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Protocol NumberRLY-2608-102
Not yet recruiting

2025-09-01 - 2031-06-30

Recruiting6

ICD-10C50.011

Malignant neoplasm of nipple and areola, right female breast

ICD-10C50.012

Malignant neoplasm of nipple and areola, left female breast

ICD-10C50.019

Malignant neoplasm of nipple and areola, unspecified female breast

ICD-10Z51.12

Encounter for antineoplastic immunotherapy

ICD-9174.0

Malignant neoplasm of female breast, nipple and areola

A phase 3, open-label, randomized trial was conducted to evaluate the efficacy and safety of RLY-2608 + Fulvestrant compared to Capivasertib + Fulvestrant in patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer that relapsed or progressed during or after CDK4/6 inhibitor therapy.

  • Trial Applicant

    IQVIA RDS Taiwan Ltd.

  • Sponsor

    IQVIA Co., Ltd.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/07/22

Investigators and Locations

Principal Investigator YEN-SHEN LU Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Ling-Ming Tseng Division of General Surgery
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Chih-Chiang Hung Division of General Surgery
Taichung Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 劉建廷 Division of Hematology & Oncology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator TSU-YI CHAO Division of Hematology & Oncology
Taipei Medical University-Shuang Ho Hospital,Ministry of Health and Welfare

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Yung-Chang Lin
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Locally advanced or metastatic breast cancer

Objectives

The efficacy of RLY-2608 + Fulvestrant was compared with that of Capivasertib + Fulvestrant, assessed by BICR in the overall body and kinase populations.

Test Drug

Capivasertib
Capivasertib
Fulvestrant
RLY-2608

Active Ingredient

Capivasertib
Capivasertib
Fulvestrant
RLY-2608

Dosage Form

Film-coated tablets
Film-coated tablets
Pre-filled injections
Capsules

Dosage

160 mg
200 mg
250 mg
100 mg

Endpoints

PFS is defined as the time from random assignment to the time when radiological deterioration is determined according to RECIST version 1.1, or death from any cause.

Inclution Criteria

1. Willing and able to provide written consent for this trial prior to any trial-specific procedures.

2. Age ≥18 years, regardless of sex.

3. East Coast Cancer Clinical Research Consortium (ECOG) Performance Status score of 0 to 1.

4. Female participants may be postmenopausal, perimenopausal, or premenopausal. Postmenopausal women must meet the following criteria:

• Age ≥60 years and ≥1 year since last menstruation, or

• Age <60 years and ≥1 year since last menstruation and cessation of all exogenous hormone therapy/chemotherapy/ovarian suppression/Tamoxifen or similar treatment. Serum estradiol and follicle-stimulating hormone (FSH) concentrations must be confirmed to be within the standard laboratory reference range, or

• Medical records of bilateral oophorectomy. Women in the premenopausal or perimenopausal period must meet the following criteria:

• Must have started GnRH agonist therapy at least 4 weeks prior to randomization and continue GnRH agonist therapy during the trial.

5. Histologically or cytologically confirmed locally advanced or metastatic breast adenocarcinoma with radiographic or objective evidence of recurrence or progression; locally advanced disease is not suitable for curative resection (if it is believed that participation in the trial treatment may lower the disease stage, thus making surgery or ablation suitable, the participant is ineligible for the trial).

6. The tumor must be estrogen receptor (ER) positive, with or without progesterone receptor co-expression, and HER2- confirmed by a local laboratory:

• ER+ is defined as >10% of tumor cells being positive for ER staining by immunohistochemical staining (IHC) (Allison 2020).

•HER2- is defined as (a) an IHC intensity of 0 or 1+, or (b) an IHC intensity of 2+, using standard methods as defined by the American Society of Clinical Oncology/American Society of Pathology (ASCO/CAP) guidelines, with no evidence of amplification based on reflective in situ hybridization (ISH) (Wolff 2018, NCCN 2024).

7. Measurable disease according to RECIST version 1.1, or evaluable bone-only disease. Participants with evaluable bone-only disease must have at least one osteolytic or mixed osteolytic/osteoblastic bone lesion evaluable by computed tomography (CT) or magnetic resonance imaging (MRI); blastic bone lesions alone are not evaluable and are not eligible for participation. Evaluable lesions must not have been previously irradiated.

