Precise Therapy for Refractory HER2 Positive Advanced Breast Cancer

• ClinicalTrials.gov Identifier: NCT05429684
• Recruitment Status: Unknown
• First Posted: June 23, 2022
• Last Update Posted: June 23, 2022
• Sponsor: First Affiliated Hospital Xi'an Jiaotong University
• Information provided by (Responsible Party): First Affiliated Hospital Xi'an Jiaotong University

Study Description

Brief Summary:

This is an open, prospective and interventional clinical study. Patients with advanced Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer resistant to trastuzumab will be enrolled in the study. Histological specimens obtained from different metastatic foci of patients, are used to conduct genome-wide sequencing together with Circulating tumor DNA (ctDNA) of blood samples. Meanwhile, investigator will construct PDO model based on biopsy tissue. Patients as well as their paired Patient-derived organoids (PDO) models are divided into six groups according to genomic signatures. Each group of patients will receive the best targeted treatment scheme from the current clinical perspective, while the matched PDO model will accept a variety of potential effective schemes intervention. The future treatment plan of patients will be timely adjusted based on the tumor inhibition rate of PDO models. This study is the first time to explore the best individualized application sequence of targeted therapy for refractory HER2 positive breast cancer by combining genome sequencing with drug sensitivity test of PDO model. The results are expected to improve the prognosis of patients with advanced HER2 positive breast cancer.

Condition or disease	Intervention/treatment	Phase
HER2+ Breast Cancer	Drug: Trastuzumab; Drug: Pertuzumab; Drug: Nab paclitaxel; Drug: Pyrotinib; Drug: Capecitabine; Drug: T-DM1; Drug: Everolimus; Drug: CDK4/6 inhibitor; Drug: AI; Drug: Anti-PD-1 monoclonal antibody	Phase 3

Detailed Description:

In previous studies, investigator found that dynamic genomics detection of metastatic foci can fully reveal the mechanism of trastuzumab resistance. Different anti-HER2 treatment strategies for different mechanisms can improve the efficacy of HER2 positive advanced breast cancer, and the PDO drug sensitivity test model of breast cancer can be prior to patients' response to the exact efficacy of specific regimens.This study aimed to explore the optimal individualized drug combination and order for patients with advanced HER2 positive breast cancer resistant to trastuzumab based on a variety of existing diagnosis and treatment methods. This is an open, prospective and interventional clinical study. Patients with advanced HER2 positive breast cancer resistant to trastuzumab will be enrolled in the study. Histological specimens obtained from different metastatic foci of patients, are used to conduct genome-wide sequencing together with ctDNA of blood samples. Meanwhile, investigator will construct PDO model based on biopsy tissue. Patients as well as their paired PDO models are divided into six groups according to genomic signatures. Each group of patients will receive the best targeted treatment scheme from the current clinical perspective, while the matched PDO model will accept a variety of potential effective schemes intervention. The future treatment plan of patients will be timely adjusted based on the tumor inhibition rate of PDO models. This study is the first time to explore the best individualized application sequence of targeted therapy for refractory HER2 positive breast cancer by combining genome sequencing with drug sensitivity test of PDO model. The results are expected to improve the prognosis of patients with advanced HER2 positive breast cancer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Precise Targeted Therapy for Refractory HER2 Positive Advanced Breast Cancer Based on Genome Signature and Drug Sensitivity of PDO Model
• Actual Study Start Date: January 1, 2021
• Estimated Primary Completion Date: February 28, 2024
• Estimated Study Completion Date: February 28, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: A. HER2 low expression; Phenotype was signatured by HER2 low expression.	Drug: Trastuzumab; Trastuzumab (6mg/Kg, iv.drip, d1, q3w); Other Name: herceptin；Inetetamab; Drug: Pertuzumab; Patuzumab (420mg iv.drip, d1,q3w); Other Name: Perjeta; Drug: Nab paclitaxel; nab-paclitaxel (200mg iv.drip, d1,d8, q3w); Other Name: Abraxane
Experimental: B. HER2 amplified; Signatured by wild type HER2 amplified.	Drug: Trastuzumab; Trastuzumab (6mg/Kg, iv.drip, d1, q3w); Other Name: herceptin；Inetetamab; Drug: Pertuzumab; Patuzumab (420mg iv.drip, d1,q3w); Other Name: Perjeta; Drug: Nab paclitaxel; nab-paclitaxel (200mg iv.drip, d1,d8, q3w); Other Name: Abraxane
Experimental: C. HER2 mutation; Signatured by HER2 mutation.	Drug: Pyrotinib; Pyroltinib (400mg po qd); Other Name: SHR-1258; Drug: Capecitabine; Capecitabine (1250mg/m2, po, bid, d1-d14, q3w).
Experimental: D. HER2 downstream mutation; Signatured by HER2 downstream mutation of PI3KCA, TP53 or PTEN.	Drug: Trastuzumab; Trastuzumab (6mg/Kg, iv.drip, d1, q3w); Other Name: herceptin；Inetetamab; Drug: Nab paclitaxel; nab-paclitaxel (200mg iv.drip, d1,d8, q3w); Other Name: Abraxane; Drug: T-DM1; T-DM1(3.6mg/Kg, iv.drip, d1, q3w); Other Name: Trastuzumab Emtansine; Drug: Everolimus; Everolimus (4mg, po, qd); Other Name: RAD001
Experimental: E. Hormone receptor pathway activation; Signatured by both ER and PR strongly expressed,or CCND1 amplified.	Drug: Trastuzumab; Trastuzumab (6mg/Kg, iv.drip, d1, q3w); Other Name: herceptin；Inetetamab; Drug: CDK4/6 inhibitor; Palbociclib (125mg, po, qd); Other Name: Palbociclib； Drug: AI; Letrozole (2.5mg, qd).; Other Name: Letrozole
Experimental: F. Immune activation; Signatured by high TMB or PD-L1 positively expressed.	Drug: Trastuzumab; Trastuzumab (6mg/Kg, iv.drip, d1, q3w); Other Name: herceptin；Inetetamab; Drug: Anti-PD-1 monoclonal antibody; Cindilimab (200mg, iv.drip, d1, q3w); Other Name: Sintilimab

Outcome Measures

Primary Outcome Measures :

1. ORR [ Time Frame: Up to six weeks, first evaluation ]
   objective response rate (ORR) according to RECIST (version 1.1) of each group
2. PDO model inhibition rate [ Time Frame: during the procedure ]
   Tumor regression rate based on the calculation of the long diameter in each group

Secondary Outcome Measures :

1. PFS1 [ Time Frame: during the procedure ]
   Progress free survival (PFS) according to RECIST (version 1.1) of each group

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 18-70 years old;
2. Women;
3. ECOG score 0-2;
4. Locally advanced or metastatic breast cancer confirmed by histopathology;
5. Positive HER2 expression in cancer tissues (IHC 3 +, or IHC 2 + but FISH amplification);
6. Resistant to trastuzumab (including disease progression during or after withdrawal of trastuzumab);
7. There were enough specimens for immunohistochemistry, gene detection and establishment of PDO model;
8. Hematology and liver and kidney function were normal within 2 weeks before treatment;
9. Imaging examination showed measurable lesions (according to RECIST v1.1);
10. Women of childbearing age agree to contraception or take contraceptive measures;
11. Be able to understand the research program and participate voluntarily.

Exclusion Criteria:

1. Symptomatic, untreated or progressive central nervous system metastases;
2. Severe heart disease (poor cardiac function);
3. Within 5 years, there was a history of other malignant tumors other than breast cancer;
4. In this study, chemotherapy, radiotherapy, immunotherapy or surgery were performed within 3 weeks before the first treatment;
5. Patients who are pregnant or lactating, or plan to become pregnant during enrollment.

Contacts and Locations

Contacts

Contact: Jin Yang, Doctor; +862985323473; 792171443@qq.com

Locations

China, Shaanxi

The First Affiliated Hospital of Xi'an Jiaotong University; Recruiting

Xi'an, Shaanxi, China, 710000

Contact: Jin Yang, PhD 0086-18991232383 1473106133@qq.com

Jin Yang; Recruiting

Xi'an, Shaanxi, China, 710061

Contact: Jin Yang +862985324600 1473106133@qq.com

Sponsors and Collaborators

First Affiliated Hospital Xi'an Jiaotong University

Investigators

• Principal Investigator: Jin Yang, Doctor; First Affiliated Hospital Xi'an Jiaotong University

More Information

• Responsible Party: First Affiliated Hospital Xi'an Jiaotong University
• ClinicalTrials.gov Identifier: NCT05429684
• Other Study ID Numbers: XJTU1AF-CRF-2020-006
• First Posted: June 23, 2022
• Last Update Posted: June 23, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Ado-Trastuzumab Emtansine; Capecitabine; Trastuzumab; Everolimus; Letrozole; Palbociclib; Pertuzumab; Antibodies; Antibodies, Monoclonal; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents, Immunological; MTOR Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Immunosuppressive Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors