Phase 3 Randomized Study of Gedatolisib Combination Therapy versus Standard Endocrine Therapy in HR‑Positive, HER2‑Negative Advanced Breast Cancer Post‑CDK4/6 Inhibitor
- Trial ID
- 2022-502145-10-00
- Protocol
- CELC-G-301
- Sponsor
- Celcuity Inc.
Trial statistics
Objectives
The primary objective evaluates the therapeutic benefit of gedatolisib in combination with palbociclib and fulvestrant (or with fulvestrant alone) by comparing progression‑free survival (PFS) against fulvestrant (Study 1) and against alpelisib + fulvestrant (Study 2) in patients with HR‑positive, HER2‑negative advanced breast cancer whose disease progressed after CDK4/6 inhibitor plus non‑steroidal aromatase inhibitor therapy; demonstrating a PFS advantage would support a new treatment option for this resistant population. Secondary objectives assess additional efficacy and safety parameters: overall survival (OS) comparisons among all treatment arms; safety and tolerability profiling; PFS comparison of the two gedatolisib‑based regimens (Arm A vs Arm B); efficacy of gedatolisib + fulvestrant (Arm F) versus alpelisib‑based regimens; subgroup analyses by HER2‑low versus HER‑negative status; objective overall response rate, duration of response, time to response and clinical benefit rate; health‑related quality‑of‑life changes; and pharmacokinetic characterization of gedatolisib.
Participants
The trial enrolled a total of 425 participants diagnosed with hormone‑receptor‑positive, HER2‑negative advanced breast cancer who had experienced disease progression following prior CDK4/6 inhibitor therapy combined with a non‑steroidal aromatase inhibitor. Eligible individuals were adults aged 18 years or older, encompassing both female and male subjects, and were required to have an Eastern Cooperative Oncology Group performance status of 0–1 and a life expectancy of at least three months. Inclusion mandated histologically confirmed metastatic or locally advanced disease with measurable lesions per RECIST v1.1, documented estrogen or progesterone receptor positivity, HER2 negativity, and sufficient tumor tissue for determination of PIK3CA mutational status. Participants also needed adequate bone‑marrow, hepatic, renal, and coagulation parameters, left‑ventricular ejection fraction ≥50 %, and resolution of prior therapy‑related toxicities to grade ≤1. Women of child‑bearing potential and male subjects were required to use effective contraception, and all subjects had to be able to adhere to study schedules and assessments. The population was selected on the basis of documented radiological progression after CDK4/6 plus aromatase inhibitor treatment, appropriate organ function, and the absence of uncontrolled comorbidities, ensuring a cohort representative of the target clinical scenario.
Plans and Procedures
The study is a Phase 3, open‑label, randomized, two‑part trial enrolling adults with HR‑positive, HER2‑negative advanced breast cancer that has progressed after prior CDK4/6 inhibitor plus non‑steroidal aromatase inhibitor therapy; participants are allocated to one of several treatment arms that compare gedatolisib in combination with palbociclib and fulvestrant, gedatolisib with fulvestrant alone, fulvestrant alone, or alpelisib with fulvestrant, depending on PIK3CA mutation status. After an initial screening visit to confirm eligibility, baseline assessments and randomization occur on Day 1, followed by administration of the assigned investigational regimen and standard‑of‑care comparators according to the specified dosing schedules. Participants return for scheduled follow‑up visits every 4 weeks for safety assessments, laboratory tests, and drug dispensing, with imaging studies performed approximately every 8 weeks to evaluate disease status. The trial continues until disease progression, unacceptable toxicity, withdrawal of consent, or completion of the planned treatment period, after which an end‑of‑study visit documents final outcomes. The primary efficacy endpoint is progression‑free survival, measured from randomization to documented radiological progression or death, and the overall participant involvement is expected to span up to 36 months of treatment and follow‑up, with the study recruitment period projected from June 2023 to September 2026.
Treatment
Gedatolisib is supplied as a powder for infusion for intravenous use. Each administered dose contains 180 mg of the active ingredient. The infusion is prepared according to the study protocol and delivered on the schedule defined for the investigational arm. Administration records and infusion logs are used to verify compliance.
