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Prifetrastat (PF-07248144) Plus Fulvestrant in Adults With Advanced HR+/HER2- Breast Cancer After Endocrine Therapy and CDK4/6 Inhibitor Treatment

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is studying advanced breast cancer that is HR+/HER2-, which means the cancer grows in response to certain hormones and does not have too much of the HER2 protein. It is being done in adults whose cancer has spread to other organs after earlier hormone treatment and a CDK4/6 inhibitor, a type of cancer medicine. The study is testing prifetrastat (PF-07248144), an oral tablet, together with fulvestrant, a medicine given by muscle injection.

The purpose of the study is to see how this treatment affects the cancer at the biological level. The study will give the medicines over repeated treatment cycles and follow how the cancer and body change over time. Samples and scans may be collected during the study to learn more about the cancer, and the treatment will be watched for side effects and other safety issues.

Prifetrastat (PF-07248144) is a new medicine that blocks a protein called KAT6, which may help slow cancer growth. ctDNA is small pieces of cancer-related DNA found in the blood, and the study will look at changes in this material to better understand the treatment’s effect. The study also includes analysis of cancer tissue and blood to learn more about how the medicines work.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Start of treatment
You start the study treatment with prifetrastat (PF-07248144) taken by mouth as a tablet at a dose of 5 mg.
You also receive fulvestrant as an intramuscular injection at a dose of 500 mg. an intramuscular injection is an injection given into a muscle.
The study evaluates the effect of this treatment on changes in ctDNA (circulating tumor dna, a small amount of tumor dna found in the blood) and on the amount of tumor-related changes in the blood.
Step 2
During cycle 1 to cycle 3
You continue receiving the study treatment during this period.
A blood test called Guardant360® is used to check ctDNA and to measure changes in 74 selected genes.
The main study result is based on the change in a measure called variant allele frequency, which shows how much a gene change is present in the blood over time.
Step 3
Baseline assessments
At the start of treatment, samples are taken to study the cancer and how it may change during treatment.
These tests include checking ER, PR, Ki67, HER2, and H3K23ac in the tumor. ER means estrogen receptor, PR means progesterone receptor, Ki67 is a marker of how fast cells are growing, HER2 is a protein found on some cancer cells, and H3K23ac is a marker related to gene activity.
Other tests at the start include whole exome sequencing (a test that reads many parts of the genes), rna sequencing (a test that studies gene activity), and ATAC-seq (a test that looks at how open the dna is for gene activity).
Step 4
During treatment
You keep taking prifetrastat 5 mg by mouth and receiving fulvestrant 500 mg by intramuscular injection as directed by the study schedule.
The study checks how the treatment is working by looking for tumor shrinkage, stable disease, or disease growth.
The study also measures the amount of prifetrastat in your blood, called trough concentration, which means the lowest level before the next dose.
Step 5
On treatment assessments
While you are on treatment, repeated samples may be taken to study changes in the tumor and blood over time.
The same tumor markers and gene tests may be repeated to see how the cancer responds to treatment.
These on-treatment tests help show how the treatment affects the cancer at the molecular level, meaning at the level of genes and cell signals.
Step 6
Assessment at progression
If the cancer gets worse, additional tests are done at that time.
These tests may again include tumor marker checks, gene tests, and ATAC-seq to compare results with earlier samples.
The study then measures how long it took before the disease worsened or before death, if that happens first.
Step 7
End of treatment evaluation
The study checks whether you had a confirmed complete response or partial response. a complete response means no signs of detectable cancer, and a partial response means the cancer has shrunk.
The study also checks whether the disease stayed stable for more than 24 weeks from the first day of treatment.
These results are used to measure the objective response rate, progression-free survival, duration of response, and clinical benefit rate.
Step 8
Safety monitoring throughout the trial
Your safety is checked throughout the study by recording any adverse events, which are unwanted medical problems or side effects.
These events are graded using NCI-CTCAE v5.0, a standard system for rating how severe side effects are.

Who can join the trial?

25 criteria

Written informed consent must be signed before any study-related tests or procedures are done. This means the patient agrees in writing to take part.
The patient must be an adult, meaning 18 years of age or older.
The patient must be enrolled in a Social Security System or an equivalent health coverage system.
The patient must be willing and able to follow the study plan, including clinic visits, treatment, blood tests, and other study procedures.
The patient must have a confirmed diagnosis by tissue or cell testing of advanced or metastatic breast cancer with estrogen receptor positive (ER+) and HER2-negative results. ER+ means the cancer cells have receptors for estrogen. HER2-negative means the cancer does not show high HER2 protein activity.
The cancer must have progressed, meaning it got worse, after treatment with a CDK4/6 inhibitor and endocrine therapy. A CDK4/6 inhibitor is a medicine that blocks proteins that help cancer cells grow. Endocrine therapy is hormone treatment.
The prior CDK4/6 inhibitor treatment must have been given either for advanced or metastatic breast cancer, or before surgery after which the cancer came back or worsened during treatment or within 12 months after the last dose.
The patient must not have had more than 3 previous lines of systemic treatment for the cancer. Systemic treatment means treatment that works throughout the body. This count includes prior CDK4/6 inhibitor treatment. Up to 2 courses of chemotherapy for cancer that has spread to organs are allowed.
Previous treatment with fulvestrant is allowed.
The most recent tumor sample must show that at least 10% of the cells are ER-positive.
The tumor must be confirmed as HER2-negative, meaning either HER2 score 0 or 1+, or score 2+ with a negative in situ hybridization (ISH) test. ISH is a test that checks for extra HER2 gene copies.
Women who have not gone through menopause must agree to receive medicine to cause medically induced menopause. Menopause means the ovaries stop making eggs and monthly periods end. The study uses an approved LHRH agonist such as goserelin or leuprolide, which are medicines that switch off hormone production from the ovaries.
The patient must have a good enough general health status for the study, called ECOG Performance Status 0 or 1. This means the patient is fully active or only slightly limited in daily activities.
The patient must have at least 1 measurable tumor lesion that has not been previously treated with radiation. A measurable lesion is a tumor area that can be measured on scans.
The patient must have at least one metastatic site that is easy to reach for a biopsy, and it must be a site that is not in bone and has not been treated with radiation. A biopsy is a small sample taken for testing.
The patient must have normal enough blood levels of potassium, magnesium, and calcium. These are minerals needed for normal body function.
The patient must be expected to live for more than 3 months.
The patient must have adequate bone marrow function, meaning the body can make enough blood cells: neutrophils at least 1,500/mm3, platelets at least 100,000/mm3, and hemoglobin at least 9 g/dL. Neutrophils are white blood cells that fight infection, platelets help blood clot, and hemoglobin carries oxygen.
The patient must have adequate kidney function, with creatinine no more than 1.5 times the upper normal limit, or kidney filtering ability of at least 50 mL/min. Creatinine is a waste product measured in blood.
The patient must have adequate liver function, with bilirubin no more than 1.5 times the upper normal limit unless they have known Gilbert syndrome. Liver enzymes AST and ALT must be no more than 2.5 times the upper normal limit, or up to 5 times if the liver is involved. Alkaline phosphatase must also be within allowed limits.
The patient must have adequate blood clotting results, with INR, PT, and either PTT or aPTT no more than 1.5 times the upper normal limit. These tests check how well the blood clots.
Any side effects from previous treatments must have improved back to the usual level or to Grade 1 or less, unless the study doctor believes the remaining effects are not a safety risk. Grade 1 means mild.
The patient must agree that stored tumor samples and blood samples may be used for future research, including tests of DNA, RNA, and proteins. DNA and RNA are genetic material.
Women who can become pregnant must have a negative pregnancy test within 3 days before joining the study.
Men and women who can become pregnant must agree to use effective contraception during the study and for a period after the last dose: at least 2 years for women and at least 5 months for men.

Who cannot join the trial?

