Adding Capivasertib to Standard Treatment in HR Positive, HER2 Negative Metastatic Breast Cancer Based on ctDNA Testing (MONITOR)

MONITOR (Molecular Assessment and Identification of ctDNA and Optimizing Treatment for HR-positive, Her2-negative Metastatic Breast Cancer)

The purpose of this research is to see if adding the investigational targeted drug capivasertib to standard endocrine therapy (hormone-blocking treatment) combined with a medicine that slows cancer cell growth can improve response to treatment for patients with metastatic breast cancer that's hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative.

Study Overview

• Status: Not yet recruiting
• Conditions: HR Positive/HER-2 Negative Breast Cancer
• Intervention / Treatment: Drug: NSAI + CDK4/6i; Diagnostic test: Guardant Reveal; Drug: NSAI + CDK4/6i + Capivasertib; Drug: Fulvestrant + CDK4/6i + Capivasertib

Detailed Description

This study is being done to answer the following questions:

Can adding the medicine capivasertib to standard treatment options help keep the cancer from growing or spreading?

Standard treatment is the care that most people receive for metastatic breast cancer. This study looks at different treatment combinations for people with metastatic breast cancer that's HR-positive and HER2-negative. Researchers hope to learn:

How well the cancer responds to different treatment combinations? How long patients live after receiving different treatment combinations? How cancer-related markers in the blood (called circulating tumor DNA or ctDNA) change with treatment - and whether those changes are linked to certain results? What happens when patients switch treatments after the cancer gets worse?

• Study Type: Interventional
• Enrollment (Estimated): 1084
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: SWOG Clinical Trials Partnerships; Phone Number: 210-614-8808; Email: CTP@swog.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Registration Step 1 Inclusion Criteria:

• Participants must have histologically or cytologically confirmed adenocarcinoma of the breast with unresectable or metastatic disease.
• Participants must have evidence of either 1) measurable disease with or without non-measurable disease, or 2) non-measurable disease only, but the non-measurable disease must include bone metastases. Participants must have a CT scan or MRI of the chest and abdomen AND a whole-body bone scan within 28 days prior to registration. X-rays, scans, or other tests for assessment of non-measurable disease must have been performed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

Note: Participants cannot have only non-measurable disease without bone involvement.

• Participants must have HER2-negative breast cancer, defined as a negative in situ hybridization test or an IHC status of 0 or 1+. If IHC is 2+ (i.e. indeterminate), a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing (as per the ASCO-CAP guidelines).
• Participants' most recent tumor biopsy or surgical resection specimen must be either ER-positive, PgR-positive, or both, as defined by immunohistochemistry (IHC) ≥1% (as per the ASCO-CAP guidelines).
• Female participants must be at post-menopausal status or be receiving ovarian ablation with a GnRH agonist such as goserelin. Pre-menopausal (and peri-menopausal, i.e. those that do not meet the criteria defined for post-menopausal below) women are eligible if amenable to treatment with an GnRH agonist. Male participants should also receive GnRH agonist. These participants must begin concomitant treatment with GnRH agonist at least 14 days prior to Cycle 1, Day 1 and must be willing to continue concomitant treatment for the duration of the study. Post-menopausal status is defined by any one of the following criteria: Prior bilateral oophorectomy, Age ≥60 years, or Age <60 and amenorrhea for 12 months following cessation of all exogenous hormonal treatments/chemotherapy/ovarian suppression/tamoxifen or similar. Participants should also have serum estradiol and follicle stimulating hormone (FSH) levels confirmed as being within the standard laboratory reference range for post-menopausal females per local institution standards.
• Participants must be ≥ 18 years old at the time of registration.
• Participants must have Zubrod Performance Status of 0 or 1.
• Participants must have a complete medical history and physical exam within 28 days prior to registration.
• Participants must have adequate organ and marrow function within 28 days prior to registration.
• Participants must have a calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration. For creatinine clearance formula see the tools on the CRA Workbench https://txwb.crab.org/TXWB/Tools.aspx.
• Participants must be given the opportunity to participate in the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) form.
• Participants must agree to have blood specimens submitted for ctDNA molecular response assessment.
• Participants must be offered the opportunity to participate in planned non-real time ctDNA analysis.

Registration Step 1 Exclusion Criteria:

• Participants must not have active central nervous system (CNS) disease or evidence of active leptomeningeal disease.
• Participants must not have had endocrine resistance as defined as breast cancer recurrence within 12 months of cessation of endocrine therapy in the adjuvant setting. Prior adjuvant CDK4/6 inhibitor use is allowed as long as participants did not have a recurrence within 12 months of completion of treatment with an adjuvant CDK4/6 inhibitor.
• Participants must not have initiated, but must be planning to initiate, NSAI + palbociclib or ribociclib as the initial therapy for unresectable or metastatic disease.
• Participants must not have received prior systemic therapy in the metastatic setting, including chemotherapy or hormone therapy. Prior exposure to any chemotherapy or anti-cancer agents including hormonal therapy in the (neo)adjuvant setting is allowed as long as appropriate washout period before randomization/enrollment is met.
• Participants must not be concurrently using hormone replacement therapy.
• Participants must not have received prior fulvestrant or PI3K/AKT inhibitor treatment.
• Participants must not have received strong inhibitors or potent inducers or substrates of CYP3A4 or substrates of CYP2D6 within 14 days (21 days for St. John's Wort) prior to registration.
• Participants must agree to not use herbal or natural products intended as treatment or prophylaxis for any type of cancer.
• Participants must not have radiotherapy within 14 days prior to the Step 1 registration.
• Participants must not have a major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 28 days prior to Step 1 registration or an anticipated need for major surgery during the study.
• Participants must not have any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of registration with the exception of alopecia, lymphocyte decrease, grade 2 lymphopenia and grade 2 prior chemotherapy-therapy related neuropathy.
• Participants must not have uncontrolled diabetes mellitus or risk for hyperglycemia within 28 days prior to registration. Participants must plan to have serum glucose performed prior to beginning Step 1 treatment.
• Participants with known human immunodeficiency virus (HIV) infection must be on effective anti-retroviral therapy at registration and have undetectable viral load on the most recent test results prior to registration. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ count of > 350, no history of AIDS-defining opportunistic infection within the past 12 months, and on anti HIV medications for at least 28 days.

Note: Lower CD4+ count values are acceptable if clinically indicated and the participant has a potentially curable malignancy or for interventions in a later stage of development that have demonstrated prior activity within a given cancer.

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results, if indicated.
• Participants must not have acute hepatitis B. Participants with a known history of chronic hepatitis B virus (HBV) infection must have both a negative HBsAg result and an HBV DNA viral load below the lower limit of quantification on the most recent test results prior to registration. Participants with a positive HBsAg due to recent vaccination are eligible if HBV DNA viral load is below the lower limit of quantification. Note: Participants receiving anti-viral therapies which are strong inhibitors or inducers of CYP3A4 will be excluded due to the potential for drug-drug interaction with capivasertib.
• Participants must not have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Participants with a history of CNS metastases or cord compression must have been clinically stable (i.e. non-active disease) for at least 28 days since completion of definitive treatment and must not be receiving systemic steroids. In the case of brain metastases, the participant must have stable or improved imaging at least 4 weeks after completion of definitive treatment.
• Participants must not have or had a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the study regimen.
• Participants must not have clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, as confirmed by triplicate ECG within 28 days prior to registration.
• Participants must not have a major known bleeding disorder (e.g., bleeding diathesis) or be receiving anticoagulant therapy that would preclude intramuscular administration of fulvestrant or Luteinizing Hormone-Releasing Hormone (LHRH) agonists.
• Participants must not have a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids or have current ILD/pneumonitis symptoms.
• Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen. Participants must have a negative urine pregnancy test within 14 days prior to registration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort A, Arm 1; Continue NSAI + CDK4/6i	Drug: NSAI + CDK4/6i; NSAI: Dosed per standard practice, Days 1-28 of every cycle; CDK4/6 Inhibitor (Palbociclib or Ribociclib): Dosed per standard practice, Days 1-21 of every cycle x 4 cycles; Other Names: Cohort B, Arm 1; Diagnostic test: Guardant Reveal; ctDNA Assay
Experimental: Cohort A, Arm 2; NSAI + CDK4/6i + Capivasertib	Diagnostic test: Guardant Reveal; ctDNA Assay; Drug: NSAI + CDK4/6i + Capivasertib; NSAI: Dosed per standard practice, Days 1-28 of every cycle; CDK4/6 Inhibitor (Palbociclib or Ribociclib): Dosed per standard practice, Days 1-21 of every cycle x 4 cycles; Capivasertib: Dosed 4 days on and 3 days off weekly, every cycle; Other Names: Cohort A, Arm 2
Experimental: Cohort A, Arm 3; Fulvestrant + CDK4/6i + Capivasertib	Diagnostic test: Guardant Reveal; ctDNA Assay; Drug: Fulvestrant + CDK4/6i + Capivasertib; NSAI: Dosed per standard practice, Days 1-28 of every cycle; CDK4/6 Inhibitor (Palbociclib or Ribociclib): Dosed per standard practice, Days 1-21 of every cycle x 4 cycles Capivasertib: Dosed 4 days on and 3 days off weekly, every cycle Fulvestrant: Dosed days 1 and 15 of Cycle 1 and Day 1 of Cycles 2+; Other Names: Cohort A, Arm 3
Active Comparator: Cohort B, Arm 1; Continue NSAI + CDK4/6i	Drug: NSAI + CDK4/6i; NSAI: Dosed per standard practice, Days 1-28 of every cycle; CDK4/6 Inhibitor (Palbociclib or Ribociclib): Dosed per standard practice, Days 1-21 of every cycle x 4 cycles; Other Names: Cohort B, Arm 1; Diagnostic test: Guardant Reveal; ctDNA Assay

