Gene Signatures to Guide HR+MBC Therapy in a Diverse Cohort

Study Overview
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Brief Summary
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This is an open-label, multicenter, two-arm Phase II clinical trial that will evaluate the impact of 2nd line chemotherapy (i.e. capecitabine) on survival in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer (MBC)

Detailed Description
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Primary Objective: - Determine the impact of early chemotherapy (i.e., capecitabine) versus endocrine therapy-based regimen on anti-tumor effect in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer Secondary Objectives: Compare the safety and tolerability of capecitabine versus endocrine therapy in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer Determine the impact of early chemotherapy (i.e., capecitabine) versus endocrine therapy-based regimen on anti-tumor effect in patients with non-Luminal A hormone receptor-positive (HR+) metastatic breast cancer Correlatives: Determine if the tumor mutations detected in cfDNA are early surrogates of response Determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to therapy

Official Title
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Integrating Gene Signatures to Guide HR+MBC Therapy in a Diverse Cohort (INSIGHT)

Conditions
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Invasive Mammary Carcinoma, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Other: Endocrine-therapy
* Other: MammoPrint ® and BluePrint assays


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent. Subjects ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence of invasive mammary carcinoma that is: ER/PR-positive (> 1% cells) by IHC and HER2 negative (by IHC or FISH) Previously progressed on: an aromatase inhibitor (AI)+ CDK4/6 inhibitor, OR a selective estrogenreceptor modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor Evaluable disease (measurable or non-measurable) Measurable disease, ie, at least 1 measurable lesion as per RECIST 1.1 (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation) Patients with bone only disease allowed if possible to evaluate on radiological exams (eg.bone scan, PET/CT, CT, MRI) even if lesions are non-measurable according to RECIST1.1. Adequate organ function including: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L Platelets ≥ 100 × 10^9/L Hemoglobin ≥ 9/g/dL (may have been transfused) Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present) Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50mL/min as calculated using the Cockcroft-Gault (CG) equation For randomized patients only: tumors must be diagnosed as non-Luminal A using the Blueprint® and Mammaprint® tests Exclusion Criteria: PIK3CA mutation Prior chemotherapy in the metastatic setting More than 1 line of prior endocrine therapy in the metastatic setting Radiation therapy ≤ 2 weeks prior to study entry. Patients who have received prior radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment (except for alopecia) Previous malignant disease other than breast cancer within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment). Symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment and off steroids) Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0]; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable. Pregnant or breastfeeding females.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Physician's Choice of Endocrine-based Therapy_Non-Luminal A subtypes<br> | Other: Endocrine-therapy<br>* Endocrine therapy administered<br>Other: MammoPrint ® and BluePrint assays<br>* Archival tissue will be analyzed using the MammoPrint ® and BluePrint assays<br>|
| Experimental: Capecitabine_Non-Luminal A subtypes<br> | Drug: Capecitabine<br>* 2000 mg taken by mouth twice daily for 7 days on, 7 days off<br>Other: MammoPrint ® and BluePrint assays<br>* Archival tissue will be analyzed using the MammoPrint ® and BluePrint assays<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at 2 years |  | Up to 2 years | 
| Overall survival at 5 years |  | Up to 5 years | 
| Overall survival at 10 years |  | Up to 10 years | 
| Clinical Benefit Rate | Percentage of patients without disease progression at 6 months | Approximately 6 months | 
| Overall response rate |  | Up to 3 years | 
| Incidence of adverse events |  | Up to 28 days post-treatment | 
| Overall impact of treatment toxicity | Will be measured using Functional Assessment of Cancer Therapy (FACT)-G (5 point Likert-type scale from 1 (none at all) to 5 (very much) | Up to 3 years |