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

Study Overview
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Brief Summary
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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.

Official Title
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Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients With Metastatic (Stage IV) Breast Cancer: A Phase 2 Randomized, Open-Label Study

Conditions
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Breast Cancer, ER-positive Breast Cancer, HER2-negative Breast Cancer, Metastatic Breast Cancer

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women age ≥ 18 years. Patients with a diagnosis of ER+, 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. 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 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) (Section 3.2). 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. 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 Renal Serum creatinine or Measured or calculated creatinine clearance (glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)) ≤ 1.5 x upper limit of normal (ULN) or CrCl ≥ 40 mL/min. CrCl should be calculated per institutional standard. Hepatic Serum total bilirubin < 1.0 ULN Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase (SGPT)). Aminotransferase (AST and ALT) ≤ 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 (Eisenhauer EA, Therasse P, Bogaerts J et al, 2009). Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. (See APPENDIX A for more information.) 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 (first injection performed ≥ 7 days before treatment initiation) 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) V 5.0 to grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at Investigator's discretion) (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_ Reference_8.5x11.pdf). 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 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 IHC3+, FISH/CISH (chromogenic in situ hybridization) amplified or FISH/CISH equivocal according to the American Society of Clinical Oncologists (ASCO) 2015 criteria (Wolff AC, Hammond MEH, Allison KH et al, 2018). 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. Patients who are ctDNA negative or with undetectable levels of ctDNA at study entry. 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. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (eg, 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 the Screening Period (Section 7.1) or within the 60 days following C1D1 in Step 1 (Section 4.3.1). Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months. 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 nonhormonal 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will have the following 3 steps: Step 1: All patients (N=450 to 500) will be receiving standard of care (SOC) frontline treatment regimens. 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). Step 3: A subset of patients in Arm 1 will be switched to new treatment at time of clinical disease progression (number to be determined).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Step 2 Arm 1: No Modification of Therapy<br>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<br>* 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<br>* Other names: Abemaciclib;Drug: SERD+CDK4/6i<br>* 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<br>* Other names: Abemaciclib;|
| Experimental: Step 2 Arm 2: Early Switch in Therapy<br>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 oral SERD 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 Chemotherapy Participants will receive this therapy for approximately 14 months. | Drug: AI+CDK4/6i<br>* 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<br>* Other names: Abemaciclib;Drug: SERD+CDK4/6i<br>* 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<br>* Other names: Abemaciclib;Drug: mTOR inhibitor + AI<br>* 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.<br>* Other names: Exemestane;Drug: mTOR inhibitor + SERD<br>* 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.<br>* Other names: Fulvestrant;Drug: mTOR inhibitor + Selective estrogen receptor modulator<br>* 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.<br>* Other names: Tamoxifen;Drug: PI3K inhibitor + SERD<br>* 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.<br>* Other names: Fulvestrant;Drug: PI3K inhibitor + AI<br>* 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.<br>* Other names: Letrozole;Drug: Chemotherapy<br>* Chemotherapy administered standard of care as an alternative therapy in Step 2 Arm 2 and Step 3.<br>* Other names: Vinorelbine;Drug: Oral SERD<br>* 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.<br>* Other names: Elacestrant;|
| Experimental: Step 3: Optional Treatment for Patients in Arm 1<br>Optional for participants who were randomized to Step 2 Arm 1 and experience clinical progression. Participants may 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. For those patients who decline to crossover into Step 3, further treatment and disease management will occur at their treating physician's discretion. | Drug: AI+CDK4/6i<br>* 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<br>* Other names: Abemaciclib;Drug: SERD+CDK4/6i<br>* 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<br>* Other names: Abemaciclib;Drug: mTOR inhibitor + AI<br>* 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.<br>* Other names: Exemestane;Drug: mTOR inhibitor + SERD<br>* 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.<br>* Other names: Fulvestrant;Drug: mTOR inhibitor + Selective estrogen receptor modulator<br>* 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.<br>* Other names: Tamoxifen;Drug: PI3K inhibitor + SERD<br>* 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.<br>* Other names: Fulvestrant;Drug: PI3K inhibitor + AI<br>* 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.<br>* Other names: Letrozole;Drug: Chemotherapy<br>* Chemotherapy administered standard of care as an alternative therapy in Step 2 Arm 2 and Step 3.<br>* Other names: Vinorelbine;Drug: Oral SERD<br>* 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.<br>* Other names: Elacestrant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival 1 (PFS1) Among Participants in Step 2 | PFS1 is defined as the elapsed time from the date of randomization (at time a rise in ctDNA ratio > 1 is detected prior to clinical progression) to the date of clinical progression or death as determined by standard clinical methods or death in randomized participants. | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The overall response rate (ORR) will be defined as the percentage of participants achieving best response of complete response (CR) or partial response (PR) to protocol therapy. Response will be assessed by treating physician using the revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. | Up to 36 months | 
| Clinical Benefit Rate (CBR) | The clinical benefit rate (CBR) is defined as the percentage of patients with best treatment response of complete response (CR), partial response (PR), or stable disease (SD) will be reported. Response will be assessed by treating physician using the revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. | Up to 36 months | 
| Progression-Free Survival 2 (PFS2) Among Participants in Step 3 | PFS in Step 3, which will be called PFS2, and is defined as the elapsed time from the date of documented first clinical progression to date of second clinical progression or death. | Up to 36 months | 
| Number of participants in Step 1 with rising ctDNA ratio > 1 | The number of participants with rising circulating tumor DNA (ctDNA) ratio > 1 and no synchronous clinical progression in Step 1 will be reported. | Up to 36 months | 
| Percentage of participants in Step 1 with rising ctDNA ratio > 1 | The percentage of participants with rising ctDNA ratio > 1 and no synchronous clinical progression in Step 1 will be reported. | Up to 36 months | 
| Median time from enrollment to rise in ctDNA ratio > 1 for Participants in Step 1 | The median time from enrollment to rise in ctDNA ratio > 1 in participants in Step1 without synchronous clinical progression will be reported. | Up to 36 months |