Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients With Metastatic (Stage IV) Breast Cancer

NCT05826964 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 20221297
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The majority of patients (pts) with breast cancer have hormone receptor positive (HR+) disease, and this holds true for pts with advanced breast cancer (ABC). Currently frontline therapy for pts with HR+ ABC is antihormonal therapy with an aromatase inhibitor or selective estrogen receptor degrader plus a CDK4/6i. The proposed trial is a randomized study to further evaluate the potential benefit of switching a frontline regimen at the time that a molecular signal, ctDNA, suggests progression prior to detection of clinical progression using standard methods. The purpose of this study is to determine whether switching treatment earlier in the disease process, based on molecular progression, will 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.

Conditions

Breast Cancer; ER-positive Breast Cancer; HER2-negative Breast Cancer; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Progression-Free Survival 1 (PFS1) Among Participants in Step 2

  PFS1 is defined as the elapsed time in months from the date of randomization (at time a rise in ctDNA ratio \> 1 is detected prior to clinical progression) to the date of first clinical progression or death as determined by standard clinical methods or death in randomized participants.

  Up to 36 months

Secondary Outcomes (9)

• Number of participants in Step 1 with rising ctDNA ratio > 1

  Up to 36 months

• Percentage of participants in Step 1 with rising ctDNA ratio > 1

  Up to 36 months

• Time from enrollment to rise in ctDNA ratio > 1 for Participants in Step 1

  Up to 36 months

• Overall Response Rate (ORR) Among Participants in Step 2

  Up to 36 months

• Clinical Benefit Rate (CBR) Among Participants in Step 2

  Up to 36 months

Study Arms (4)

Step 2 Arm 1: No Modification of Therapy

EXPERIMENTAL

Participants in Step 2 Arm 1 will first undergo ctDNA monitoring in Step 1, providing blood samples for ctDNA testing at the following timepoints until a rise in ctDNA leading to a ratio (ctDNA result at time of assessment/ctDNA level at baseline) greater than (\>) 1 occurs: * Cycle 1 day 1 (C1D1), * Day 30 (D30) post-treatment initiation (±3 days), * Day 60 (D60) post-treatment initiation (±3 days), and then * every 8-9 weeks (±1 week). Participants will have no change in standard of care therapy administered in Step 1.

Drug: AI+CDK4/6i; Drug: SERD+CDK4/6i

Step 2 Arm 2: Early Switch in Therapy

EXPERIMENTAL

Participants in Step 2 Arm 2 undergo an early switch in standard of care therapy received in Step 1: * From AI+CDK4/6i in Step 1 to one of the following alternate endocrine therapies (ET) or chemotherapy: * SERD+CDK4/6i * mTOR Inhibitor + AI * mTOR Inhibitor+SERD * mTOR inhibitor + Selective estrogen receptor modulator * PI3K inhibitor + SERD * AKT inhibitor + SERD * Oral SERD * PARPi * Clinical Trial * Chemotherapy * From SERD+CDK4/6i in Step 1 to one of the following alternate ET or chemotherapy: * mTOR Inhibitor + AI * mTOR Inhibitor+SERD * mTOR inhibitor + Selective estrogen receptor modulator * PI3K inhibitor + AI * PI3K inhibitor + SERD * Oral SERD * PARPi * Clinical Trial * Chemotherapy Participants will receive this therapy for approximately 14 months.

Drug: AI+CDK4/6i; Drug: SERD+CDK4/6i; Drug: mTOR inhibitor + AI; Drug: mTOR inhibitor + SERD; Drug: mTOR inhibitor + Selective estrogen receptor modulator; Drug: PI3K inhibitor + SERD; Drug: PI3K inhibitor + AI; Drug: Chemotherapy; Drug: Oral SERD; Drug: PARPi; Drug: AKT inhibitor

Step 3: Treatment for Patients in Arm 1

EXPERIMENTAL

For participants who were randomized to Step 2 Arm 1 and experience first clinical progression. Participants will receive second-line treatment, having the option to change from their AI+CDK4/6i to SERD+CDK4/6i, or from SERD+CDK4/6i treatment to alternative endocrine therapy or chemotherapy. Therapy options for Step 3 are the same as listed for participants randomized to Step 2 Arm 2 and is administered standard of care. Participants will receive this therapy for approximately 6 months.

Drug: AI+CDK4/6i; Drug: SERD+CDK4/6i; Drug: mTOR inhibitor + AI; Drug: mTOR inhibitor + SERD; Drug: mTOR inhibitor + Selective estrogen receptor modulator; Drug: PI3K inhibitor + SERD; Drug: PI3K inhibitor + AI; Drug: Chemotherapy; Drug: Oral SERD; Drug: PARPi; Drug: AKT inhibitor

Step 3: Treatment for Patients in Arm 2

EXPERIMENTAL

For participants who were randomized to Step 2 Arm 2 and experience first clinical progression. Total participation duration is approximately 6 months.

Other: Step 3 Arm 2

Interventions

AI+CDK4/6i DRUG

Participants will receive standard of care one of three available AI therapies in combination with one of three available CDK4/6i therapies: * AI: Anastrozole, Letrozole or Exemestane * CDK4/6i: Palbociclib, Ribociclib or Abemaciclib

Also known as: Aromatase Inhibitor (AI) + Cyclin dependent kinase 4 and 6 inhibitor (CDK4/6i), Anastrozole, Letrozole, Exemestane, Palbociclib, Ribociclib, Abemaciclib

Step 2 Arm 1: No Modification of Therapy; Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

SERD+CDK4/6i DRUG

Participants will receive standard of care SERD therapy in the form of Fulvestrant, in combination with one of three one of three available CDK4/6i therapies: * SERD: Fulvestrant * CDK4/6i: Palbociclib, Ribociclib or Abemaciclib

Also known as: Selective Estrogen Receptor Degrader (SERD) + CDK4/6i, Fulvestrant, Palbociclib, Ribociclib, Abemaciclib

Step 2 Arm 1: No Modification of Therapy; Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

mTOR inhibitor + AI DRUG

Participants will receive standard of care mTOR inhibitor therapy (Everolimus) in combination with AI therapy (Exemestane) in Step 2 Arm 2 and Step 3. mTOR inhibitor + AI therapy administered as one of the available options for early switch from AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.

Also known as: Mammalian target of rapamycin (mTOR) inhibitor + Aromatase Inhibitor (AI), Everolimus, Exemestane

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

mTOR inhibitor + SERD DRUG

Participants will receive standard of care mTOR inhibitor therapy (Everolimus) in combination with SERD therapy (Fulvestrant), in Step 2 Arm 2 and Step 3. mTOR inhibitor + SERD therapy administered as one of the available options for early switch from AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.

Also known as: Everolimus, Fulvestrant

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

Oral SERD DRUG

Participants will receive standard of care oral SERD therapy (Elacestrant) in Step 2 Arm 2 and Step 3. Oral SERD therapy administered as one of the available options for early switch from AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.

Also known as: Elacestrant

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

mTOR inhibitor + Selective estrogen receptor modulator DRUG

Participants will receive standard of care mTOR inhibitor therapy (Everolimus) in combination with selective estrogen receptor modulator therapy (Tamoxifen) in Step 2 Arm 2 and Step 3. mTOR inhibitor + Selective estrogen receptor modulator therapy administered as one of the available options for early switch from AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.

Also known as: Everolimus, Tamoxifen

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

PI3K inhibitor + SERD DRUG

Participants will receive standard of care one PI3K inhibitor therapy (Alpelisib), in combination with SERD therapy (Fulvestrant) in Step 2 Arm 2 and Step 3. PI3K inhibitor + SERD therapy administered as one of the available options for early switch from AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.

Also known as: Phosphoinositide 3-kinase (PI3K) inhibitor + SERD, Alpelisib, Fulvestrant

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

PI3K inhibitor + AI DRUG

Participants will receive standard of care a PI3K inhibitor therapy (Alpelisib), in combination with an AI therapy (Letrozole) in Step 2 Arm 2 and Step 3. PI3K inhibitor + AI therapy administered as one of the available options for early switch from SERD+CDk4/6i therapy in administered in Step 1.

Also known as: Alpelisib, Letrozole

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

Chemotherapy DRUG

Chemotherapy administered standard of care as an alternative therapy in Step 2 Arm 2 and Step 3.

Also known as: Taxane, Eribulin, Capecitabine, Vinorelbine

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

PARPi DRUG

For participants with germline breast cancer gene (BRCA) mutation(s). Participants will receive standard of care PARPi (Olaparib or Talazoparib) therapy in Step 2 and Step 3.

