Evaluation of Circulating Tumor DNA Levels as a Predictive Marker for Switching Treatment Earlier in Patients with Metastatic Breast Cancer

Status: temporarily closed to accrual

This phase II trial evaluates circulating tumor deoxyribonucleic acid (ctDNA) levels as a predictive marker on switching treatment earlier in patients with breast cancer that has spread from where it first started (breast) to other places in the body (metastatic). Many patients with metastatic breast cancer have a specific tumor characteristic (estrogen receptor positive [ER+], HER2-) that can be targeted with different cancer medications, including CDK kinase, mTOR, PI3K, AKT, and PARP inhibitors that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, as well as estrogen receptor inhibitors that block the action of estrogen on tumor cells. This can slow or stop the growth of some breast tumors that need estrogen to grow. Standard treatments also include aromatase inhibitors which can help lower estrogen levels by stopping an enzyme in fat tissue (called aromatase) from changing other hormones into estrogen, as well as chemotherapy which work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving patients these medications early in the disease process may help control their cancer; however, patients with metastatic breast cancer generally do not change their treatment until there is clinical evidence of disease progression based on diagnostic imaging results. Because many types of tumors, including breast cancer, tend to lose cells or release different types of chemical products into the blood before changes can be seen on diagnostic imaging scans, health care providers can measure the level of these tumor cell products in blood, tissue, or other clinical samples to determine which patients are at higher risk for disease progression. This study measures the amount of DNA that the tumors may be releasing into the blood (known as ctDNA). DNA is the set of instructions the body uses to build proteins. DNA released from tumors can be measured and analyzed in a patient’s blood by comparing the results with DNA analyzed from a tumor biopsy collected from the same patient. By using this test, health care providers may be able to identify disease progression earlier than imaging tests and either restart or change treatments based on the amount of ctDNA in the blood before the cancer becomes unresponsive to treatment. Changing treatment earlier based on changing levels of ctDNA may increase the amount of time that a patient’s metastatic breast cancer is controlled compared to patients with metastatic breast cancer who receive treatment later based on diagnostic imaging results or other methods currently used in medical practice.

Inclusion Criteria

Men or women age ≥ 18 years
Patients with a diagnosis of ER+, HER2- metastatic (Stage IV) breast cancer. ER positivity status is defined as > 10% staining for ER, and HER2 negative status is defined as immunohistochemistry (IHC) 0+ or IHC 1 or IHC 2+ staining for HER 2 and in situ hybridization (ISH) negative with standard pathology staining methods
Patients with de novo metastatic disease at the Screening Visit must undergo a standard of care (SOC) diagnostic biopsy
Archived or fresh tumor tissue available * NOTE 1: Patients with prior history of breast cancer and for which archived tissue is not available and for whom biopsy is feasible, she/he will undergo a biopsy as part of SOC procedures for confirmatory diagnosis. In this situation, a portion of the patient’s fresh tumor sample would be processed and sent along with a blood sample to the ctDNA assay manufacturer for ctDNA and genomic analysis. With the patient’s consent, a portion of this sample will be stored for future research studies * NOTE 2: Patients with prior history of breast cancer and for which archived tissue is not available and for whom biopsy is not feasible may still be considered for study enrollment
Women and men with proven locally advanced, locoregionally recurrent or metastatic adenocarcinoma of the breast not amenable to curative therapy * Note: patients relapsing while on adjuvant tamoxifen or AI are eligible for this study
No prior systemic anticancer therapy for metastatic or advanced disease (chemotherapy, targeted therapy or ET) * Note 1: prior endocrine therapy in the metastatic setting is not allowed unless initiated ≤ 42 days from study initiation or Cycle 1, Day 1 (C1D1) * Note 2: prior initiation of LHRH agonist or bone-directed agents, however, is allowed.
No visceral crisis. Visceral crisis is defined as advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
Platelets ≥ 100,000 cells/mm^3
Hemoglobin ≥ 9.0 g/dL or ≥ 8.0 g/dL for patients with bone metastases and/or menstruating females with evidence of iron deficiency
Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or measured of calculated creatinine clearance (CrCl) ≥ 40 mL/min (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) * CrCl should be calculated per institutional standard
Serum total bilirubin < 1.0 ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 2.5 x ULN or 5 x ULN for patients with liver metastases
Albumin ≥ 2.5 mg/dL
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1) or non-measurable disease that is evaluable
Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
Ability to understand and the willingness to sign a written informed consent document
Life expectancy > 3 months
Postmenopausal women, women with suppressed ovarian function, or premenopausal women, provided they are being treated with monthly LHRH analogues and are willing to continue to receive LHRH agonist therapy for the duration of the trial. Menopausal patients or patients with suppressed ovarian function are defined as follows: * Women with bilateral oophorectomy * Postmenopausal women, as defined by any of the following criteria: ** Age 60 or over ** Age 50–59 years and meets the following criterion: *** Amenorrhea for ≥ 12 months and follicle-stimulating hormone and estradiol levels within the postmenopausal range * Women with hysterectomy or chemotherapy-induced amenorrhea. Note: Patients with hysterectomy or chemotherapy-induced amenorrhea must display follicle-stimulating hormone and estradiol levels within the postmenopausal range
Resolution of all acute toxic effects from prior anticancer therapy or surgical procedures as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 to grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion)

Exclusion Criteria

Patients who are currently receiving or have received treatment for a secondary cancer other than resected non-melanoma skin cancer lesions or in situ cancer within the past 24 months
Prior exposure to CDK4/6i ≤ 12 months prior to enrollment
Use of investigational drugs ≤ 28 days prior to study enrollment
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or that makes participation in the trial to be not in the best interest of the patient in the opinion of the investigator
Locally advanced breast cancer or locoregional relapse amenable for any treatment with curative intent
HER2+ or equivocal tumor status either on the primary or on the recurrent tumor defined as IHC3+, FISH/CISH (fluorescent or chromogenic in situ hybridization) amplified or FISH/CISH equivocal according to the American Society of Clinical Oncologists (ASCO) 2015 criteria
Prior endocrine therapy in the metastatic setting is not allowed unless initiated ≤ 42 days from study initiation or cycle 1, day 1 (C1D1)
Prior treatment with any CDK 4/6 inhibitor in the metastatic setting is not allowed
Any major surgery (defined as requiring general anesthesia) or significant traumatic injury within 4 weeks of treatment; however, surgical diagnostic procedure is allowed (even if under general anesthesia)
Known active, bleeding diathesis
Any serious known concomitant systemic disorder incompatible with the study (at the discretion of the investigator)
Patients unable to swallow tablets
History of malabsorption syndrome or other condition that would interfere with enteral absorption
Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment initiation
Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, or CDK4/6i or any of their excipients
Uncontrolled electrolyte disorders that can compound the effects of a corrected QT interval (QTc) prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesaemia)
Patients treated within the last 7 days prior to treatment start in the study with medications that are known to be cytochrome (CYP) 3A4 inhibitors or drugs that are known to be CYP3A4 inducers
Patients requiring palliative radiation within 7 days prior to C1D1 and within 30 days following C1D1 in Step 1
Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months of enrollment in this study
Any stage II, III, or IV cancer within 5 years preceding patient enrollment in the trial; however, multiple breast cancers (contralateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+
Any history of hematologic malignancy
Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months

PRIMARY OBJECTIVE:

I. To assess in Step 2 of the study whether an early switch of endocrine therapy (ET) coupled with CDK4/6 inhibitors (CDK4/6i) (Arm 2) will improve treatment efficacy compared to non-switch treatment (Arm 1) in the first 160 patients (80/arm) selected from Step 1.

SECONDARY OBJECTIVES:

I. Determine the number and percentage of patients with the following event “ctDNA ratio > 1 and no synchronous clinical progression,” where ctDNA ratio is calculated as the ctDNA value at time of assessment over enrollment or at time of first detectable level of ctDNA (if ctDNA level was undetectable at enrollment). (Step 1)

II. Determine the median time from enrollment to the event of “ctDNA ratio > 1 and no synchronous clinical progression.” (Step 1)

III. Compare objective response rate (ORR) between Arms 1 and 2 at the end of Step 2. (Step 2)

IV. Compare composite benefit rate (CBR) between Arms 1 and 2 at the end of Step 2. (Step 2)

V. A subset of alive patients who progress in Arm 1 during Step 2 and receive second-line treatment among the options provided to patients in Arm 2. (Subset 1 - Step 3)

VI. A subset of alive patients who progress in Arm 2 during Step 2 and receive third-line treatment. (Subset 1 - Step 3)

VII. To determine PFS2, defined as the elapsed time from randomization in Step 2 to date of second clinical progression or death during Step 3 in Subsets 1 and 2.

VIII. To determine PFS3, defined as the elapsed time from date of first clinical progression in Step 2 to date of second clinical progression or death during Step 3 in Subsets 1 and 2.

IX. To determine ORR with treatment given under Step 3 in Subsets 1 and 2.

X. To determine CBR with treatment given under Step 3 in Subsets 1 and 2.

EXPLORATORY OBJECTIVES:

I. Describe changes in quality-of-life (QoL) measures in both arms over time by assessing the change in Functional Assessment of Cancer Therapy with additional questions for patients with breast cancer (FACT-B) scores from time of randomization and at 4-, 8-, 12-, 18-, and 24-months (±2 weeks) post-entry in Step 2.

II. Describe the changes in Comprehensive Score for Financial Toxicity (COST) associated with early change in treatment by assessing the change in COST scores from time of randomization and at 4-, 8-, 12-, 18-, and 24-months (±2 weeks) post-entry in Step 2.

III. Characterize the patient clinical factors (age, ethnicity, Eastern Cooperative Oncology Group [ECOG], prior CDK 4/6i, visceral metastasis) and the genomic factors of the archived (or fresh, if available) tumor sample and ctDNA collected from patients prior to initiation of frontline treatment and of ctDNA collected at randomization in Step 2.

OUTLINE:

STEP 1: Patients receive standard of care (SOC) frontline treatment with either a CDK4/6i (palbociclib, ribociclib, or abemaciclib) and an aromatase inhibitor (AI) (anastrozole, letrozole, or exemestane) or a CDK4/6i and fulvestrant (or another selective estrogen receptor degrader [SERD] orally [PO]) as per the treating physician’s choice while on study. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection for ctDNA testing at baseline, at cycle 1 day 1 (C1D1), on days 30 and 60 post-treatment initiation, and then every 8-9 weeks until a rise in ctDNA to a ratio > 1 while on study. Patients also undergo computed tomography (CT), bone scan, positron emission tomography (PET)/CT and/or magnetic resonance imaging (MRI) as well as blood sample collection throughout the trial. Patients may undergo biopsy throughout the trial at time of first clinical progression.

STEP 2: Patients with a ctDNA ratio > 1 and no synchronous clinical progression are randomized to 1 of 2 arms.

ARM 1: Patients continue their SOC frontline treatment regimen as in Step 1. Patients also undergo CT, bone scan, PET/CT and/or MRI as well as blood sample collection throughout the trial. Patients may undergo biopsy throughout the trial at time of first clinical progression.

ARM 2: Patients undergo an early switch in treatment to one of the following SOC regimens depending on the treatment combination received in Step 1. Patients may receive either CDK4/6i (palbociclib, ribociclib, or abemaciclib) with fulvestrant (or another SERD), everolimus with exemestane, everolimus with fulvestrant (or another SERD), everolimus with tamoxifen, alpelisib (for PIK3CA-mutated tumors) with fulvestrant (or another SERD), alpelisib (for PIK3CA-mutated tumors) with letrozole, capivasertib (tumors with one or more PIK3CA/AKT1/PTEN alterations) with fulvestrant (or another SERD), elacestrant alone, poly [ADP-ribose] polymerase 1 inhibitor (PARPi) (for germline BRCA mutation[s]) (olaparib or talazoparib), chemotherapy (taxane, eribulin, capecitabine or vinorelbine), or receive an investigational product as part of a clinical trial, per the treating physician’s choice. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, bone scan, PET/CT and/or MRI as well as blood sample collection throughout the trial. Patients may undergo biopsy throughout the trial at time of first clinical progression.

STEP 3: Patients randomized to Arm 1 in Step 2 and experience first clinical progression may receive treatment option as in Arm 2 of Step 2. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, bone scan, PET/CT and/or MRI as well as blood sample collection throughout the trial. Patients may undergo biopsy throughout the trial at time of first clinical progression.

Have a question?
We're here to help

Chat with us: LiveHelp
Call us: 1-800-4-CANCER
(1-800-422-6237)

Which trials are right for you?

Use the checklist in our guide to gather the information you’ll need.

Evaluation of Circulating Tumor DNA Levels as a Predictive Marker for Switching Treatment Earlier in Patients with Metastatic Breast Cancer

Inclusion Criteria

Exclusion Criteria

United States

Florida

Miami

Have a question?
We're here to help

Which trials are right for you?

Evaluation of Circulating Tumor DNA Levels as a Predictive Marker for Switching Treatment Earlier in Patients with Metastatic Breast Cancer

Description

Eligibility Criteria

Locations & Contacts

Trial Objectives and Outline

Trial Phase & Type

Lead Organization

Trial IDs

Have a question?We're here to help

Which trials are right for you?

Have a question?
We're here to help