A Study Using ctDNA to Guide Treatment for People with HER2-positive Breast Cancer, HERizon-Breast Trial
This phase II trial tests how well a personalized sequential treatment approach, based on circulating tumor deoxyribonucleic acid (ctDNA) and imaging response, works in treating patients with HER2-positive breast cancer that has spread to nearby tissue or lymph nodes and cannot be removed by surgery (locally advanced unresectable) or that has spread from where it first started (primary site) to other places in the body (metastatic). The sequential treatments used in this study include chemotherapy drugs (like paclitaxel, docetaxel, and nab-paclitaxel), which stop the growth of cancer cells either by killing the cells or by stopping them from dividing; targeted therapy drugs (like trastuzumab, pertuzumab, trastuzumab-deruxtecan, trastuzumab emtansine, tucatinib, and capecitabine), which act directly on the genes or proteins that contribute to cancer growth and survival; and endocrine therapy drugs (like tamoxifen, letrozole, anastrozole, and exemestane), which stop hormones like estrogen from helping cancer cells to grow. The Food and Drug Administration (FDA) has approved paclitaxel, docetaxel, nab-paclitaxel, trastuzumab, pertuzumab, trastuzumab deruxtecan, trastuzumab emtansine, tucatinib, capecitabine, tamoxifen, letrozole, anastrozole, and exemestane for the treatment of metastatic breast cancer. These drugs will be given in regimens, doses, and treatment sequences that are approved by the FDA, but using a personalized approach based on a patient's disease response according to imaging scans and ctDNA, which has not been approved by the FDA. A personalized treatment approach that delivers approved treatments using ctDNA and standard imaging may be effective for treating patients with HER2-positive locally advanced unresectable or metastatic breast cancer.
Inclusion Criteria
- Male or female participants who are >= 18 years old with histologically confirmed diagnosis of unresectable locally advanced or metastatic breast cancer (MBC)
- Stage IV at the diagnosis (i.e., de novo metastatic) as per American Joint Committee on Cancer (AJCC) 8
- HER2 immunohistochemistry (IHC) results of 3+
- Life expectancy of >= 12 weeks
- Must be deemed medically fit for surgery and be surgical candidates upfront, or potentially operable if there is response to induction therapy
- Must have measurable disease per PERCIST 1.0
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Absolute neutrophil count (ANC) >= 1500/uL (within 14 days prior to the start of study intervention)
- Platelets >= 100,000/uL (within 14 days prior to the start of study intervention)
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 14 days prior to the start of study intervention) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for participant with creatinine levels > 1.5 x ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (within 14 days prior to the start of study intervention) * Creatinine clearance (CrCl) should be calculated per institutional standard
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 14 days prior to the start of study intervention)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (within 14 days prior to the start of study intervention)
- International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to the start of study intervention)
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention * A WOCBP must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [B-hCG]) within 72 hours before the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy * Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of therapy * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below: ** Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration
- Criteria for known hepatitis B and C positive subjects: hepatitis B and C screening tests are required as per Memorial Sloan Kettering (MSK) policy but do not need to be repeated prior to study unless there is a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- Participants who have active hepatitis B infection (defined as hepatitis B virus surface antigen [HBsAg] positive and/or detectable HBV deoxyribonucleic acid [DNA]) are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow MSK guidelines for HBV anti-viral therapy post completion of study intervention
- Participants with a history of HCV infection (defined as anti-HCV antibody [Ab] positive and detectable HCV ribonucleic acid [RNA]) are eligible if HCV viral load is undetectable at screening. Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization
Exclusion Criteria
- Patients diagnosed with HER2+ breast cancer as per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines with HER2 IHC results of 1-2+ and positive fluorescence in situ hybridization (FISH) or in situ hybridization (ISH)
- Prior exposure to anti-HER2 therapy of any kind or any systemic anti-cancer treatment of any kind for breast cancer
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 2 weeks prior to the first dose of study intervention
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses > 10 mg daily of oral prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Inhaled, intranasal, intra-articular, or topical steroid use are allowed
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, which have undergone potentially curative therapy are not excluded
- Has known CNS metastases and/or leptomeningeal carcinomatosis
- Has a history or evidence of active pneumonitis or interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
- Has grade >= 3 neuropathy of any etiology
- Has an active infection requiring antibiotics
- Has a known history of human immunodeficiency virus (HIV) infection
- Has an inability to swallow capsules or tablets
- Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
- Has had an allogeneic tissue/solid organ transplant
- Has significant cardiovascular impairment within 12 months of the first dose of study drug: such as New York Heart Association (NYHA) class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
- Has a left ventricular ejection fraction (LVEF) below the institutional normal range of 50%, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
- Known intolerance to any of the study drugs (or any of the excipients)
- Has had major surgery within 3 weeks prior to first dose of study interventions. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07459673.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
PRIMARY OBJECTIVE:
I. To evaluate the proportion of patients who maintain complete radiographic response (CR) and molecular complete response (mCR) for 12 months from initiation of the maintenance/surveillance phase.
SECONDARY OBJECTIVES:
I. To evaluate the proportion of patients who remain free of disease progression at 4 years from the time of enrollment in the study.
II. To determine the disease-free survival rate (maintaining CR and mCR) at 36 months from initiation of the maintenance/surveillance phase.
III. To assess overall survival defined as time between the date of induction start date and the date of death from any cause.
IV. To assess the correlation between 1-year CR and mCR with progression-free survival (PFS).
V. To assess overall response rate after the induction, and salvage induction phases according to Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0, overall response rate (ORR) will be defined as proportion of patients who have a partial response (PR) or CR to therapy.
VI. To determine time to complete response, defined as time since start of the induction phase to CR.
VII. To determine time to molecular complete response, defined as time since start of the induction phase to mCR.
VIII. To assess duration of complete response, defined as time from documentation of CR and mCR to the date of documented disease progression or death, whichever occurs first.
IX. To assess the progression-free survival, defined as time between the date of start of induction and the date of documented disease progression or death, whichever occurs first.
X. To assess the time to central nervous system (CNS) relapse defined as the time from the start of the induction phase to CNS relapse.
XI. To assess the time interval between molecular progression of disease (mPD) and radiographic progression of disease (PD) in maintenance/surveillance phase.
XII. To assess toxicity of sequential induction and consolidation therapies as determined by rate of grade >= 3 adverse events.
XIII. To determine the rate of cerebrospinal fluid (CSF) circulating tumor cells (CTC) and/or ctDNA positivity at baseline and after induction, salvage induction and consolidation phases.
XIV. To determine the rate of rate of CSF clearance after induction, salvage induction and consolidation phases.
CORRELATIVE OBJECTIVES:
I. To evaluate the relationship between relevant blood, CSF and/or tissue biomarkers at baseline in predicting induction and maintenance of CR and mCR, at the different phases of the trial (induction, salvage, consolidation, maintenance/surveillance).
II. To explore ctDNA total fraction and individual mutant allele fraction kinetics in serum and cerebrospinal fluid during the different phases of treatment and their association with PFS, overall survival (OS), time to CNS relapse, ORR, duration of response.
III. To explore changes in the tumor microenvironment in surgical resection specimens of primary breast tumors.
IV. To evaluate the relationship between preclinical model biomarkers and induction and maintenance of CR and mCR.
V. To study the genomic evolution of resistance clones throughout therapy utilizing serial liquid biopsy and analysis of surgical specimens and post-progression biopsies.
VI. To explore the association between clinical, genomic, pathologic, and radiographic characteristics of the disease at baseline and primary outcomes.
OUTLINE:
INDUCTION: Patients receive taxane (paclitaxel intravenously [IV] on days 1, 8, and 15 or docetaxel IV on day 1 or nab-paclitaxel IV on days 1, 8, and 15), trastuzumab intramuscularly (IM) on day 1, and pertuzumab IV on day 1 of each cycle. Cycles repeat every 3 weeks for 6-9 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR and mCR after 9 cycles or 2 consecutive CRs and mCRs after 6 cycles then receive trastuzumab IM on day 1 and pertuzumab IV on day 1 of each cycle for 3 additional cycles. Patients who maintain CR and mCR following completion of these 3 cycles undergo breast surgery with or without radiation according to standard of care and then proceed to consolidation. Patients who develop clinical or radiographic progression during taxane/trastuzumab/pertuzumab (THP), who do not achieve a CR and mCR after 9 cycles of THP or the subsequent 3 cycles of trastuzumab/pertuzumab (HP), who develop molecular CSF disease without evidence of neurologic or radiographic CNS disease, who do not achieve a pCR in the breast, or who do not receive at least 6 cycles of THP due to toxicity receive salvage induction therapy.
SALVAGE INDUCTION: Patients receive trastuzumab deruxtecan or trastuzumab emtansine IV on day 1 of each cycle. Cycles repeat every 21 days for 9-15 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR and mCR after 9-15 cycles undergo breast surgery with or without radiation therapy according to standard of care and then proceed to consolidation.
CONSOLIDATION: Patients receive tucatinib orally (PO) twice daily (BID) on days 1-21, capecitabine PO BID on days 1-14, and trastuzumab IM on day 1 of each cycle. Cycles repeat every 3 weeks for up to 8 cycles (6 months) in the absence of disease progression or unacceptable toxicity. Patients who maintain CR and mCR proceed to maintenance/active surveillance.
MAINTENANCE/ACTIVE SURVEILLANCE: Patients receive trastuzumab IM on day 1 and pertuzumab IV on day 1 of each cycle. Cycles repeat every 3 weeks for up to 8 cycles (6 months) in the absence of disease progression or unacceptable toxicity. Patients may also receive endocrine therapy (tamoxifen PO once daily [QD], letrozole PO QD, anastrozole PO QD, or exemestane PO QD) for a minimum of 5 years, if indicated. Following completion of 8 cycles of HP, patients undergo active surveillance with positron emission tomography (PET)/computed tomography (CT) and ctDNA assessment every 3 months for 3 years.
All patients also undergo collection of blood samples, ctDNA assessment, PET/CT, MRI, lumbar puncture, and multigated acquisition scan (MUGA)/echocardiography (ECHO) throughout the trial.
After completion of study treatment, patients are followed up every 6 months for up to 10 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorPedram Razavi
- Primary ID25-258
- Secondary IDsNCI-2026-01854
- ClinicalTrials.gov IDNCT07459673