Palbociclib is provided as a film‑coated tablet for oral use. The tablet strength is 125 mg. The drug is taken according to the dosing schedule specified in the protocol, and pill counts are performed at each visit to monitor adherence.
Fulvestrant is supplied as a solution for injection for intramuscular use. Each dose contains 500 mg of fulvestrant. The injection is administered as outlined in the study regimen. Injection logs are maintained to ensure correct dosing.
Alpelisib is supplied as a film‑coated tablet for oral use. The tablet strength used in the comparator arm is 300 mg. The medication is taken as directed by the protocol, and compliance is assessed by counting returned tablets and reviewing patient diaries.
Dexamethasone is provided as a mouthwash formulation for oromucosal use, with a volume of 40 ml per administration. It is used as a background medication according to the study requirements. Usage is documented in the treatment record.
The trial evaluates several treatment arms in patients with HR-positive, HER2-negative advanced breast cancer. Arm A and Arm D receive the combination of gedatolisib, palbociclib, and fulvestrant. Arm B receives gedatolisib together with fulvestrant. Arm C receives fulvestrant alone as the standard‑of‑care comparator. Arm E receives alpelisib in combination with fulvestrant for patients with PIK3CA‑mutated disease. All oral agents are administered once daily as per protocol, and intravenous infusions are given on scheduled study days. Compliance monitoring includes pill counts, infusion logs, and review of dosing diaries.
Efficacy
Efficacy will be primarily evaluated by progression‑free survival (PFS) using Kaplan‑Meier survival curves. PFS is defined as the time from randomization to death or the first documented radiological disease progression, whichever occurs first, and progression events are confirmed according to RECIST v1.1 criteria by blinded independent central review (BICR). Hazard ratios with 95 % confidence intervals will be calculated to compare treatment arms.
Secondary efficacy assessments include overall survival (OS) curves and landmark survival rates at 12, 24, 36, and 48 months, also derived by the Kaplan‑Meier method. Tumor response will be characterized by overall response rate (ORR), defined as the proportion of participants achieving a complete or partial response per RECIST v1.1, as well as duration of response (DOR), time to response (TTR), and clinical benefit rate (CBR) (complete response, partial response, or stable disease ≥24 weeks), all evaluated by BICR. Patient‑reported outcomes are captured using the Functional Assessment of Cancer Therapy – 24 Breast (FACT‑B) questionnaire, the Patient‑Reported Outcomes Measurement Information System (PROMIS®) Short Form v2.0 – Physical Function 8c, and the EuroQol 5 Dimension 5 Level (EQ‑5D‑5L) instrument, with scores recorded at predefined study visits. All efficacy parameters will be analyzed according to the pre‑specified statistical analysis plan.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults ≥18 years of age and meet one of the following criteria: a. Women who are postmenopausal, defined as one of the following: i. Women 18–59 years of age (at the time of consent) with cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and serum estradiol and follicle-stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females ii. Women ≥60 years of age (at the time of consent) with cessation of menses for at least 12 consecutive months iii. Documented bilateral oophorectomy iv. Medically confirmed ovarian failure b. Pre/perimenopausal women with medically-induced menopause by treatment with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin, the gonadotropin releasing hormone (GnRH) agonist leuprolide (Lupron Depot), or equivalent agents to induce chemical menopause c. Male subjects must use an effective and/or acceptable contraceptive method from screening until 1 year after the last dose of study treatment
- Negative pregnancy test for women of childbearing potential. Female subjects of childbearing potential must use an effective and/or acceptable contraceptive method from screening until 1 year (2 years for fulvestrant) after the last dose of study treatment
- Histologically or cytologically confirmed diagnosis of metastatic or locally advanced breast cancer
- Confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive, as per American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines (2020), based on most recent tumor biopsy utilizing an assay consistent with local standards
- Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance (Wolff 2018); if result by IHC is +2 (equivocal), an in situ hybridization test must be performed.
