Disitamab Vedotin (RC48) in Hormone Receptor Positive, HER2-low Metastatic Breast Cancer (the Rosy Trial)

Official title

Disitamab Vedotin or Endocrine Therapy for Patients With Metastatic Breast Cancer With Hormone Receptor-positive and HER2-low-expression

Overview

Hormone receptor positive, HER2-low expression metastatic breast cancer is the main type of breast cancer, accounting for about 50% - 60%. However, this type of patients lack ideal therapeutic drugs after the failure of first-line standard endocrine therapy, and the median overall survival time is only 30 months. Therefore, finding more efficient and safe therapeutic drugs for these patients has become a big clinical challenge at present. Disitamab Vedotin (DV), as a new class I Antibody-Drug Conjugates drug, can achieve high efficiency and precise tumor killing effect with low toxicity. According to previous study with same sample size, DV also showed good efficacy in metastatic breast cancer with Hormone receptor positive and HER2- low expression as a posterior line treatment.Therefore, we intend to explore the efficacy and safety of DV in the treatment of HER2-low expressioin /Hormone receptor positive metastatic breast cancer patients with endocrine resistance through a scientifically designed, randomized, phase III clinical study.

Interventions

• Drug Disitamab vedotin
  Disitamab Vedotin 2mg/kg was injected every 2 weeks,
• Other Endocrine therapy
  Doctors choose endocrine therapy independently

Primary outcome measures

• Progression free survival (PFS) [Time frame: 24 months]

Secondary outcome measures (9)

• Overall survival (OS) [Time frame: 36 months]
• Objective response rate (ORR) [Time frame: 12 months]
• Disease Control Rate (DCR) [Time frame: 12 months]
• Clinical Benefit Rate (CBR) [Time frame: 12 months]
• Quality of life assessed by EORTC-C30 [Time frame: 12 months]
• Psychological condition assessed by GAD-7 [Time frame: 12 months]
• Pittsburgh Sleep Scale [Time frame: 12 months]
• Incidence of adverse events(AE) [Time frame: from the date of enrollment to one year]
• Biomarkers and treatment sensitivity analysis [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Adult female patients (aged 18-70 years, including 18 and 70 years) with metastatic breast cancer confirmed by pathology or imaging are not suitable for surgical resection or radiotherapy for the purpose of cure;
• Pathological examination confirmed that ER and / or PR were positive, and HER-2 was low expression (ER expression: immunohistochemical staining of tumor cells ≥ 10%; PR expression: immunohistochemical staining of tumor cells ≥ 10%; HER2-low: immunohistochemical staining of 2 + and FISH is not expanded, IHC 1 +);
• Patients who have received endocrine therapy ;
• According to the efficacy evaluation criteria for solid tumors (RECIST) version 1.1, there is at least one evaluable target lesion or only osteolytic bone metastasis;
• Patients with stable brain metastasis or asymptomatic brain metastasis;
• ECOG physical condition score ≤ 2 points, and the estimated survival time is not less than 3 months;
• Prior treatment-related toxicity must be relieved to ≤ 1 degree (according to NCI CTCAE 5.0) before enrollment (except for hair loss or other toxicity that is considered as no risk to the safety of patients according to the judgment of the researcher);
• Adequate bone marrow functional reserve: a. WBC ≥ 3.0 × 10 \^ 9 ／ L, b. Neutrophil count (ANC) ≥ 1.5 × 10 \^ 9 ／ L, c. Platelet count (PLT) ≥ 70 × 10\^9／L;
• Liver, kidney and heart function tests were basically normal within one week before enrollment (based on the normal values of laboratories in each research center): A. total bilirubin (TBIL) ≤ 1.5 × upper limit of normal value (ULN), B. alanine aminotransferase (ALT / AST) ≤ 2.5 × ULN (liver metastasis patients ≤ 5xuln), C. serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 ml / min; d. left ventricular ejection fraction (LVEF) ≥ 55%, e. QTcF(Fridericia correction) ≤ 470 ms;
• Patients understand the research process, voluntarily participate in the research, and sign the informed consent form.

Exclusion criteria

• Patients who had received chemotherapy, radiotherapy, immunotherapy, and endocrine therapy for breast cancer within 2 weeks before enrollment.;
• Patients who had performed major surgery within 2 weeks before enrollment.
• Severe heart disease or discomfort within 12 months, including, but not limited to, the following: unstable angina pectoris, myocardial infarction, cerebral hemorrhage and cerebral infarction (except for silent lacunar cerebral infarction without treatment);
• Have active autoimmune diseases (such as corticosteroids or immunosuppressive drugs) requiring systemic treatment in the past 2 years, excluding those with adrenal insufficiency requiring corticosteroid replacement therapy;
• Have a clear history of neurological or mental disorders, including epilepsy or dementia;
• According to the judgment of the researchers, there are some accompanying diseases that seriously endanger the safety of patients or affect patients to complete the study.
• Those who have been known to have allergic history to Disitamab Vedotin or similar drugs;
• According to the estimation of the investigator , the patient's compliance with the clinical study is insufficient or the researcher believes that there are other factors that are not suitable for the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 3 centers

• Sun Yat-sen Memorial Hospital, Sun Yat-sen University — Guangzhou
• The Second Affiliated Hospital， Shantou University Medical College — Shantou
• Hainan Qionghai People's Hospital — Qionghai

Publications

• 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. PMID 28288388
• 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. PMID 26578067
• 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( PMID 29846122
• Giuliani S, Ciniselli CM, Leonardi E, Polla E, Decarli N, Luchini C, Cantaloni C, Gasperetti F, Cazzolli D, Berlanda G, Bernardi D, Pellegrini M, Triolo R, Ferro A, Verderio P, Barbareschi M. In a cohort of breast cancer screened patients the proportion of HER2 positive cases is lower than that earlier reported and pathological characteristics differ between HER2 3+ and HER2 2+/Her2 amplified case PMID 27097809
• Schalper KA, Kumar S, Hui P, Rimm DL, Gershkovich P. A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria. Arch Pathol Lab Med. 2014 Feb;138(2):213-9. doi: 10.5858/arpa.2012-0617-OA. Epub 2013 Oct 28. PMID 24164555
• Modi S, Park H, Murthy RK, Iwata H, Tamura K, Tsurutani J, Moreno-Aspitia A, Doi T, Sagara Y, Redfern C, Krop IE, Lee C, Fujisaki Y, Sugihara M, Zhang L, Shahidi J, Takahashi S. Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. J Clin Oncol. 2020 Jun 10;38(17):1887-1896. doi: 10.1200/JCO.19.02318. Epu PMID 32058843
• 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. PMID 26253944
• 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. PMID 32005279

Identifiers

NCT: NCT05904964 · SYSKY-2022-208-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