Precision Treatment of HR+ HER2- Advanced Breast Cancer Based on SNF Molecular Subtyping (abemaSNF1/3)

To explore the efficacy and safety of Everolimus (SNF1 subtype) or Fluzoparib (SNF3 subtype) combined with Fulvestrant and Abemaciclib vs. Fulvestrant combined with Abemaciclib in patients with HR+/HER2- breast cancer of SNF1/SNF3 subtype who have progressed after CDK 4/6 inhibitor treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Everolimus; Drug: Fulvestrant; Drug: Fluzoparib; Drug: Abemaciclib

Detailed Description

This is a randomized, controlled, open-label, phase II study to explore the efficacy and safety of a three-drug combination of Everolimus or Fluzoparib plus Fulvestrant and Abemaciclib compared to a two-drug combination of Fulvestrant plus Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF1/SNF3 subtype who have progressed after CDK 4/6 inhibitor treatment. The study consists of Safety Lead-in phase, which aims to explore the safety and preliminary efficacy of the three-drug combination, and phase II, which aims to explore the efficacy of the three-drug combination.

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhimin C Shao, MD, PhD; Phone Number: 02164175590; Email: zhimingshao@yahoo.com
• Study Contact Backup: Name: Yin Liu, MD; Phone Number: 02164175590; Email: liuyinfudan@163.com

Study Locations

• China
  • Shanghai, China, 200032
    • 270 Dongan Road, Fudan University Shanghai Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must meet all of the following inclusion criteria to be enrolled in this study:

  1. Females aged ≥ 18 years and ≤ 70 years.
  2. Histologically confirmed HR-positive HER2-negative (specific definition: tumors are defined as ER positive when ≥ 1% tumor cells are positive by immunohistochemistry (IHC), and tumors are defined as HER2 negative when HER2 is 0-1+ or HER2 is ++ but the FISH or CISH result is negative and no amplification) locally advanced breast cancer (no radical local treatment is possible) or recurrent metastatic breast cancer with digital pathological staging of SNF1 or SNF3 subtype.
  3. Progression after CDK 4/6 inhibitor treatment. If CDK 4/6 inhibitors are used in the adjuvant treatment, metastatic relapse should occur during the administration of CDK 4/6 inhibitor or within 12 months after the end of the administration. If CDK 4/6 inhibitors are used in the first-line treatment for metastatic relapse, disease progression should occur during the administration.
  4. Have received ≤ first-line systemic therapy after metastatic relapse.
  5. Have at least one assessable lesion according to RECIST version 1.1.

  6. The patient has adequate organ function for all of the following criteria, as defined below:

     Hematologic: HB ≥ 90 g/L (no transfusion within 14 days); ANC ≥ 1.5 × 109 /L; PLT ≥ 100 × 109 /L.

  7. Hepatic: TBIL ≤ 1.5 × ULN (upper limit of normal) Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted. ALT and AST ≤ 3 × ULN; serum Cr ≤ 1 × ULN, endogenous creatinine clearance > 50 mL/min (Cockcroft-Gault formula).
  8. Have not received endocrine therapy, targeted therapy, and surgery within 3 weeks prior to the start of the study and have recovered from acute toxic reactions to previous treatment (if surgery was performed, the wound has fully healed).
  9. Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomization.
  10. Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the patient did not receive radiotherapy).
  11. The patient is able to swallow oral medications.
  12. ECOG score ≤ 1 and life expectancy ≥ 3 months.
  13. Female subjects of childbearing potential are required to use a medically approved contraceptive measure during the study treatment and for at least 3 months after the last dose of investigational drug.
  14. Subjects are voluntarily enrolled in this study, have signed informed consent form, have good compliance and cooperate with follow-up.

Exclusion Criteria:

• Patients with any of the following could not be enrolled in this study:

