression or death (for any reason)	Estimated 30 months
Secondary	Overall Survival (OS)	From enrollment to death (for any reason)	Estimated 8 years
Secondary	Disease control rate (DCR)	Ratio of complete response (CR) , partial response (PR) and stable disease (SD) in all subjects	Estimated 30 months
Secondary	Objective Response Rate (ORR)	Ratio of CR and PR in all subjects	Estimated 30 months
Secondary	Clinical Benefit rate (CBR)	Ratio of CR,PR and SD greater than or equal to 24 weeks in all subjects	Estimated 30 months
Secondary	Adverse Events (Based on CTCAE 5.0 standards)	Safety	From informed consent through 28 days following treatment completion
Secondary	Quality of Life (QoL) by Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B)	QoL was assessed using FACT-B. FACT-B is a 37-item questionnaire with 5 subscales assessing physical, social, emotional, and functional well-being, with scores ranging from 0 to 4 for each question. Higher scores generally indicating a better quality of life.	Estimated 30 months
Secondary	Exploration of biomarkers	Next Generation Gene Sequencing (NGS) detection of tissue and blood specimens, including ERBB1/ERBB2/ERBB3/ERBB4/AKT/TP53/PIK3CA and so on. Objective to explore the correlation between biomarkers and the objective response rate (ORR), as well as progression-free survival (PFS).	Estimated 30 months