8. Medical records show the presence of one or more known primary oncogenic PIK3CA mutations in tissue or blood, as confirmed by validated local assessment, and this is confirmed by central ctDNA testing via next-generation sequencing (NGS) prior to randomization. If central testing fails to confirm the PIK3CA mutation due to insufficient ctDNA shedding, the participant may still be eligible for enrollment in the trial with the approval of the trial commissioner, and must provide tumor tissue for retrospective central PIK3CA confirmation.

Note: Eligible PIK3CA mutations are defined as follows:
Kinase domain mutations: H1047R, H1047L, H1047Y, M1043V, M1043I, and G1049R
Non-kinase domain mutations: E542K, E545A, E545D, E545Q, E545K, E545G, Q546E, Q546K, Q546R, Q546P, R88Q, N345K, and C420R

9. There must be radiographic evidence of progression during or after prior HR+/HER2- ABC treatment, and:

a. At least one and no more than two lines of ET (single-drug or combination therapy) are used in the following situations:

• (Pre-)Adjuvant: If radiographic evidence of breast cancer progression or recurrence occurs during (pre-)adjuvant ET or within 12 months after completion of treatment, ET counts as first-line treatment

or
•ABC: Radiographic evidence of worsening during or after prior ET.

Note: ET options include, but are not limited to, AIs, SERMs, and SERDs (including fulvestrant).

And
b. First-line prior CDK4/6 inhibitor therapy is received in one of the following situations:

• CDK4/6 inhibitor + ET in the ABC situation, or

• If worsening or relapse occurs during or within 12 months after completing (pre-)adjuvant CDK4/6 inhibitor combined with ET therapy, the (pre-)adjuvant CDK4/6 inhibitor therapy will be counted as first-line prior therapy. If worsening or relapse occurs 12 months after completing (pre-)adjuvant CDK4/6 inhibitor therapy, the (pre-)adjuvant therapy will not be counted as first-line prior CDK4/6 inhibitor therapy.

• Participants who experience worsening or relapse during (pre-)adjuvant CDK4/6 inhibitor therapy or within 12 months after completing treatment, and who received CDK4/6 inhibitor therapy in advanced disease conditions, are considered to have previously received >1 line of CDK4/6 inhibitor therapy and are ineligible for the trial.

Note: Switching to another CDK4/6 inhibitor to control toxicity within a first-line therapy regimen without disease worsening is not counted as a new first-line therapy. If switching to another CDK4/6 inhibitor is medically unsuitable, the CDK4/6 inhibitor discontinued due to toxicity may be counted as a first-line prior therapy.

10. Chemotherapy in ABC cases must not exceed 1 line.

11. Participants agree to provide tumor tissue (in stock or, if deemed safe and medically feasible, newly acquired sections) for retrospective confirmation of PIK3CA mutation status. If a participant is eligible for the trial based on central ctDNA testing conducted via NGS during the screening period, but there is no available stock of tumor tissue or tumor suitable for tumor sectioning, the participant may be eligible to participate in the trial after consultation with the trial commissioner.

Exclusion Criteria

1. Metaplastic or inflammatory breast cancer.

2. Type 1 diabetes, or type 2 diabetes requiring antihyperglycemic agents, or fasting plasma glucose ≥140 mg/dL, or glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol).

3. History of other primary malignancies diagnosed or requiring treatment within the past 5 years. Note: This does not need to be ruled out if the following malignancies have a history: squamous cell carcinoma of the skin, cured localized thyroid cancer, cured localized cervical cancer, and any completely resected carcinoma in situ.

4. Known active, uncontrolled, or symptomatic central nervous system (CNS) metastases associated with progressive neurological symptoms, or requiring continuous use of corticosteroids or antiepileptic drugs to control symptoms. Any carcinomatous meningitis or leptomeningeal disease. If a participant's CNS metastases are already treated and they have been stable and asymptomatic for at least 4 weeks prior to randomization, without requiring steroid or antiepileptic drug support, they may be eligible after consultation with the trial commissioner. If there is clinical evidence of CNS disease, baseline CNS imaging is mandatory. CNS lesions cannot be selected as target lesions.

5. Organ metastasis with critical symptoms posing an immediate risk of life-threatening complications according to national or local treatment guidelines, or requiring cytotoxic chemotherapy at trial entry. Exclusion is not necessary if there is only visceral disease without an urgent critical condition.

6. Gastrointestinal (GI) impairment or GI disease, such as refractory nausea and vomiting, malabsorption syndrome, inflammatory bowel disease, diverticulitis, previous major bowel resection, or other conditions that may significantly alter the absorption or excretion of RLY-2608 or Capivasertib. The participant must be able to swallow the pills.

7. A history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis (requiring steroid treatment), or any evidence of clinically active interstitial lung disease.

8. Any effusion requiring recurrent drainage, such as pleural effusion, pericardial effusion, or ascites.

9. Meeting any of the following cardiac criteria:

a. A mean resting-corrected QT interval (QTcF) >460 msec based on three consecutive ECGs using the Fridericia formula. Any clinically significant abnormality in the rhythm, conduction, or morphology of the resting ECG (e.g., bundle branch block, ventricular pacing, grade II or III cardiac conduction block); clinically significant and uncontrollable arrhythmias, including sinoatrial node dysfunction or bradycardia that could lead to QT prolongation.

b. Any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, electrolyte abnormalities, known untreated hypothyroidism, congenital long QT syndrome, a family history of long QT syndrome or unexplained sudden death, and concurrent use of medications that may prolong the QT/QTc interval, including antiarrhythmic drugs. Please refer to Appendix 3 for a list of medications that prolong the QT interval. The inclusion of participants using any of the above medications should be discussed with the trial commissioner or medical monitor.

c. Clinically significant and uncontrolled cardiovascular disease, including congestive heart failure of class III and IV according to the New York Heart Association (NYHA) classification; uncontrolled hypertension (class 3 or higher); history of myocardial infarction, angina, coronary artery bypass surgery, angioplasty, or stent placement.

d. For participants who have received anthracycline-type drugs, left chest irradiation, or other risk factors that may be associated with cardiotoxicity, an echocardiogram will be performed during screening. Participants should not be included in the trial if their ejection fraction, as measured by echocardiography, exceeds the trial facility's normal range or is <50% (whichever is higher) (or, if echocardiography is not possible or the results are inconclusive, multichannel ventricular function testing [MUGA] should be performed).

10. Organ dysfunction, defined as:

a. Platelet count <100 × 10⁹/L.

b. Absolute neutrophil count (ANC) <1.5 × 10⁹/L.

c. Hemoglobin <9 g/dL (any erythrocyte transfusion and erythropoietin must have been administered ≥2 weeks prior to randomization).

d. Without liver metastases, aspartate transaminase (AST) or alanine transaminase (ALT) >2.5 times the upper limit of normal (ULN); with liver metastases, >5 times the ULN.

e. Total bilirubin >1.5 times the ULN; if Gilbert's disease is present, >3 times the ULN and direct bilirubin <1.5 times the ULN.

f. Estimated glomerular filtration rate (using the Chronic Kidney Disease Epidemiology Collaborative Study or the Kidney Disease Diet Adjustment Formula) or measured creatinine clearance <60 mL/min.

g. Any hypokalemia, hypomagnesemia, or hypo/hypercalcemia. Abnormalities must be corrected to the normal range during screening and must have been within the normal range for 3 days prior to randomization. Other Grade 1 electrolyte abnormalities may be accepted if the trial administrator deems them clinically insignificant.

11. A known HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection is required unless the following criteria are met:

a. Participants with a known HIV infection are eligible to participate in the trial if they meet the following criteria:

i. A CD4+ T cell count ≥350 cells/μL and undetectable HIV RNA recorded within 4 weeks prior to randomization;

ii. No occurrence of acquired immunodeficiency syndrome defined as opportunistic infection within the past 12 months prior to randomization;

iii. Received established antiretroviral therapy for at least 4 weeks prior to randomization.

b. Participants with known HBV infection are eligible to participate in the trial if they meet the following criteria:

i. Documented HBV DNA <1000 IU/mL within 4 weeks prior to randomization, and

ii. Serological evidence of chronic HBV infection (detectable HBV DNA) or remission (negative hepatitis B surface antigen [HBsAg], positive anti-hepatitis B core antibody [anti-HBc]) must have been treated with anti-HBV for at least 4 weeks prior to randomization.

c. Participants with known HCV infection are eligible to participate in the trial if they meet the following criteria:

i. Positive HCV antibody within 4 weeks prior to randomization due to completion of prior antiviral therapy or spontaneous remission of infection, and negative HCV RNA documented in their medical records.

12. History of allergy to Fulvestrant or drugs in the same class as Fulvestrant, RLY-2608, or Capivasertib (including their excipients).

13. Any other prior or ongoing clinically significant illness, medical condition, surgical history, physical examination findings, or abnormal laboratory test results that the trial administrator determines may affect the safety of the participant.

14. Previous treatment with any of the following:
* CDK2 or selective CDK4 inhibitors or any investigational therapy targeting CDKs.
* PI3K, AKT, or mTOR inhibitors, or any drug whose mechanism of action inhibits the PI3K/AKT/mTOR pathway.
* Immunotherapy.
* Antibody-drug complexes.

15. Previous treatment with >2-line ET for ABC. Participants are ineligible for the trial if their condition worsens within the first 6 months of receiving first-line ET (with or without a CDK4/6 inhibitor) for ABC.

16. Participants must have received anti-tumor therapy, including systemic chemotherapy, antibody therapy, hormone therapy, or other investigational drugs, within 2 weeks prior to randomization, except in the following circumstances:

• Concurrent hormone deprivation therapy is permitted, including but not limited to Goserelin or Leuprolide.

• Participants must discontinue ET within 14 days or 5 half-lives (whichever is shorter) prior to randomization, except for premenopausal or perimenopausal women requiring endocrine suppression with GnRH stimulators. Male participants may receive concurrent GnRH stimulator therapy if deemed appropriate by the trial administrator.

• If a participant is receiving Fulvestrant during the screening period, treatment may continue without washout.

• Trial treatment may begin within a 2-week washout period if the trial administrator deems the trial treatment safe and in the best interests of the participants, and with prior approval from the trial commissioner.

17. Received extensive radiation therapy within 4 weeks prior to randomization, and/or limited radiation therapy for palliative purposes within 2 weeks prior to randomization.

18. Known activating AKT mutations, loss-of-function PTEN mutations, or loss of PTEN expression leading to activation of downstream oncogenic pathways of PI3K.

19. Treatment with contraindicated drugs or herbal remedies requiring precautions, and which must not be discontinued within ≥2 weeks or 5 half-lives (whichever is shorter) prior to randomization. Contraindicated drugs include:

• Chronic systemic corticosteroids for palliative or supportive purposes. Acute emergency administration, topical application, inhalation sprays, eye drops, or limited local injection of corticosteroids may be administered if medically necessary. Systemic steroid therapy is not permitted within 28 days prior to randomization.

See Section 6.8.1 for the complete list.

20. Underwent major surgery within 4 weeks prior to randomization (procedures such as tumor needle biopsy are not considered major surgery). The trial center should discuss with the trial client whether other minor surgeries qualify.

21. Currently breastfeeding.

Reproduction
22. Women who are not postmenopausal or surgically sterilized, and who are unwilling to abstain from sex or use highly effective contraception for at least 199 days after the last dose of RLY-2608, 1 month after the last dose of Capivasertib, or 2 years after the last dose of Fulvestrant (whichever is later) during the treatment period. Unsurgery-sterilized men, and who are unwilling to abstain from sex or use highly effective contraception for at least 109 days after the last dose of RLY-2608, at least 4 months after the last dose of Capivasertib, or 2 years after the last dose of Fulvestrant during the treatment period.

23. Pregnancy: A positive serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained within 7 days prior to randomization, consistent with pregnancy. If the β-hCG level is within the pregnancy range but pregnancy is not confirmed (false positive), the individual may be included in the trial after ruling out pregnancy and with the written consent of the trial client. Women who are infertile (more than 1 year postmenopausal, bilateral tubal ligation, bilateral oophorectomy, hysterectomy) do not require serum β-hCG testing.

The Estimated Number of Participants

  • Taiwan

    10 participants

  • Global

    540 participants

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