- Adequate tumor tissue for the analysis of PIK3CA mutational status by Therascreen®PIK3CA RGQ PCR test and identified PIK3CA status (mutant or nonmutant) b. Patients with confirmed PIK3CA MT are eligible for treatment with alpelisib in combination with fulvestrant (per PIQRAY® USPI, SmPC) and will be assigned to Study 2 c. All other patients who do not have confirmed PIK3CA MT will be assigned to Study 1 (unless Study 1 enrollment has been completed)
- Subjects must have documentation of radiological disease progression on or after the last prior treatment and also have (measurable disease according to RECIST v1.1, per local assessment a. In case of bone only disease i. Subjects must have at least one lytic bone lesion or mixed lytic/blastic bone lesion with identifiable soft tissue components that can be evaluated for changes in size ii. Subjects with only blastic bone lesions with no soft tissue component are not eligible for enrollment b. If radiotherapy was used during ≤3 months prior to randomization, the lesions selected for response assessment must be outside of the field of prior radiotherapy or have documented progression following radiation therapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0–1
- Life expectancy of at least 3 months
- Progressed during or after CDK4/6 inhibitor combination treatment with non-steroidal aromatase inhibitor (AI)
- Resolution of all toxicities related to prior therapies or surgical procedures to NCI CTCAE v.5.0 Grade ≤1 (except alopecia)
- Left ventricular ejection fraction ≥50% at baseline
- At least 2 weeks beyond treatment with a targeted therapy, hormonal therapy, or major surgery and at least 3 weeks beyond immunotherapy and/or radiation therapy and recovered from all acute toxicities prior to randomization (adverse events [AEs] from prior anticancer agents recovered to Grade ≤1 or lower; except alopecia)
- Adequate bone marrow, hepatic, renal and coagulation function as defined by the following: a. Absolute neutrophil count ≥1.5 × 109/L (maintained without growth factor support within 7 days of C1D1) b. Hemoglobin ≥9.0 g/dL (90 g/L) (maintained without transfusion support within 7 days of C1D1) c. Platelets ≥100 × 109/L e. Potassium within normal limits, or corrected with supplements f. Calcium (corrected for serum albumin) and magnesium within normal limits or Grade ≤1 if judged clinically not significant by the Investigator g. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) (if no hepatic metastases); if hepatic tumor involvement, AST and ALT ≤5 × ULN h. Total bilirubin ≤1.5 × ULN (total bilirubin≤3.0 × ULN and direct bilirubin ≤1.5 × ULN in patients with Gilbert’s Syndrome) i. Serum amylase ≤1.5 × ULN (subjects with values >1.5 × ULN may be allowed if there are no clinical and radiological signs of pancreatitis) j. Serum lipase ≤1.5 × ULN (subjects with values >1.5 × ULN may be allowed if there are no clinical and radiological signs of pancreatitis) k. Prothrombin time (PT)/International Normalized Ratio (INR) ≤1.5 × ULN if not on anticoagulants l. Calculated creatinine clearance (CrCL) >50 mL/min using the Cockcroft and Gault equation i. Subjects with CrCL 40-50 mL/min who, in the opinion of the Investigator, are able to safely undertake study therapy may be eligible after discussion with Sponsor’s medical monitor
- Must be willing and able to comply with protocol-specified schedules of assessments, treatment plans, laboratory tests, and other study procedures
- Ability to understand the investigational nature of the study and sign the informed consent
Exclusion Criteria
- History of malignancies other than adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥3 years
- Known and untreated, or active, brain or leptomeningeal metastases a. Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria: do not require supportive therapy with steroids; do not have seizures and do not exhibit uncontrolled neurological symptoms; stable disease confirmed by radiographic assessment within at least 4 weeks prior to enrollment
- Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complication in the short-term
- History of clinically significant cardiovascular abnormalities such as: a. Congestive heart failure (New York Heart Association (NYHA) classification ≥ II [NYHA 1994]) within 6 months of study entry b. Myocardial infarction within 12 months of study entry c. History of any uncontrolled (or untreated) 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), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months d. Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or without antihypertensive medication (initiation or adjustment of antihypertensive medication[s] is allowed prior to screening) e. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, or history of clinically significant/symptomatic bradycardia ii. On screening, inability to determine the corrected QT interval using Fridericia’s formula (QTcF) on the ECG (i.e., unreadable or not interpretable) or QTcF >480 msec (determined by mean of triplicate ECGs at screening)
- Gastrointestinal tract disease resulting in an inability to absorb oral medication
- History of acute pancreatitis within 12 months of screening or past medical history of chronic pancreatitis
- Unable to swallow oral medication tablets/capsules
- Known hypersensitivity to the study drugs or their components
- History of pulmonary embolus or deep vein thrombosis diagnosed and/or treated within the previous 6 months
- History of drug induced pneumonitis or interstitial lung disease
- Subjects that, in the opinion of the Investigator, are unable to undertake study therapy or comply with study requirements a. Current uncontrolled medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results b. Where applicable per country regulation, the subject must not currently be committed to an institution by virtue of an order issued either by judicial or administrative authorities
- Prior treatment with a phosphoinositide 3 kinase (PI3K) inhibitor, a protein kinase B (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor
- Pregnant or breast-feeding women
- Concurrent participation in another interventional clinical trial a. Subjects must agree not to participate in another clinical trial (other than observational trials) during participation in VIKTORIA-1 and until discontinuation of study treatment
- Prior treatment with chemotherapy and antibody drug conjugates (e.g., Enhertu®) for advanced disease is not permitted (prior adjuvant or neoadjuvant chemotherapy is permitted). Subjects whose disease progressed to metastatic or advanced within less than 6 months of completing adjuvant or neoadjuvant therapy will be considered as having received chemotherapy for advanced disease.
- More than 2 lines of prior endocrine therapy treatment for metastatic or locally advanced breast cancer
- Bone only disease that is only blastic with no soft tissue component
- Subjects with type 1 diabetes or uncontrolled type 2 diabetes
- Active human immunodeficiency virus (HIV) infection. a. Subjects with well controlled HIV infection may be allowed if CD4+ T-cell (CD4+) counts >350 cells/μL b. Subjects without a history of AIDS-defining opportunistic infections may be eligible for enrollment
- Known seropositive for or active viral infection with hepatitis B virus a. Hepatitis B surface antigen (HBsAg) positive b. HBsAg negative, hepatitis B surface antibody (anti-HBs) positive and/or hepatitis B core antibody (anti-HBc) positive and detectable viral DNA by PCR [Note: Subjects who are HBsAg negative and viral DNA PCR negative are eligible.]
- Known seropositive for, or active infection with hepatitis C virus a. Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative PCR test for HCV
- Medical history or concurrent conditions that are contraindicated for investigational treatments in this study (alpelisib) a. Active osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab b. History of severe cutaneous reactions (e.g., Stevens-Johnson syndrome)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Jun 2023 | 16 |
 Belgium | Not Recruiting | 01 Jun 2023 | 22 |
 Bulgaria | Not Recruiting | 01 Jun 2023 | 14 |
 Czechia | Not Recruiting | 01 Jun 2023 | 14 |
 France | Not Recruiting | 01 Jun 2023 | 18 |
 Germany | Not Recruiting | 01 Jun 2023 | 25 |
 Greece | Not Recruiting | 01 Jun 2023 | 35 |
 Hungary | Not Recruiting | 01 Jun 2023 | 11 |
 Italy | Not Recruiting | 01 Jun 2023 | 22 |
 Poland | Not Recruiting | 01 Jun 2023 | 17 |
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 |
|---|---|---|---|---|---|---|
IBRANCE 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 125 | 48 | PRD8173498 |
Piqray 150 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 300 | 48 | PRD8234895 |
Gedatolisib | Test | POWDER FOR INFUSION | INTRAVENOUS USE | 180 | 48 | PRD9979206 |
Dexamethasone | Other | MOUTHWASH | OROMUCOSAL USE | 40.00 | 48 | PRD10101671 |
IBRANCE 125 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 125 | 48 | PRD8173525 |
Piqray 50 mg and 200 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 300 | 48 | PRD8235739 |
IBRANCE 75 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 125 | 48 | PRD8173497 |
Piqray 200 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 300 | 48 | PRD8234907 |
Fulvestrant EVER Pharma 250 mg Injektionslösung in einer Fertigspritze | Comparator | INJEKTIONSLÖSUNG IN EINER FERTIGSPRITZE | INTRAMUSCULAR USE | 500 | 48 | PRD6824954 |