26 criteria

Symptomatic brain metastases that need steroids. Brain metastases means cancer that has spread to the brain. People with past brain metastases may still qualify only if they finished treatment, recovered from surgery or radiation side effects, stopped steroids for at least 3 weeks, and have been neurologically stable for 2 months.
Current use, or likely need, of medicines or foods that strongly or moderately block CYP3A4/5, which are liver enzymes that help break down medicines, within the required time before the first study dose.
Current use, or likely need, of medicines or foods that strongly speed up CYP3A4/5, within the required time before the first study dose.
Advanced or metastatic cancer with symptoms and spread to organs inside the body that is likely to cause life-threatening problems soon, including large uncontrolled fluid buildup around the lungs, heart, or abdomen, lung lymph vessel spread, or more than 50% of the liver involved.
Current use, or likely need, of medicines or foods that moderately or strongly block CYP2C9, another liver enzyme that helps process medicines, within the required time before the first study dose.
Current use, or likely need, of medicines that moderately or strongly speed up CYP2C9, within the required time before the first study dose.
Being pregnant, breastfeeding, or planning to become pregnant.
Another medical or mental health problem, including recent or current thoughts of suicide or suicidal behavior, or an abnormal lab result, if it could make study participation unsafe or unsuitable.
Being unable or unwilling to follow the study visits and medical checks because of travel distance, family, social, or psychological reasons.
Being legally deprived of liberty or under protective custody or guardianship.
Having another active cancer within the past 3 years, except for well-treated basal cell skin cancer, squamous cell skin cancer, or carcinoma in situ (an early cancer that has not spread).
Abnormal ECG results that could affect safety or study reading. An ECG is a heart tracing test. This includes a too-long QTc interval (a measure of the heart’s electrical recovery time), certain heart rhythm problems, signs of a heart attack, or other serious heart conduction problems.
Major surgery within 3 weeks before randomization.
Radiation therapy within 3 weeks before randomization.
Systemic anti-cancer therapy within 3 weeks before randomization, or within 28 days or 5 half-lives, whichever is shorter, if the last treatment was an antibody-based medicine.
Previous radiation to more than 25% of the bone marrow, which is the soft tissue inside bones that makes blood cells.
Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B, hepatitis C, or known HIV or AIDS-related illness. People with treated hepatitis C may qualify only if they have a documented cure response. HIV-positive people may be considered only in selected cases after review.
Fluid buildup in the abdomen called ascites that cannot be controlled.
Current use, or likely need, of pimozide or cisapride.
Any of these within the previous 6 months: heart attack, long QT syndrome, Torsade de Pointes (a dangerous heart rhythm), important atrial or ventricular arrhythmias, serious heart conduction problems, unstable chest pain, bypass surgery, symptomatic heart failure, severe heart failure class III or IV, stroke, transient ischemic attack, symptomatic pulmonary embolism, or other significant blood clot problems. Ongoing abnormal heart rhythm of grade 2 or higher also excludes participation unless allowed by sponsor review.
Therapeutic anticoagulation, meaning full-dose blood thinner treatment.
High blood pressure that cannot be controlled with the best medical treatment, such as 160/100 mmHg or higher.
Participation in another study with an investigational drug within 3 weeks before study entry, or within 5 half-lives of that drug, whichever is longer.
Known or suspected allergy or severe sensitivity to the study medicine or its ingredients, such as lactose.
Previous treatment with prifetrastat. Previous treatment with fulvestrant is allowed.
Active inflammatory gastrointestinal disease, ongoing severe diarrhea that does not improve, or previous stomach or bowel surgery that could greatly change how prifetrastat is absorbed. Gastroesophageal reflux disease under treatment is allowed.

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

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Centre De Lutte Contre Le Cancer Eugene Marquis
Rennes, France
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Centre Leon Berard
Lyon, France
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Comite Entreprise Paul Papin
Angers, France

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Investigated drugs

PF-07248144 (prifetrastat)
is an oral tablet taken by mouth. It is the study medicine being tested in this trial. It is a KAT6 inhibitor, which means it is designed to block a protein that may help cancer cells grow. The trial is checking whether this medicine, given with fulvestrant, can help treat advanced hormone receptor-positive, HER2-negative breast cancer.
Fulvestrant
is a hormone therapy given as an injection into a muscle. It is used to block the effect of estrogen, a hormone that can help some breast cancers grow. In this study, it is combined with PF-07248144 to see whether the two treatments together work better against the cancer.

What is already known about the treatment

PF-07248144 (prifetrastat)
This medicine is given by mouth as a tablet. It is still an investigational drug, so it is not yet a standard treatment in routine medical practice, but it is being studied in medical literature for advanced hormone receptor-positive, HER2-negative breast cancer. It is a KAT6 inhibitor, which means it blocks a protein that helps control how genes are turned on and off in cancer cells, and this may slow tumor growth and make the cells less able to survive.
Fulvestrant
This medicine is given as an injection into a muscle, usually in the buttock, and it is supplied as a solution for injection. It is an established medicine in oncology and is well described in medical literature as a treatment for hormone receptor-positive breast cancer, especially when the disease has spread or returned. It works by attaching to the estrogen receptor and causing it to break down, which lowers the effect of estrogen on cancer cells and helps slow their growth; it is classified as an estrogen receptor blocker and downregulator.

Investigated diseases

Hormone receptor-positive, HER2-negative breast cancer - This is a type of breast cancer in which the cancer cells grow in response to hormones such as estrogen or progesterone and do not show HER2 overexpression. It usually begins in the breast and may later spread to nearby lymph nodes or distant organs. In advanced stages, the disease continues to grow and spread despite prior treatment, and the cancer cells may develop additional genetic changes over time.