Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Breast Carcinoma Prognostic Stage IV Breast Cancer AJCC v8
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief summary:
This phase II trial studies how well letrozole, anastrozole, or fulvestrant work when given together with ribociclib, palbociclib, and/or abemaciclib in treating patients with hormone receptor (HR) positive breast cancer that has spread to other places in the body (metastatic) and has an ERS1 activating mutation. Letrozole, anastrozole, ribociclib, palbociclib, and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. It is not yet known if giving letrozole, anastrozole, or fulvestrant with ribociclib, palbociclib, and/or abemaciclib will work better in treating patients with breast cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess progression free survival (PFS) with transition to fulvestrant compared with continuing aromatase inhibitor (AI) therapy in patients with emergence of estrogen receptor 1 (ESR1) mutations in plasma.

SECONDARY OBJECTIVES:

I. To assess circulating tumor deoxyribonucleic acid (ctDNA) ESR1 mutant allele fraction (MAF) and kinetics with fulvestrant compared with AI.

II. To assess the prevalence of ESR1 mutations in patients with secondary resistance to endocrine therapy.

III. To correlate ctDNA with cancer antigens (CA) 15-3 tumor marker changes. IV. To assess overall survival (OS) with transition to fulvestrant compared with continuing AI therapy in patients with emergence of ESR1 mutations.

V. To assess PFS and time to next treatment (TTNT) on next line of therapy after progression on fulvestrant versus (vs.) AI in combination with CDKI.

EXPLORATORY OBJECTIVES:

I. Characterize other co-existing actionable genomic alterations of interest in relation to ESR1 and clinical outcomes.

II. To determine frequency of other actionable genomic alterations and frequency of enrollment on genotype-matched therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ribociclib orally (PO) once daily (QD), palbociclib PO QD on days 1-21, and/or abemaciclib PO twice daily (BID) on days 1-28. Patients also receive fulvestrant intramuscularly (IM) for 2 injections over 1-2 minutes each on days 1 and 15 of cycle 1 and day 2 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ribociclib orally PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive letrozole PO QD or anastrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive ribociclib PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive fulvestrant IM for 2 injections over 1-2 minutes each on days 1 and 15 of cycle 1 and day 2 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ribociclib orally PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive letrozole PO QD or anastrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Abemaciclib intervention 2: Anastrozole intervention 3: Fulvestrant intervention 4: Letrozole intervention 5: Palbociclib intervention 6: Ribociclib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given IM intervention 4: Given PO intervention 5: Given PO intervention 6: Given PO

Protocol document:
Prot_SAP_000.pdf: 
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Appendix 1   Schedule of clinical assessments  
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Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 
12 
End of 
treatment/ 
Progression 
Physical exam, 
Vital Signs 
Xa 
 
 
 
 
 
ECOG PS 
Xa 
 
 
 
 
 
Hematology and 
Chemistry 
Z 
 
 
 
 
 
Coagulation 
(PT/PTT/INR) 
Z 
 
 
 
 
 
Pregnancy Test 
(urine)* 
X 
 
 
 
 
 
Liquid Biopsy ** 
X** 
 
X*** 
X*** 
X*** 
X** 
Concomitant 
medications 
Xa 
 
 
 
 
 
Fulvestrant d 
administration 
 
X 
X 
X 
X 
 
Imaging 
Xb 
 
 
X 
X 
X 
Tumor marker 
X 
 
X 
Xc 
X 
 
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