Phase II PF-07248144 plus fulvestrant in advanced HR+/HER2- breast cancer after prior endocrine therapy and CDK4/6 inhibitor treatment
- Trial ID
- 2025-521982-29-00
- Protocol
- UC-GMP-2504
- Sponsor
- Unicancer
Trial statistics
Objectives
The primary objective is to assess the effect of prifetrastat plus fulvestrant on ctDNA-based mutation burden in patients with advanced HR+/HER2- breast cancer, which is clinically relevant for evaluating molecular response to treatment. Secondary objectives include characterization of mechanisms of action and resistance through paired tumor and biological sample analyses, including changes in molecular subtype, ESR1, PIK3CA/AKT/PTEN alterations, transcriptional effects on ER signaling, cell cycle regulation, and immune gene signatures, as well as epigenetic effects. Additional objectives are to identify candidate predictors of primary resistance or outcome and mechanisms of secondary resistance, to characterize trough plasma concentrations of prifetrastat, to evaluate antitumor activity by objective response rate, progression-free survival, duration of response, and clinical benefit rate, and to assess overall safety according to NCI-CTCAE v5.0.
Participants
The sponsor did not provide the total number of participants. The trial population consisted of adult patients, both women and men, aged 18 years and older, with advanced or metastatic breast cancer that was hormone receptor positive and HER2-negative. Participants were required to have progressive disease after prior CDK4/6 inhibitor-based endocrine therapy, with no more than three prior lines of systemic therapy. The population was selected on the basis of histological or cytological confirmation, documented tumor receptor status, ECOG performance status 0 or 1, measurable disease, and adequate organ function. Additional requirements included willingness and ability to comply with study procedures, use of effective contraception when applicable, and consent for tissue and blood sample use in future research. No lifestyle considerations were provided.
Plans and Procedures
The study is a phase II clinical trial in advanced HR+/HER2- breast cancer and evaluates prifetrastat (PF-07248144) in combination with fulvestrant. The trial is designed to assess biological activity and safety, with ctDNA-based mutation burden as the primary endpoint. The planned treatment period extends from the first dose until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Study procedures begin with a screening visit to confirm eligibility, obtain informed consent, and perform required baseline assessments, including disease evaluation, laboratory testing, pregnancy testing when applicable, and collection of tumor and blood samples. Treatment visits are followed by protocol-specified on-treatment assessments for efficacy, safety, pharmacokinetics, and biomarker analyses, including repeated molecular and tissue-based evaluations at baseline, during treatment, and at progression. An end-of-study visit is performed after treatment discontinuation to complete final safety and study assessments. Participant involvement is expected to last for the duration of the study procedures and treatment period. Early termination may occur in case of disease progression, unacceptable adverse events, protocol non-compliance, withdrawal of consent, or failure to meet eligibility requirements.
Treatment
The investigational treatment consisted of PF-07248144, identified as prifetrastat, supplied as a tablet for oral use. The administered dose was 5 mg or 0.5 mg, with oral administration. The study title identified prifetrastat as a KAT6 inhibitor. The source data do not specify the dosing frequency or dosing schedule.
The non-experimental treatment was fulvestrant, supplied as a solution for injection and administered by intramuscular injection at a dose of 500 mg. The source data do not specify the frequency of administration or additional dosing details.
The source data do not provide information on participant compliance monitoring, dose modifications, or other administration procedures.
Efficacy
Efficacy will be assessed by ctDNA-based mutation burden using the Guardant Health Guardant360® assay for ctDNA detection and sequencing. The primary endpoint is the mean change in Variant Allele Frequency (VAF) across 74 prespecified genes from cycle 1 to cycle 3. This endpoint will be evaluated per cohort and in the overall population.
Additional efficacy assessments include objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and clinical benefit rate (CBR), all assessed by investigator evaluation according to RECIST v1.1. ORR is based on confirmed complete response or partial response. PFS is measured from the first day of treatment until disease progression or death from any cause, whichever occurs first. DoR is measured from the first assessment of confirmed response until progression or death, whichever occurs first. CBR is defined as confirmed complete response, partial response, or stable disease for more than 24 weeks from the first day of treatment.
Mechanism of action assessments include IHC evaluation of ER, PR, Ki67, HER2, and H3K23ac staining at baseline, on treatment, and at progression. Additional analyses include WES at baseline and progression, RNA-Seq at baseline, on treatment, and at progression, and ATAC-Seq at baseline, on treatment, and at progression.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient must have signed the written informed consent prior to any study specific screening procedures.
- ECOG Performance Status PS 0 or 1
- Expected survival of more than 3 months.
- Adequate bone marrow function, including: a. ANC ≥1,500/mm3 or ≥1.5 x 109/L; b. Platelets ≥100,000/mm3 or ≥100 x 109/L; c. Hemoglobin ≥9 g/dL
- Adequate renal function, including serum creatinine ≤1.5 x ULN or estimated creatinine clearance GFR ≥50 mL/min as calculated using the method standard for the institution. In equivocal cases, a 24-hour urine collection test can be used to estimate creatinine clearance more accurately
- Adequate liver function, including: a. Total serum bilirubin ≤1.5 x ULN unless the participant has documented Gilbert syndrome; b. AST and ALT ≤2.5 x ULN; AST and ALT ≤5.0 x ULN if there is liver involvement. Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 × ULN in case of liver or bone metastasis)
- Adequate blood clotting function: International Normalized Ratio (INR)/Prothrombin Time (PT) and either partial thromboplastin Time (PTT) or activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN
- Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1 except for AEs not constituting a safety risk by investigator judgment
- Participants must consent to the use of their archived and/or collected tumor specimen, as well as blood samples, as detailed in the protocol, for future scientific research which includes, but is not limited to DNA, RNA, and protein-based biomarker detection.
- Women of childbearing potential must have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) result within 3 days of enrolment
- Men or women of childbearing potential must agree to the use of effective contraceptive for the study duration and for at least 2 years after the last dose of study treatment for women, and at least 5 months after the last dose for men.
- Adult participants age ≥18 years.
- Patients must be affiliated to a Social Security System (or equivalent).
- Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
- Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer.
- Participants must have progressive disease (PD) after receiving prior CDK4/6 inhibitor in one of the following settings as described below: - CDK4/6i plus endocrine therapy (ET) in the advanced or metastatic breast cancer setting; or - CDK4/6i plus ET in adjuvant setting with documented PD or recurrence during or within 12 months after the last dose of CDK4/6i. In addition, participants must not have received more than 3 prior lines of systemic therapies (adjuvant CDK4/6i included), including up to 2 lines of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting. Note that prior treatment with fulvestrant is permitted.
- Participants must have documentation of ER-positive tumor (≥10% positive stained cells) based on most recent tumor biopsy utilizing an assay consistent with local standards.
- Participants must have documentation of HER2-negative tumor, defined as immunohistochemistry (IHC) score 0 or 1+, or an IHC score of 2+ with a negative in situ hybridization (ISH) (HER2/CEP17 ratio <2 or, for single probe assessment, HER2 copy number <4).
- Female participants with premenopausal status (see section 5.8.4) must be willing to undergo medically induced menopause by treatment with approved LHRH agonist such as goserelin, leuprolide or equivalent agents to induce chemical menopause
- Participants must have at least 1 measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated.
- Participants must present with a metastatic site easily accessible to a biopsy procedure and be a non-bone and non-irradiated site.
- Adequate serum potassium , serum magnesium and serum calcium (>LLN)
Exclusion Criteria
- Participants with known symptomatic brain metastases requiring steroids. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for these metastases for at least 3 weeks and are neurologically stable for 2 months (requires MRI confirmation).
- Baseline 12 -lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (e.g., baseline QTc interval >450 msec for men, or >470 msec for women, complete LBBB, signs of an acute myocardial infarction, ST changes suggestive of active myocardial ischemia, second- or third- degree AV block, or serious bradyarrhythmia or tachyarrhythmias). If the baseline uncorrected QT interval is >470 msec, this interval should be rate corrected using the Fridericia method and the resulting QTcF- should be used for decision making and reporting. If QTcF exceeds >450 msec for men, or 470 msec for women, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant’s eligibility. Computer -interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants. Cases must be discussed in detail with sponsor to judge eligibility
- Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, clinically important atrial or ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious conduction system abnormalities (eg, bifascicular block [defined as right bundle branch and left anterior or posterior hemiblock], 3rd degree AV block), unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart Association class III or IV, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and/or other clinical significant episode of thrombo embolic disease and ongoing cardiac dysrhythmias of NCI CTCAE ≥Grade 2. For Grade 2 atrial fibrillation, may be considered eligible with sponsor approval (e.g if improved to Grade 1 with non-urgent medical intervention or chronic Grade 2 atrial fibrillation with good rate control with non-urgent medical intervention). If a participant has a cardiac rhythm device/pacemaker placed and QTcF >470 msec, the participant can be considered eligible. Participants with cardiac rhythm device/pacemaker must be discussed in detail with sponsor’s medical monitor to judge eligibility
- Therapeutic anticoagulation.
- Hypertension that cannot be controlled by optimal medical therapy (eg, ≥160/100 mmHg).
- Participation in other studies involving investigational drug(s) within 3 weeks prior to study entry (or 5 half-lives prior to first dose of study intervention). Participation in observational or in long term follow-up of other studies is allowed if no procedures which may interfere with the interpretation of study results will be performed.
- Known or suspected hypersensitivity or severe allergy to active ingredient/excipients of study drug(s) such as lactose.
- Prior treatment with prifetrastat. Note that prior treatment with fulvestrant is permitted
- Active inflammatory GI disease, refractory and unresolved chronic diarrhea or previous gastric resection, lap band surgery or other GI conditions and surgeries that may significantly alter the absorption of prifetrastat. Gastroesophageal reflux disease under treatment is allowed.
- Current use or anticipated need for food or drugs that are known moderate or strong CYP3A4/5 inhibitors, including their administration within 10 days or 5 half-lives of the CYP3A4/5 inhibitor, whichever is longer prior to first dose of study intervention (see Appendix 8 for a non-exhaustive list of exemplary strong/moderate CYP3A4/5 inhibitors).
- Current use or anticipated need for food or drugs that are known strong CYP3A4/5 inducers, including their administration within 10 days or 5 half-lives of the CYP3A4/5 inducer, whichever is longer prior to the first dose of study intervention (see Appendix 7 for a non-exhaustive list of exemplary strong/moderate CYP3A4/5 inducers).
- Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including participants with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement). Note: Participants with indwelling catheter for drainage, or requirement for drainage no more frequently than once a month will be allowed.
- Current use or anticipated need for food or drugs that are known moderate/strong CYP2C9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone), including their administration within [10 days or 5 half-lives of the CYP2C9 inhibitor, whichever is longer] prior to first dose of investigational product (see Appendix 8 for a non-exhaustive list of exemplary strong/moderate CYP2C9 inhibitors).
- Current use or anticipated need for drugs that are known moderate/strong CYP2C9 inducers (e.g., carbamazepine, rifampin), including their administration within [10 days or 5 half-lives of the CYP2C9 inducer, whichever is longer] prior to the first dose of investigational product (see Appendix 8 for a non-exhaustive list of exemplary strong/moderate CY2C9 inducers).
- Patient is currently pregnant, breastfeeding, or planning to become pregnant.
- Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
- Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.
- Person deprived of their liberty or under protective custody or guardianship.
- Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. Other indolent cancers that do not interfere with assessment of primary cancer under study may be allowed with prior sponsor approval.
- Major surgery within 3 weeks prior to randomization.
- Radiation therapy within 3 weeks prior to randomization.
- Systemic anti-cancer therapy within 3 weeks prior to randomization. If the last immediate anti-cancer treatment contained an antibody-based agent(s) (approved or investigational), then an interval of 28 days or 5 half-lives (whichever is shorter) of the agent(s) prior to receive the study intervention treatment is required.
- Prior irradiation to >25% of the bone marrow.
- Participants with active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) HBV, HCV, known HIV or AIDS related illness. HIV seropositive subjects who are healthy and low risk for AIDS-related outcomes could be considered eligible. Active HBV is defined as HBsAg reactive, active HCV is defined as HCV RNA [qualitative] detected. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks. Eligibility criteria for HIV-positive subjects should be evaluated and discussed with sponsor’s medical monitor and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS-defining conditions (e.g., opportunistic infections), and status of HIV treatment. Also, the potential for drug-drug interactions will be taken into consideration. In equivocal cases, with positive serology, those participants with a negative viral load are potentially eligible provided the other entry criteria are met.
- Unmanageable ascites (limited medical treatment to control ascites is permitted, but all participants with ascites require review by sponsor).
- Current use or anticipated need for pimozide (Orap®) and cisapride (Prepulsid®).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 May 2026 | 51 |
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 |
|---|---|---|---|---|---|---|
PF-07248144 | Test | TABLET | ORAL USE | 5 | 1 | PRD11848863 |
FULVESTRANT ZENTIVA 250 mg, solution injectable en seringue préremplie | Test | SOLUTION INJECTABLE EN SERINGUE PRÉREMPLIE | INTRAMUSCULAR INJECTION | 500 | 1 | PRD8298991 |
PF-07248144 | Test | TABLET | ORAL USE | 0.5 | 1 | PRD11848805 |