Phase 2 Study of Fulvestrant and Alpelisib in PIK3CA-Mutated HR+ HER2- Advanced Breast Cancer Post-Fulvestrant Progression
- Trial ID
- 2024-514965-20-00
- Protocol
- BOOG 2021-01
- Sponsor
- BOOG Study Center B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the SEQUEL-Breast study is to investigate the **efficacy** of the combination of fulvestrant and alpelisib in patients with hormone-receptor positive, HER2 negative advanced breast cancer that harbors an activating PIK3CA mutation. This study specifically targets pre- or postmenopausal women and men who have experienced disease progression following 1st or 2nd line therapy with fulvestrant, either as a monotherapy or in combination with a CDK 4/6 inhibitor. The clinical relevance of this objective lies in its potential to provide a new therapeutic strategy for patients with limited treatment options after progression on standard therapies. Previous treatment with a CDK 4/6 inhibitor is a mandatory criterion for participation, ensuring the study population has a consistent treatment background.
Participants
The clinical trial involves **adult** participants diagnosed with **breast cancer**, specifically those with HR+HER2- advanced breast cancer harboring an activating PIK3CA mutation. The study population includes both pre- and postmenopausal women and men, aged 18 years and older. Participants must have a proven diagnosis of adenocarcinoma of the breast with locoregional recurrent or metastatic disease that is not amenable to resection or radiation therapy with curative intent. The trial is open to both genders, and the participants are required to have progressed on fulvestrant as a preceding treatment line. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the requirement for women to be postmenopausal, have had a bilateral oophorectomy, or receive a luteinizing hormone-releasing hormone (LHRH) analogue, while men must receive an LHRH-analogue. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and adequate organ and marrow function. The selection criteria ensure that participants have a histologically confirmed diagnosis with specific receptor expressions and have previously been treated with a CDK 4/6 inhibitor in the advanced setting.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **alpelisib** and fulvestrant in patients with advanced breast cancer characterized by PIK3CA mutations. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to last until March 2026, with recruitment having commenced in June 2022. Participants will be involved in the study for a maximum treatment period of 52 weeks, during which they will receive oral doses of Piqray film-coated tablets, containing alpelisib, in varying strengths (150 mg, 200 mg, and a combination of 50 mg and 200 mg). The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes.
Inclusion criteria require participants to be adults with a confirmed diagnosis of hormone receptor-positive, HER2-negative advanced breast cancer, who have previously progressed on fulvestrant therapy. Participants must have an activating PIK3CA mutation and have been treated with a CDK4/6 inhibitor. The primary endpoint is progression-free survival, defined as the time from study enrollment to disease progression or death. Secondary endpoints include objective response rate, clinical benefit rate, duration of response, safety, and quality of life assessments. Participants may be withdrawn from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The trial aims to provide insights into the management of alpelisib-induced hyperglycemia and other potential side effects, ensuring a comprehensive evaluation of the treatment's efficacy and safety.
Treatment
The clinical trial involves the administration of **Piqray** (alpelisib) in various dosages as part of the treatment regimen. Piqray is available in film-coated tablet form and is manufactured by Novartis Europharm Limited. The active substance, alpelisib, is a chemical compound with the chemical name (2S)-N1-(4-METHYL-5-(1-(1,1,1-TRIFLUORO-2-METHYLPROPAN-2-YL)PYRIDIN-4-YL)-1,3-THIAZOL-2-YL)PYRROLIDINE-1,2-DICARBOXAMIDE, also known by the synonym BYL719. The tablets are administered orally, with a maximum daily dose of 300 mg, and the treatment period can extend up to 52 weeks. The pharmaceutical form is consistent across all dosages, ensuring uniformity in administration.
The trial utilizes several dosages of Piqray, including 150 mg, 200 mg, and a combination of 50 mg and 200 mg film-coated tablets. Each dosage form is designed to deliver the active ingredient, alpelisib, effectively through oral administration. The tablets are not formulated for pediatric use and are intended for adult participants. The maximum total dose per day is 300 mg, regardless of the specific tablet strength used, and the treatment duration is standardized at 52 weeks. Compliance with the dosing schedule is monitored to ensure adherence to the trial protocol.
In addition to the experimental medication, the study involves the use of fulvestrant, a standard-of-care therapy for hormone-receptor positive, HER2-negative advanced breast cancer. Fulvestrant is administered in combination with alpelisib following progression on prior fulvestrant therapy, either as monotherapy or in combination with a CDK 4/6 inhibitor. The trial aims to evaluate the efficacy of this combination in patients with tumors harboring an activating PIK3CA mutation. The inclusion of fulvestrant as a comparator treatment provides a basis for assessing the added benefit of alpelisib in this patient population.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from study enrollment to disease progression or death from any cause, with censoring when fulvestrant and alpelisib are stopped and another treatment is initiated without confirmed disease progression. Secondary endpoints include PFS 'on treatment', Objective Response Rate (CR/PR), Clinical Benefit Rate (SD/CR/PR), Duration of Response (DoR), safety and tolerability, risk factors for alpelisib-induced hyperglycemia, management and resolution time of alpelisib-induced hyperglycemia, Quality of Life (QoL), Patient Reported Outcome Measures (PROMs), comparison of PFS in patients with the 11 most frequent activating PIK3CA mutations versus those with unselected mutations, Overall Survival (OS), and pharmacokinetics of alpelisib.