  1. Use of radiotherapy within 3 weeks prior to treatment.
  2. Patients with known CNS metastases or a history of CNS metastases prior to screening. For patients with clinically suspected CNS metastases, enhanced CT or enhanced magnetic resonance imaging (MRI) must be performed within 28 days prior to the first dose to rule out CNS metastases.
  3. The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
  4. The patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
  5. The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
  6. ≥ grade 1 adverse reactions due to previous treatment that are still ongoing. Exceptions are alopecia or the cases that, in the opinion of the investigator, should not be excluded. Such cases should be clearly documented in the investigator's notes.
  7. The patient has had major surgery within 14 days prior to randomization.
  8. Females who are pregnant or lactating.
  9. Malignant tumor within the past five years (except cured basal-cell carcinoma and cervical carcinoma in situ)
  10. Inability to swallow, chronic diarrhoea and intestinal obstruction, and the presence of multiple factors that affect the administration and absorption of medication.
  11. Presence of third spacing that cannot be controlled by drainage or other methods (e.g., large amounts of pleural effusion and ascites).
  12. Non-healing wounds for a long time or fractures that are not fully healed.
  13. Allergic individuals, or those with a known history of allergy to the components of the drug involved in this protocol.
  14. Long-term use of oral steroid hormones. For occasional use in the past, a 4-week discontinuation period is required before enrollment.
  15. Previous use of PAM pathway inhibitors such as Everolimus and PARP inhibitors such as Fluzoparib.
  16. Use of any chemotherapy drugs during metastatic relapse.
  17. Have received specific regimen of Abemaciclib combined with Fulvestrant during metastatic relapse (i.e., the control group in this study).
  18. Have received CDK 4/6 inhibitors for > 1 treatment period.
  19. The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to randomization, or is currently enrolled in any other type of medical research (for example: medical device) judged by the sponsor not to be scientifically or medically compatible with this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SNF 1 safety lead-in phase; Everolimus plus Fulvestrant and Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF1 subtype who have progressed after CDK4/6 inhibitor treatment.	Drug: Everolimus; Everolimus; Drug: Fulvestrant; Fulvestrant; Drug: Abemaciclib; Abemaciclib
Active Comparator: SNF 1 Phase II Control; Fulvestrant and Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF1 subtype who have progressed after CDK4/6 inhibitor treatment.	Drug: Fulvestrant; Fulvestrant; Drug: Abemaciclib; Abemaciclib
Experimental: SNF 1 Phase II Experimental; Everolimus plus Fulvestrant and Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF1 subtype who have progressed after CDK4/6 inhibitor treatment.	Drug: Everolimus; Everolimus; Drug: Fulvestrant; Fulvestrant; Drug: Abemaciclib; Abemaciclib
Experimental: SNF 3 safety lead-in phase; Fluzoparib plus Fulvestrant and Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF3 subtype who have progressed after CDK4/6 inhibitor treatment.	Drug: Fulvestrant; Fulvestrant; Drug: Fluzoparib; Fluzoparib; Drug: Abemaciclib; Abemaciclib
Active Comparator: SNF 3 Phase II Control; Fulvestrant and Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF3 subtype who have progressed after CDK4/6 inhibitor treatment.	Drug: Fulvestrant; Fulvestrant; Drug: Abemaciclib; Abemaciclib
Active Comparator: SNF 3 Phase II Experimental; Fluzoparib plus Fulvestrant and Abemaciclib in patients with HR+ HER2-advanced breast cancer of SNF3 subtype who have progressed after CDK4/6 inhibitor treatment.	Drug: Fulvestrant; Fulvestrant; Drug: Fluzoparib; Fluzoparib; Drug: Abemaciclib; Abemaciclib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0( Safety lead-in Phase)	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
objective response rate (ORR)( Safety lead-in Phase)	objective response rate (ORR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Progression-free survival (PFS)(Phase II)	Progression-free survival (PFS)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)(Phase II)	Overall survival (OS)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
objective response rate (ORR)(Phase II)	objective response rate (ORR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
clinical benefit rate (CBR)(Phase II)	clinical benefit rate (CBR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
duration of response (DOR)(Phase II)	duration of response (DOR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
time to first response (TTR)(Phase II)	time to first response (TTR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0(Phase II)	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Clinical benefit rate (CBR)( Safety lead-in Phase)	Clinical benefit rate (CBR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Progression-free survival (PFS)( Safety lead-in Phase)	Progression-free survival (PFS)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Zhimin C Shao, MD, PhD, Fudan U

Study record dates

Study Major Dates

• Study Start (Estimated): August 21, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: July 21, 2024
• First Submitted That Met QC Criteria: August 17, 2024
• First Posted (Actual): August 19, 2024

Study Record Updates

• Last Update Posted (Actual): August 19, 2024
• Last Update Submitted That Met QC Criteria: August 17, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: post-CDK4/6 inhibitor; abemeciclib; subtyping -based medicine
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; MTOR Inhibitors; Fulvestrant; Everolimus; Fluzoparib
• Other Study ID Numbers: SCHBCC-N038

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No