Clinical trial evaluating the biological activity of a new drug identified as prifetrastat (PF-07248144), combined with fulvestrant for the treatment of patients with hormone receptor positive (HR+) and HER2 negative (HER2-) breast cancer extended to other organs

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-05-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PFIZER

External identifiers

EU CT number

2025-521982-29-00

ClinicalTrials.gov

NCT07340619

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic

The primary objective of the study is to assess the effect of prifetrastat with fulvestrant on ctDNA-based mutation burden among patients with HR+/HER2- mBC.

Secondary objectives 4

1. To conduct ancillary studies to characterize mechanisms of action of prifetrastat alone or with fulvestrant in patients’ biological samples including paired pre/on and post-treatment biopsies and to identify mechanisms of secondary resistance - Description of prifetrastat effects alone or with fulvestrant on breast cancer molecular subtype changes using IHC (ER/PR/HER2) and using RNA-Seq - Description of prifetrastat effects alone or with fulvestrant on ESR1, PIK3CA/AKT/PTEN mutation using tumor WES and/or ctDNA molecular profiling - Description of transcriptional effects of prifetrastat alone or with fulvestrant on ER signaling, cell cycle regulation and immune gene signature using RNA-Seq - Description of epigenetic effects of prifetrastat alone or with fulvestrant using ATAC-Seq - Identify candidate predictors of primary resistance or outcome - Identify mechanisms of secondary resistance
2. To characterize trough plasma concentrations of prifetrastat
3. To evaluate the antitumor activity in terms of : - Objective Response rate (ORR) - Progression Free Survival (PFS) - Duration of response (DOR) - Clinical benefit rate (CBR)
4. To evaluate the safety of prifetrastat plus fulvestrant overall by NCI-CTCAE v5.0

Conditions and MedDRA coding

Adult patients with advanced hormone receptor positive (HR+), HER2- breast cancer after at least a first line of endocrine therapy combined with CDK4/6 inhibitor in the metastatic setting

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Patient must have signed the written informed consent prior to any study specific screening procedures.
2. ECOG Performance Status PS 0 or 1
3. Expected survival of more than 3 months.
4. 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
5. 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
6. 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)
7. 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
8. 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
9. 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.
10. 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
11. 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.
12. Adult participants age ≥18 years.
13. Patients must be affiliated to a Social Security System (or equivalent).
14. 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.
15. Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer.
16. 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.
17. 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.
18. 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).
19. 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
20. Participants must have at least 1 measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated.
21. Participants must present with a metastatic site easily accessible to a biopsy procedure and be a non-bone and non-irradiated site.
22. Adequate serum potassium , serum magnesium and serum calcium (>LLN)

Exclusion criteria 26

1. 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).
2. 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
3. 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
4. Therapeutic anticoagulation.
5. Hypertension that cannot be controlled by optimal medical therapy (eg, ≥160/100 mmHg).
6. 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.
7. Known or suspected hypersensitivity or severe allergy to active ingredient/excipients of study drug(s) such as lactose.
8. Prior treatment with prifetrastat. Note that prior treatment with fulvestrant is permitted
9. 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.
10. 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).
11. 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).
12. 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.
13. 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).
14. 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).
15. Patient is currently pregnant, breastfeeding, or planning to become pregnant.
16. 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.
17. Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.
18. Person deprived of their liberty or under protective custody or guardianship.
19. 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.
20. Major surgery within 3 weeks prior to randomization.
21. Radiation therapy within 3 weeks prior to randomization.
22. 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.
23. Prior irradiation to >25% of the bone marrow.
24. 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.
25. Unmanageable ascites (limited medical treatment to control ascites is permitted, but all participants with ascites require review by sponsor).
26. Current use or anticipated need for pimozide (Orap®) and cisapride (Prepulsid®).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. A Guardant Health (Guardant360®) assay will be used for ctDNA detection and sequencing and evaluation of tumor mutation burden defined by the mean change in Variant Allele Frequency (VAF) of 74 prespecified genes, from cycle 1 to cycle 3. Primary endpoint will be evaluated per cohort (as defined in section “Therapeutic regimen” below) and in the overall population.

Secondary endpoints 7

1. Mechanism of action of prifetrastat will be evaluated per cohort and in the overall population: -Assessment of ER/PR/Ki67,HER2 and H3K23ac staining with IHC,at baseline,on treatment and at progression.-Dynamics of genomic alterations interest through Whole Exome Sequencing (WES) at baseline at progression and RNA-Sequencing at baseline, on treatment at progression. -Epigenetics change through ATAC-Seq, at baseline,on treatment, at progression.-Molecular changes at genomics and transcriptomics
2. Trough Cconcentration of prifetrastat
3. Anti-tumor activity endpoints will be evaluated per cohort and the overall population by the objective response rate (ORR) on investigator assessment, defined as the percentage of patients with at least a confirmed (per RECIST v1.1) complete response (CR) or partial response (PR), based on the best objective response values.
4. Anti-tumor activity endpoints will be evaluated per cohort and the overall population by - Progression Free Survival (PFS) is defined as the time from first day of treatment until disease progression (per RECIST v1.1) or death from any cause, whichever occurs first, by investigator assessment. At the time of analysis, a patient alive and without disease progression will be censored at the date of the last valid tumor assessment
5. Anti-tumor activity endpoints will be evaluated per cohort and the overall population by - Duration of Response (DoR) will be evaluated in patients with either a complete response (CR) or partial response (PR). DoR is defined as the time from the first assessment of a confirmed CR or PR until the date of the first occurrence of progressive disease (PD) or death from any cause (if death occurred within predefined period), whichever occurs first, by investigator assessment.
6. Anti-tumor activity endpoints will be evaluated per cohort and the overall population by Clinical Benefit Rate (CBR) is defined as the percentage of patients with a confirmed complete response (CR) or partial response (PR) or stable disease (SD) for more than 24 weeks from first day of treatment assessed according to RECIST 1.1 criteria, by investigator assessment.
7. The safety will be evaluated according to the incidence of adverse events (AEs) graded by NCI-CTCAE v5.0 (Appendix 6).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications