A Phase ll, Interventional, Single-arm Study Evaluating the Efficacy and Safety of Inavolisib Plus Ribociclib and Fulvestrant in Chinese Patients With PIK3CA-mutant, HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer.

This is a prospective, multicenter, open-label, single-arm phase II investigator-initiated study designed to evaluate the efficacy and safety of inavolisib in combination with ribociclib and fulvestrant as first-line treatment in Chinese patients with PIK3CA-mutant, hormone receptor-positive (HR+), HER2-negative (HER2-), endocrine-resistant metastatic breast cancer (mBC). Approximately 160 patients will be enrolled at around 16 centers in China.

The study consists of a screening period of up to 28 days, a treatment period, and a post-treatment follow-up period.

PIK3CA mutation status must be determined in blood or tumor tissue using polymerase chain reaction (PCR)-based assays or next-generation sequencing (NGS) performed in a local clinical laboratory. Patients with locally confirmed PIK3CA mutations who meet all eligibility criteria will be enrolled and receive study treatment with inavolisib, ribociclib, and fulvestrant. Details of the treatment regimen are provided in the Study Treatment section. Study treatment will continue until radiologically confirmed disease progression as determined by the investigator, unacceptable toxicity, withdrawal of informed consent, or study termination, whichever occurs first.

Patients must have measurable disease according to RECIST v1.1. Patients with bone-only metastases are not eligible, even if the lesions are considered measurable. Locally advanced disease must be unsuitable for surgical resection or other local treatment with curative intent.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Inavolisib + Ribociclib + Fulvestrant

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jianli Zhao; Phone Number: 15920589334; Email: zhaojianii1988@126.com

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 criteria:

  1. Signed informed consent form (ICF).
  2. Female, aged ≥18 years at the time of signing the ICF.

  3. Must meet one of the following definitions of postmenopausal status:

     1. Age ≥60 years; OR
     2. Age <60 years with amenorrhea for ≥12 consecutive months in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone (GnRH) agonists/antagonists, and with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range per local laboratory assessment; OR

     3. Documented bilateral oophorectomy performed ≥14 days before Cycle 1 Day 1 (first treatment), with recovery to baseline status.

        For premenopausal or perimenopausal women (i.e., those not meeting postmenopausal criteria), the following is also required:

     4. Ongoing treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin or leuprorelin) initiated at least 2 weeks before Cycle 1 Day 1 and continued throughout study treatment.
  4. Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and not amenable to curative surgery or radiotherapy.
  5. Estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive tumor per ASCO/CAP guidelines, defined as ≥1% of tumor cells showing positive staining on the most recent tumor biopsy.
  6. HER2-negative per ASCO/CAP guidelines, defined as: HER2 IHC score 0 or 1+, or IHC 2+ with negative ISH (FISH/CISH/SISH), or HER2/CEP17 ratio <2.0 on the most recent biopsy, based on local laboratory assessment.
  7. Biomarker eligibility: PIK3CA mutation status must be determined by PCR or NGS testing of blood or tumor tissue at a local or regional laboratory. Blood samples should represent metastatic disease and be collected after the most recent anticancer therapy; tumor tissue should preferably be from metastatic lesions.
  8. Disease progression during or within 12 months after completion of adjuvant endocrine therapy (aromatase inhibitor or tamoxifen). If CDK4/6 inhibitor was used in neoadjuvant/adjuvant setting, time from completion of CDK4/6 inhibitor to progression must be >12 months.
  9. At least one measurable lesion per RECIST v1.1. Patients with only bone metastases are not eligible, even if lesions are measurable.
  10. Women of childbearing potential must agree to abstinence or use effective non-hormonal contraception (failure rate <1% per year) during treatment and for specified post-treatment periods (depending on study drug), and must not donate oocytes.
  11. ECOG performance status 0-1.
  12. Life expectancy >6 months.

  13. Adequate hematologic and organ function within 14 days prior to treatment initiation, including:

      ANC ≥1500/μL Hemoglobin ≥9 g/dL Platelets ≥100,000/μL Fasting glucose <126 mg/dL and HbA1c <6.0% Total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert syndrome) Albumin ≥2.5 g/dL AST/ALT ≤2.5×ULN (≤5×ULN with liver metastases) ALP ≤2.5×ULN (≤5×ULN with liver/bone metastases) Creatinine clearance ≥60 mL/min (Cockcroft-Gault) INR <1.5×ULN and aPTT <1.5×ULN (with specified exceptions for anticoagulation)

  14. Ability and willingness to comply with study procedures as judged by the investigator.

Exclusion Criteria:

1. Metaplastic breast carcinoma.
2. Any history of leptomeningeal disease or carcinomatous meningitis.
3. Prior systemic therapy for metastatic breast cancer (mBC).
4. Prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), except neoadjuvant use ≤6 months.
5. Prior exposure to PI3K, AKT, or mTOR inhibitors, or any drugs targeting the PI3K-AKT-mTOR pathway.
6. Requirement for cytotoxic chemotherapy at study entry (e.g., visceral crisis as per local guidelines).
7. Type 2 diabetes requiring ongoing systemic treatment at enrollment, or history of type 1 diabetes.
8. Inability or unwillingness to take oral medication or receive intramuscular injections.
9. Malabsorption syndrome or any condition affecting gastrointestinal absorption.
10. Untreated or active CNS metastases (progressive disease or requiring anticonvulsants or corticosteroids for symptom control).
11. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage more frequently than every 2 weeks.
12. Severe infection requiring intravenous antibiotics within 7 days prior to enrollment.
13. Any concurrent ocular or intraocular disease requiring intervention during the study to prevent or treat potential vision loss.
14. Active inflammatory or infectious ocular disease, or history of autoimmune/idiopathic uveitis.
15. Requirement for daily supplemental oxygen therapy.
16. Symptomatic active pulmonary disease, including pneumonia.
17. Active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or current immunosuppressive treatment for such disease.
18. Any active intestinal inflammation, including diverticulitis.
19. Symptomatic hypercalcemia requiring ongoing bisphosphonate or denosmab therapy.
20. Clinically significant active liver disease, including severe hepatic impairment (Child-Pugh B/C), viral hepatitis, cirrhosis, or current alcohol abuse.
21. Known HIV infection.
22. Any severe, uncontrolled systemic disease (e.g., significant cardiopulmonary, metabolic, or infectious disease) that may affect study safety or interpretation.
23. Anticancer therapy within 2 weeks prior to first dose.
24. Investigational drug use within 4 weeks prior to first dose.
25. Prior irradiation of ≥25% of bone marrow, or prior stem cell/bone marrow transplantation.
26. Unresolved toxicities from prior therapy (except alopecia, hot flashes, or peripheral neuropathy ≤Grade 2).
27. Other malignancy within 5 years prior to screening, except low-risk cancers (e.g., treated cervical carcinoma in situ, non-melanoma skin cancer, or stage I uterine cancer).

28. Significant cardiovascular disease, including:

    • Stroke or TIA within 6 months
    • Myocardial infarction within 6 months
    • NYHA class III-IV heart failure or clinically significant CHF
    • Uncontrolled arrhythmias or ventricular arrhythmias requiring treatment
    • Clinically significant coronary artery disease or unstable angina
    • QTc prolongation (>470 ms using Fridericia formula) or history of long/short QT syndrome, Brugada syndrome, or torsades de pointes
    • Clinically significant ECG abnormalities (e.g., complete LBBB, high-grade AV block)
    • Evidence of prior myocardial infarction on ECG
29. Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia).
30. Chronic use of ≥10 mg/day prednisone equivalent or other systemic corticosteroids/immunosuppressants.
31. Known hypersensitivity to inavolisib, ribociclib, or fulvestrant components.
32. Use of strong CYP3A4 inhibitors or inducers within 1 week or 5 half-lives (whichever is longer) prior to treatment initiation.
33. Pregnancy, breastfeeding, or planning pregnancy during study or within defined post-treatment periods (inavolisib 7 days, ribociclib 21 days, fulvestrant up to 2 years).
34. Major surgery or significant trauma within 28 days prior to Cycle 1 Day 1, or expected need for major surgery during the study.
35. Minor surgery within 7 days prior to first dose without adequate recovery (including proper wound healing).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Inavolisib + Ribociclib + Fulvestrant

Drug: Inavolisib + Ribociclib + Fulvestrant; A total of 160 Chinese patients who meet the eligibility criteria and are confirmed to have PIK3CA-mutant breast cancer will receive the following treatment regimen: **Inavolisib:** 9 mg tablet, administered orally once daily (PO QD), on Days 1-28 of each 28-day cycle, starting from Cycle 1 Day 1;; **Ribociclib:** 600 mg capsule or tablet, administered orally once daily (PO QD), on Days 1-21 of each 28-day cycle, starting from Cycle 1 Day 1;; **Fulvestrant:** 500 mg administered by intramuscular injection (IM) on Days 1 and 15 of Cycle 1, and thereafter on Day 1 of each subsequent 28-day cycle (approximately every 4 weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Progression-free survival (PFS), defined as the time from initiation of the first study treatment to the first occurrence of disease progression (PD) or death from any cause, whichever occurs first, as assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).	From the date of first study treatment until documented disease progression or death from any cause, whichever occurs first, assessed up to 33 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Objective response rate (ORR), defined as the proportion of patients who achieve a confirmed complete response (CR) and/or partial response (PR) on at least two consecutive assessments performed at least 4 weeks apart, as assessed by the investigator according to RECIST v1.1.	From the date of first study treatment until documented disease progression or death from any cause, whichever occurs first, assessed up to 33 months
Duration of Response (DOR)	Duration of response (DOR), defined as the time from the first documented CR or PR to the first occurrence of disease progression (PD) or death from any cause, whichever occurs first, as assessed by the investigator according to RECIST v1.1.	From the date of first study treatment until documented disease progression or death from any cause, whichever occurs first, assessed up to 33 months
Clinical Benefit Rate (CBR)	Clinical benefit rate (CBR), defined as the proportion of patients who achieve CR, PR, and/or stable disease (SD) lasting for at least 24 weeks, as assessed by the investigator according to RECIST v1.1.	From the date of first study treatment until documented disease progression or death from any cause, whichever occurs first, assessed up to 33 months

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Collaborators: Novartis; Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: May 25, 2026
• First Submitted That Met QC Criteria: May 25, 2026
• First Posted (Actual): June 1, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 25, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: breast cancer; HER2-negative; HR-positive; PIK3CA-mutant
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; ribociclib; inavolisib
• Other Study ID Numbers: SYSKY-2026-061-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No