Also known as: Poly(ADP-ribose) inhibitor (PARPi), Olaparib, Talazoparib

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

AKT inhibitor DRUG

For participants with tumors with one or more phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) or AKT serine/threonine kinase 1 (AKT1) or phosphatase and tensin homolog (PTEN) alterations. Participants in Step 2 and Step 3 will receive standard of care AKT inhibitor as an alternative therapy.

Also known as: Capivasertib, Protein kinase B (AKT) Inhibitor

Step 2 Arm 2: Early Switch in Therapy; Step 3: Treatment for Patients in Arm 1

Step 3 Arm 2 OTHER

Participants will receive third-line treatment standard of care as per their treating physician's choice according to National Comprehensive Cancer Network (NCCN) guidelines.

Step 3: Treatment for Patients in Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men or women age ≥ 18 years.
• Patients with a diagnosis of ER+, human epidermal growth factor receptor 2 negative (HER2-) metastatic (Stage IV) breast cancer. Positivity status is defined as \>10% staining for ER and immunohistochemistry (IHC) 0+ or IHC 1 or 2+ staining for HER-2, and fluorescence in situ hybridization (FISH) negative with standard pathology staining methods.
• Patients with de novo metastatic disease at the Screening Visit must undergo a SOC diagnostic biopsy.
• Archived tumor tissue available.
• Women and men with proven locally advanced, locoregionally recurrent or metastatic disease 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 endocrine therapy (ET)).
• Note 1: prior endocrine therapy in the metastatic setting is not allowed unless initiated \<30 days from study initiation or Cycle 1, Day 1 (C1D1).
• Note 2: prior initiation of luteinizing hormone-releasing hormone (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.
• Adequate organ and marrow function as defined below:
• Hematological
• Absolute neutrophil count (ANC) ≥1,500 cells/mm³
• Platelets ≥100,000 cells/mm³
• Hemoglobin ≥9.0 g/dL or ≥8.0 g/dL for patients with bone metastases and/or menstruating females with evidence of iron deficiency
• Renal

You may not qualify if:

• 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 and during the study.
• 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 IHC 3+, FISH/chromogenic in situ hybridization (CISH) 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 \< 30 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 (e.g., 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.

Sponsors & Collaborators

• University of Miami: lead

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Aromatase Inhibitors; Cyclin-Dependent Kinase 4; Anastrozole; Letrozole; exemestane; palbociclib; ribociclib; abemaciclib; Fulvestrant; Sirolimus; TOR Serine-Threonine Kinases; Everolimus; Selective Estrogen Receptor Modulators; Tamoxifen; Phosphatidylinositol 3-Kinases; Alpelisib; Drug Therapy; taxane; eribulin; Capecitabine; Vinorelbine; elacestrant; Poly Adenosine Diphosphate Ribose; olaparib; talazoparib; capivasertib; Proto-Oncogene Proteins c-akt

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cyclin-Dependent Kinases; Proline-Directed Protein Kinases; Protein Serine-Threonine Kinases; Protein Kinases; Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases; Transferases; Enzymes; Enzymes and Coenzymes; Cell Cycle Proteins; Proteins; Amino Acids, Peptides, and Proteins; Intracellular Signaling Peptides and Proteins; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Macrolides; Lactones; Estrogen Receptor Modulators; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Therapeutics; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Adenosine Diphosphate Ribose; Adenosine Diphosphate Sugars; Nucleoside Diphosphate Sugars; Nucleotides; Glycosides; Carbohydrates; Polyribonucleotides; Polynucleotides; Ribonucleotides; Proto-Oncogene Proteins; Oncogene Proteins; Neoplasm Proteins

Study Officials

• Frances Valdes-Albini, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Clinical Medicine

Model Details: The study will have the following 3 steps: 1. Step 1: All patients (N=450 to 500) will be receiving standard of care (SOC) frontline treatment regimens. 2. Step 2: A subset of patients in Step 1 (N=160) will be randomized to continue same treatment (Arm 1) or switch to new treatment (Arm 2). 3. Step 3: A subset of patients in Arms 1 and 2 will be switched to new treatment at time of first clinical progression, which is either second-line treatment for patients in Arm 1 or third-line treatment for patients in Arm 2.

Study Record Dates

• First Submitted: April 12, 2023
• First Posted: April 24, 2023
• Study Start: June 12, 2023
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2029
• Last Updated: January 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)