The trial will involve the administration of Piqray (alpelisib) in combination with fulvestrant to participants with HR+HER2- advanced breast cancer harboring an activating PIK3CA mutation. The treatment period is set for a maximum of 52 weeks. Efficacy assessments will be conducted at specified intervals throughout the trial duration, with data collection and analysis performed according to established clinical trial protocols. The trial aims to provide comprehensive insights into the efficacy and safety of the treatment regimen, contributing to the understanding of therapeutic outcomes in this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult women and men 18 years of age) with proven diagnosis of adenocarcinoma of the breast with locoregional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated. Women must be postmenopausal, have had a bilateral oophorectomy, or receive an luteinizing hormone releasing hormone (LHRH)analogue. Men must receive an LHRH-analogue.
- Documentation of histologically confirmed diagnosis of estrogen receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancer based on local laboratory results. In case ER 10% and PR >10% the ER and PR expression need to be confirmed in a referral center. Tumor must be HER2- as defined by ASCO-CAP guidelines. If HER2 status is unavailable then testing must be performed/repeated.
- Patients must have progressed on fulvestrant as a preceding treatment line (as first or second line therapy). In case of fulvestrant discontinuation, this discontinuation has not exceeded 12 weeks. In case fulvestrant plus a CDK4/6 inhibitor has been given in 1st line as last treatment, the patient must have progressed during or shortly (<12 months) after stopping adjuvant treatment with an (NS)AI.
- Previous treatment with a CDK4/6 inhibitor in the advanced setting is mandatory.
- The presence of an activating PIK3CA mutation; preferably detected in a metastasis as PIK3CA mutation status may change during the course of the disease. In case a biopsy from a metastasis is not obtainable, mutation analysis may be performed on the primary tumor or archival tumor material.
- Evaluable disease* as defined per RECIST v.1.1 (Eisenhauer et al, 2009). Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented. * Evaluable disease in this study is defined as measurable and non-measurable disease according to RECIST, with the exception of truly non-measurable disease only (i.e. ascites or pleural effusion as only site of disease). In case of truly non-measurable disease only, a patient is NOT considered evaluable according to RECIST. Bone-only disease is considered evaluable.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2.
- Adequate organ and marrow function defined as follows: a) ANC 1.0 x 10e9 /L; b) Platelets 75 x 10e9 / L; c) Estimated creatinine clearance 30 mL/min as calculated using the method standard for the institution; d) Total serum bilirubin ≤3x ULN (≤5x ULN if Gilbert's disease); e) ASAT and ALAT ≤3x ULN (≤5x ULN if liver metastases present)
- Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.03 Grade except other toxicities not considered a safety risk for the patient at investigator's discretion.
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study before any study-specific activity is performed.
Exclusion Criteria
- Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in the short term (visceral crisis), e.g. patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and >50% liver involvement
- Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable without the use of steroids for at least 4 weeks before enrollment.
- Prior treatment with an PI3K /AKT/mTOR inhibitor
- Prior treatment with chemotherapy in the advanced setting.
- (Prior) use of oral SERD in any setting
- Type 1 diabetes or uncontrolled type 2 diabetes. Type 2 diabetes is deemed uncontrolled when the Hba1C at screening exceeds 68 mmol/mol.
- Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
- Major surgery, any investigational agents, or other anticancer therapy within 2 weeks before enrollment.
- Diagnosis of any other malignancy prior to enrollment, except those that are not believed to influence the prognosis and do not require any further treatment. This includes but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix.
- Known allergy for alpelisib or fulvestrant or previous unacceptable toxicity during treatment with fulvestrant.
- Clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following: 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; Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470 msec at screening (mean of triplicate ECGs); Any recent cardiac events that would -in the opinion of the treating clinician- potentially intervene with study treatment.
- Current use of any of the following medications and these medications cannot be discontinued 7 days prior to the start of the treatment: Strong CYP3A4 inducers Inhibitors of BCRP See appendix B for forbidden co-medications.
- For women: pregnancy. For sexually active males: unwillingness to take precautions to make sure they do not inseminate.
- Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the clinician or investigator, would make the patient inappropriate for entry into this study, include, but are not limited to: - History of severe cutaneous reactions, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); - History of pancreatitis; - Unresolved osteonecrosis of the jaw; - Severe cases of auto-immune disease; - Clinically relevant pneumonitis; - Suicidal ideations / suicidal behavior.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 02 Jun 2022 | — |
| Netherlands | — | — | 130 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Piqray 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8234899 |
Piqray 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8234911 |
Piqray 50 mg and 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8235739 |
Piqray 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8234907 |
Piqray 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8234895 |
Piqray 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8234903 |
Piqray 50 mg and 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8235743 |
Piqray 50 mg and 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8235735 |
Piqray 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 52 | PRD8232877 |