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	To evaluate progression-free survival (PFS) in participants with HR-positive and HER2 negative unresectable or metastatic breast cancer with detectable circulating tumor DNA (ctDNA) at baseline who do not achieve molecular response but show no evidence of progression per RECIST 1.1 after three cycles of standard of care (SOC) treatment with non-steroidal aromatase inhibitor (NSAI) + CDK4/6 inhibitor in Arms 2 and 3. PFS will be evaluated separately in participants randomized to NSAI + CDK4/6 inhibitor + capivasertib (Arm 2) and fulvestrant + CDK4/6 inhibitor + capivasertib (Arm 3) and compared to historical control.	Up to 5 years after Step 1 Registration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular Response	All Participants: To assess the percentage of participants who achieve molecular response after cycle 3 of SOC treatment and show stable disease or better per RECIST 1.1.	Up to 15 weeks after Step 1 Registration
Cohort A Overall Survival	To evaluate the overall survival (OS) for participants on Arms 1, 2, and 3 (separately).	Up to 5 years after Step 1 Registration
Cohort A Clinical Benefit Rate	To estimate the clinical benefit rate (CBR) (confirmed or unconfirmed complete or partial response or stable disease ≥ 6 months per RECIST 1.1) separately in Arms 1, 2 and 3 of this participant population from Step 2 Registration.	Up to 5 years after Step 1 Registration
Cohort A Overall Response Rate	To estimate the overall response rate (ORR) (confirmed complete and partial responses per RECIST 1.1) separately in Arms 1, 2 and 3 of this participant population, among those with measurable disease at Step 2 Registration.	Up to 5 years after Step 1 Registration
Cohort A Toxicities	To estimate the frequency and severity of toxicities in each arm of this participant population.	Up to 5 years after Step 1 Registration
Cohort A PFS Differences	To explore differences in the following clinical outcome for participants in Arms 1, 2, and 3: PFS.	Up to 5 years after Step 1 Registration
Cohort A ORR Differences	To explore differences in the following clinical outcome for participants in Arms 1, 2, and 3: ORR.	Up to 5 years after Step 1 Registration
Cohort A CBR Differences	To explore differences in the following clinical outcome for participants in Arms 1, 2, and 3: CBR.	Up to 5 years after Step 1 Registration
Cohort B PFS	To assess PFS in participants who achieve molecular response and show stable disease or better per RECIST 1.1 after three cycles of SOC treatment and then continue SOC treatment with non-steroidal aromatase inhibitor + CDK4/6 inhibitor.	Up to 5 years after Step 1 Registration
Cohort B Toxicities	To evaluate the frequency and severity of toxicities in this participant population.	Up to 5 years after Step 1 Registration
Cohort C PFS2	To evaluate PFS2 in participants from Cohort A, Arm 1 who subsequently switch to Fulvestrant + CDK4/6 inhibitor + Capivasertib after progression on SOC treatment.	Up to 5 years after Step 1 Registration
Cohort C Toxicities	To evaluate the frequency and severity of toxicities in this participant population.	Up to 5 years after Step 1 Registration
Specimen Banking	To bank specimens for future correlative studies.	Up to 2 years after Step 1 Registration
PRO-CTCAE	To compare the severity and frequency of participant-reported symptoms using selected PRO-CTCAE items (including nausea, vomiting, shortness of breath, rash, diarrhea, fatigue, abdominal pain among Cohort A, Arms 1, 2, and 3, Cohort B, Arm 1, and Cohort C, Arm 3.	Up to 5 years after Step 1 Registration

Collaborators and Investigators

• Sponsor: SWOG Cancer Research Network
• Collaborators: AstraZeneca; Guardant Health, Inc.; SWOG Clinical Trials Partnerships, LLC
• Investigators: Principal Investigator: Kevin Kalinsky, M.D., SWOG Cancer Research Network

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2026
• Primary Completion (Estimated): October 30, 2034
• Study Completion (Estimated): October 30, 2035

Study Registration Dates

• First Submitted: August 28, 2026
• First Submitted That Met QC Criteria: September 1, 2026
• First Posted (Actual): September 3, 2026

Study Record Updates

• Last Update Posted (Actual): September 3, 2026
• Last Update Submitted That Met QC Criteria: September 1, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Metastatic; Capivasertib; HR Positive, HER2 Negative
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Skin Diseases; Breast Diseases; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Breast Neoplasms; Neoplasm Metastasis; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; capivasertib
• Other Study ID Numbers: 21CTP.BREAST01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes