Phase III Randomized Trial of Trastuzumab, Alpelisib, and Fulvestrant Versus Trastuzumab and Chemotherapy in PIK3CA-Mutated HER2+ Advanced Breast Cancer

Trial ID: 2024-514611-98-00
Sponsor: Fundacion Grupo Espanol De Investigacion En Cancer De Mama

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Diseases & Conditions

Breast cancer metastatic HER2 positive breast cancer

Objectives

The primary objective of this randomized phase III trial is to evaluate the efficacy of the **PI3K inhibitor alpelisib** in combination with trastuzumab, with or without fulvestrant, compared to trastuzumab plus chemotherapy (vinorelbine, capecitabine, or eribulin) in patients with previously treated **HER2+**/**HR-** and **HER2+**/**HR+** **PIK3CA mutated advanced breast cancer**. Efficacy will be measured by progression-free survival (PFS), which is clinically relevant as it may indicate a delay in disease progression and potentially improve patient outcomes.

Secondary objectives include:

Comparing additional measures of efficacy, such as overall survival (OS) and objective response rate (ORR), between treatment arms per cohort of patients.
Assessing safety and tolerability between treatment arms per cohort of patients.

These secondary objectives are crucial for understanding the broader impact of the treatment on patient health and quality of life.

Participants

The clinical trial involves participants diagnosed with **PIK3CA mutated HER2+ advanced or relapsed breast cancer** who have previously been treated with trastuzumab. The study population includes both male and female subjects, aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) Performance Status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate cardiac function, measurable disease, or at least one evaluable bone lesion, and a life expectancy of at least 12 weeks. The trial includes individuals with a history of at least one prior line of anti-HER2 based therapy for metastatic breast cancer and at least one prior line of trastuzumab in the metastatic or (neo)adjuvant setting. The sponsor has not provided the total number of participants involved in the study. The selection criteria ensure that participants have resolved acute toxic effects from prior therapies and possess adequate organ and marrow function. The trial population was selected based on specific medical and laboratory criteria, ensuring a focus on individuals with the targeted mutation and treatment history. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **alpelisib** in combination with trastuzumab, with or without fulvestrant, compared to trastuzumab plus chemotherapy in patients with PIK3CA mutated, previously treated HER2+ advanced breast cancer. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response (OR), and safety and tolerability. The trial is expected to run from June 2021 to June 2026, with a maximum treatment period of 9 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and previous treatment history. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 9 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants will receive alpelisib in the form of film-coated tablets, with a maximum daily dose of 300 mg, administered orally. The trial will ensure that all acute toxic effects of prior therapies are resolved to an acceptable level before enrollment. Adequate organ and marrow function, as well as cardiac function, are required for participation. The study will adhere to ethical standards, with informed consent obtained from all participants prior to any study-specific procedures.

Treatment

The clinical trial involves the administration of **Alpelisib**, an experimental medication, in the form of a film-coated tablet. The active substance, **Alpelisib**, is of chemical origin and is identified by the scientific product evaluation code SUB180707. The medication is administered orally, with a maximum daily dose of 300 mg and a total maximum dose of 81,000 mg over the treatment period. The treatment duration is set for a maximum of 9 months. The tablets are supplied in commercial boxes labeled specifically for clinical trial use, ensuring proper identification and compliance with trial protocols.

In addition to the experimental treatment, the study includes a comparator treatment consisting of **trastuzumab** combined with chemotherapy agents such as vinorelbine, capecitabine, or eribulin, as per the physician's choice. This standard-of-care therapy serves as a control to evaluate the efficacy of the experimental regimen. The trial also explores the combination of **Alpelisib** with **trastuzumab** and **fulvestrant** in certain patient cohorts, providing a comprehensive assessment of treatment efficacy across different therapeutic combinations.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's objective is to determine the efficacy of the **PI3K inhibitor Alpelisib** in combination with other treatments, as measured by progression-free survival (PFS) in patients with PIK3CA mutated, previously treated HER2+ advanced breast cancer. The study is conducted under strict clinical guidelines to maintain the integrity and reliability of the results.

Efficacy

Efficacy in the clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which is defined as the time from randomization to objective disease progression based on the investigator's assessment according to the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death from any cause. Secondary endpoints include **Overall Survival (OS)**, which measures the time from randomization to death from any cause, and **Objective Response (OR)**, which evaluates the complete or partial response as the best overall response based on the investigator’s assessment according to RECIST version 1.1. Additionally, safety and tolerability will be monitored, with adverse events (AEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, and AE terms coded using the MedDRA dictionary.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.Written informed consent prior to any specific study procedures, showing patient willingness to comply with all study procedures.
10.Measurable disease or at least one evaluable bone lesion, lytic or mixed (lytic+blastic), which has not been previously irradiated and is assessable by computer tomography (CT)/magnetic resonance imaging (MRI) in the absence of measurable disease according to RECIST 1.1 criteria.
11.Life expectancy ≥ 12 weeks.
12.Adequate organ and marrow function defined as follows: • Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5x109/L). • Platelets ≥ 100,000/mm3 (100x109/L). • Hemoglobin ≥ 9g/dL (90g/L). • Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ grade 1 according to NCI-CTCAE version 5.0 if judged clinically not significant by the investigator. • Creatinine <1.5 x upper limit of normal (ULN) or creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula (if creatinine is ≥1.5 ULN). • Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at enrollment) except for patients with Gilbert’s syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN. • Potassium within normal limits or corrected with supplements. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN. If patient has liver metastasis, AST and ALT ≤ 5.0 x ULN. • Fasting serum amylase ≤ 2.0 x ULN. • Fasting serum lipase ≤ ULN. • Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) ≤ 6.4%.
2.Histologically or cytologically documented locally recurrent inoperable or metastatic breast cancer with HER2+ status based on local laboratory determination, preferably on the most recent available FFPE tumor sample, and according to American Society of Clinical Oncology (ASCO)/Collegue of American Pathologists (CAP) international guidelines valid at the time of the assay. In case of discordance in HER2+ status in different biopsies, the result from the most recent biopsy will be used.
3.Documented HR status based on local laboratory, preferably on the most recent available FFPE tumor sample, and according to ASCO/CAP international guidelines valid at the time of the assay. In case of discordance in HR status in different biopsies, the result from the most recent biopsy will be used. HR+ will be defined as ≥1% positive cells by immunohistochemistry for Estrogen Receptor (ER) and/or Progesterone Receptor (PgR). HR- will be defined as <1% positive cells by immunohistochemistry for both ER and PgR. Considering that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive, for the purpose of this study, patients with ER and PgR expression between 1 and 10% (considered to be HR low by the most recent ASCO/CAP guidelines) will be eligible for inclusion in the HR- cohort.
4.Patients with a PIK3CA tumor mutation at central laboratory determination on the most representative archival FFPE tumor sample (ie, a block with sufficient tumor surface and cellularity) from the primary tumor or a metastatic lesion. If the tumor analysis is not informative or inconclusive for the mutation analysis, detection of PIK3CA mutations by the central laboratory on ctDNA extracted from a blood sample will be allowed.
5.At least 1 prior line of anti-HER2 based therapy for metastatic breast cancer (MBC).
6.At least 1 prior line of trastuzumab in the metastatic setting, or in the (neo)adjuvant setting (provided the patient relapsed while on therapy or within 6 months after completing adjuvant trastuzumab).
7.Female or male patient is at least 18 years of age.
8.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
9.Patients can be either males or premenopausal/perimenopausal or postmenopausal females. In the HR+ cohort, males and females who are not post-menopausal must have been on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin or leuprorelin) for at least 14 days prior to starting study treatment. Premenopausal status is defined as either: • Last menstrual period occurred within the last 12 months, or • If on tamoxifen: last menstrual period occurred within the past 14 days, plasma estradiol is ≥ 10 pg/mL and follicle-stimulating hormone (FSH) ≤ 40 IU/l or in the premenopausal range, according to local laboratory definition, or • In case of therapy induced amenorrhea: plasma estradiol is ≥ 10 pg/mL and FSH ≤ 40 IU/l or in the premenopausal range, according to local laboratory definition. Postmenopausal status is defined as either: • Natural (spontaneous) amenorrhea lasting more than 12 months and either age from 49 to 59 years and/or history of vasomotor symptoms (e.g., hot flush) in the absence of other medical justification, or • Levels of plasma estradiol ≤ 20 pg/mL and follicle-stimulating hormone (FSH) ≥ 40 IU/l or in the postmenopausal range, according to local laboratory definition, or • Surgical bilateral oophorectomy. Perimenopausal status is defined as neither premenopausal nor postmenopausal.
13.Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
14.Adequate cardiac function as defined by left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography or multi-gated acquisition (MUGA) scans.

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Exclusion Criteria

1.Have recently received study agent(s) in any of the following scenarios: • Fulvestrant within 12 months prior to the start of the study treatment (HR+ cohort only). • All the chemotherapy options, vinorelbine, capecitabine and eribulin within 12 months prior to start the study treatment. Patients that have received one or more of these chemotherapies more than 12 months prior can received them again as study therapy.
2.Symptomatic visceral disease or any disease burden that makes the patient ineligible for experimental therapy per the investigator’s best judgment.
3.Symptomatic central nervous system (CNS) metastases. However, patients with CNS metastases who have been adequately treated, are asymptomatic and do not require corticosteroid or anti-epileptic medication are eligible.
4.Presence of leptomeningeal carcinomatosis.
5.Other invasive malignancy (different from the current breast cancer) at the time of enrollment or previous diagnosis of a completely removed malignancy within 3 years prior to randomization except for adequately treated (including complete surgical removal) of International Federation of Gynecology and Obstetrics (FIGO) stage I grade 1 endometrial cancer, basal or squamous cell carcinoma of the skin, thyroid cancer limited to thyroid gland, in situ carcinoma of the cervix, and grade 1-2 early stage bladder cancer defined as T1 or less, without nodal involvement (N0).
6.Patients with an established diagnosis of diabetes mellitus type I or not controlled type II (FPG > 140 mg/dL [7.7 mmol/L] or HbA1c > 6.4%), or history of gestational diabetes (as per ACOG guidelines) or documented steroid-induced diabetes mellitus.
7.Prior treatment with any mTOR, AKT or PI3K inhibitor.
8.Patients treated within the last 7 days prior to treatment initiation with: • Drugs that are strong inducers of CYP3A4. • Drugs that are inhibitors of BCRP (Breast Cancer Resistance Protein).
9.Patients who received before randomization: • Any investigational agent or other anti-cancer therapy not listed below within 4 weeks prior to starting study treatment (all acute toxic effects, including peripheral neurotoxicity must be resolved to NCI-CTCAE version 5.0 grade ≤1, except toxicities not considered a safety risk for the patient at the investigator´s discretion). • Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1 week for weekly chemotherapy). • Biologic therapy (e.g., antibodies, other than trastuzumab which is permitted): within 4 weeks prior to starting study treatment. • Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2 weeks prior to starting study treatment. • Corticosteroids within 2 weeks prior to starting study treatment. Note: the following uses of corticosteroids are permitted at any time: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular). • Radiotherapy within 2 weeks prior to starting study treatment (all acute toxic effects must be resolved to NCI-CTCAE version 5.0 grade <1, except toxicities not considered a safety risk for the patient at investigator´s discretion). Patients who received prior radiotherapy to >25% of bone marrow are not eligible regardless of when it was administered. • Major surgery within 4 weeks prior to starting study treatment and/or if patient has not recovered from major side effects.
10.Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following: • History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis or myocardial infarction within 6 months of randomization. • History of documented congestive heart failure (New York Heart Association functional classification III-IV). • Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place). • Uncontrolled hypertension defined by a Systolic Blood Pressure ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening. • Long QT syndrome, family history of idiopatic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470msec.
11.Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term (> 6 months) anticoagulant therapy, other than antiplatelet therapy and low dose coumarin derivatives, provided that the International Normalised Ratio (INR) is less than 1.5.
12.History of clinically significant bowel disease including abdominal fistula, or gastrointestinal perforation.
13.Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease (e.g., ulcerative diseases).
14.Known hypersensitivity to trastuzumab, alpelisib or fulvestrant or any of their excipients. If known hypersensitivity to either vinorelbine, capecitabine, eribulin or any of their excipients, patient will be eligible as long as the investigator’s choice avoids that drug in the control arm. If known hypersensitivity to all three cytostatics (vinorelbine, capecitabine and eribulin), the patient will not be eligible.
15.Active infection for hepatitis B or hepatitis C.
16.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
17.Patients with currently documented pneumonitis/interstitial lung disease (the chest Computed Tomography [CT] scan performed at screening for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
18.Patient with liver disease with a Child Pugh score B or C.
19.Patient with a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
20.Patient has a history of Steven-Johnson-Syndrome (SJS), Erythema Multiforme (EM), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or Toxic Epidermal Necrolysis (TEN).
21.Patient is nursing (lactating) or is pregnant as confirmed by a positive serum human Chorionic Gonadotropin (hCG) test prior to initiating study treatment.
22.Patient is a woman of child-bearing potential or a partner of a woman of child-bearing potential, unless agreement to remain abstinent or use single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment, except for patients receiving fulvestrant in which this period should be of at least 2 years. • Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. • Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. • Examples of non-hormonal contraceptive methods with a failure rate of <1% per year include tubal ligation, male sterilization (only if he is the sole partner and have been performed at least 6 months prior to screening), and certain intrauterine devices. • Alternatively, a combination of two barrier methods (e.g., a condom and a cervical cap) is also acceptable. Barrier methods must always be supplemented with the use of a spermicide. • Male participants must not donate sperm during study and up to the time period specified above. Note: Female patients or partners of male patients are not considered of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential. If local regulations to prevent pregnancy deviate from the contraception methods listed above, local regulations apply and will be described in the Informed Consent Form (ICF).