Fulvestrant and Neratinib, Alpelisib, Everolimus or Abemaciclib for the Treatment of Estrogen Receptor Positive HER2 Negative Metastatic or Locally Recurrent Breast Cancer Previously Treated with a CDK4/6 Inhibitor, GERTRUDE Trial

Status: active

This phase II trial tests how well combination therapy with fulvestrant and neratinib, alpelisib, everolimus or abemaciclib works in treating post-menopausal patients with estrogen receptor (ER) positive HER2 negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or that has come back to the area near the primary site (locally recurrent) and has received a CDK4/6 inhibitor. Fulvestrant blocks the use of estrogen by the tumor cells.This may help stop the growth of tumor cells that need estrogen to grow. Neratinib maleate a tyrosine kinase inhibitor, and alpelisib, a kinase inhibitor, block certain proteins, which may help keep tumor cells from growing and may kill them. Everolimus is a kinase inhibitor and is also a type of angiogenesis inhibitor. Everolimus works by stopping tumor cells from reproducing and by decreasing blood supply to the tumor cells. Abemaciclib, a type of cyclin-dependent kinase inhibitor, blocks certain proteins, which may help keep tumor cells from growing. Combination therapy with fulvestrant and neratinib, alpelisib, everolimus or abemaciclib may be effective in treating patients with ER positive, HER2 negative metastatic or locally recurrent breast cancer previously treated with a CDK4/6 inhibitor.

Inclusion Criteria

Post-menopausal women ≥ 18 years of age with metastatic ER+ breast cancer, or with locally recurrent ER+ disease not amenable to therapy for curative intent
Patient must be post-menopausal per National Comprehensive Cancer Network (NCCN) guidelines
Patient must have been treated with a CDK4/6i (either palbobclib, ribociclib, or abemaciclib) alone or in combination with an endocrine agent in the advanced disease setting * Up to 3 lines of therapy following CDK4/6i are permissible * Any number of prior lines of endocrine-containing therapy is permissible * Up to 1 prior line of chemotherapy is permissible
Histologic documentation of ER+ breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥ 1 site(s) of metastatic or locally recurrent disease performed as standard of care. * Exceptions: patients with bone-dominant metastatic disease, or non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained, with a history of ER+ breast cancer are eligible, and biopsy is not required, providing their primary cancer is consistent with the ER criteria
ER+ status defined as ER staining by immunohistochemistry in ≥ 1% of malignant cell nuclei
Tumor must be HER2-non-amplified as defined by an immunohistochemistry score of 0-1+, or with a fluorescence in situ hybridization (FISH) ratio < 2 if immunohistochemistry (IHC) is 2+ or if IHC has not been done (as per American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the principal investigator (PI)
Genetic profiling of a tumor or plasma specimen acquired after disease progression on a CDK4/6i must have been performed in a CAP-accredited, Clinical Laboratory Improvement Act (CLIA)-certified laboratory using clinically validated methods. Profiling must minimally include analysis of study-relevant alterations in ERBB2, PIK3CA, AKT1, MTOR, PTEN, and RB1 * If not done: Profiling of a tumor (preferable) or plasma specimen will be performed as part of the study in the Dartmouth Hitchcock Medical Center (DHMC) Pathology Laboratory. A plasma specimen may be obtained for study-specific genetic profiling to direct treatment assignment. Tumor specimens must be obtained outside of this study (e.g., by biopsy)
If available, archived tumor tissue must be accessible for research purposes, sufficient to make ≥ 10 five-micron sections; more tumor tissue is preferred
Radiographic staging performed as standard of care, including specifically either PET/CT, or contrast CT (chest, abdomen, pelvis [CAP]) and bone scan
Patient must be capable and willing to provide informed written consent for study participation

Exclusion Criteria

Treatment with abemaciclib in the most recent or current line of therapy
During the study treatment phases, no concurrent anti-cancer therapies are allowed with the following exception: anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted
Any investigational cancer therapy in the last 3 weeks
Known untreated central nervous system (CNS) disease, unless clinically stable for ≥ 3 months

PRIMARY OBJECTIVE:

I. Determine the rate of clinical benefit from abemaciclib/fulvestrant therapy in patients previously treated with a CDK4/6 inhibitor (i).

SECONDARY OBJECTIVES:

I. Determine the combined rate of clinical benefit from either neratinib/fulvestrant, alpelisib/fulvestrant, or everolimus/fulvestrant in patients previously treated with a CDK4/6 inhibitor.

II. Determine progression-free survival and objective response rate within each treatment arm.

III. Determine associations between

IIIa. Clinical benefit and progression-free survival (PFS) during abemaciclib/fulvestrant; and

IIIb. Prior clinical benefit and PFS during CDK4/6i therapy; or

IIIc. Number of lines of intervening therapy.

IV. Determine adverse event profiles of study treatments in this patient population.

EXPLORATORY OBJECTIVE:

I. Identify genetic lesions in tumor tissue and plasma predictive of clinical benefit, objective response, and progression-free survival to study drugs.

OUTLINE:

SCREENING PHASE: Patients may continue current therapy and undergo genetic profiling at progression. Patients may also undergo blood sample collection throughout the screening phase.

PRIMARY TREATMENT PHASE: Patients with a qualifying ERBB2 mutation are assigned to Arm A. Patients without a qualifying ERBB2 mutation and have a qualifying PIK3CA mutation are assigned to Arm B. Patients with no qualifying ERBB2 and PIK3CA mutation and with a qualifying mutation/alteration in AKT1, MTOR, or PTEN are assigned to Arm C. Patients with no qualifying mutation/alteration for Arms A, B or C and do not have a mutation or loss of RB1 are assigned to Arm D.

ARM A: Patients receive neratinib orally (PO) once daily (QD) on days 1-28 of each cycle and fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, computed tomography (CT) or positron emission tomography (PET)/CT and bone scan throughout the study.

ARM B: Patients receive alpelisib PO QD on days 1-28 of each cycle and fulvestrant IM on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT or PET/CT and bone scan throughout the study.

ARM C: Patients receive everolimus PO QD on days 1-28 of each cycle and fulvestrant IM on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT or PET/CT and bone scan throughout the study.

ARM D: Patients receive abemaciclib PO BID on days 1-28 of each cycle and fulvestrant IM on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT or PET/CT and bone scan throughout the study.

SECONDARY TREATMENT PHASE: Patients in Arms A, B and C with progression during the primary treatment phase may be re-evaluated for assignment to Arm D.

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Fulvestrant and Neratinib, Alpelisib, Everolimus or Abemaciclib for the Treatment of Estrogen Receptor Positive HER2 Negative Metastatic or Locally Recurrent Breast Cancer Previously Treated with a CDK4/6 Inhibitor, GERTRUDE Trial

Inclusion Criteria

Exclusion Criteria

United States

New Hampshire

Lebanon

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Fulvestrant and Neratinib, Alpelisib, Everolimus or Abemaciclib for the Treatment of Estrogen Receptor Positive HER2 Negative Metastatic or Locally Recurrent Breast Cancer Previously Treated with a CDK4/6 Inhibitor, GERTRUDE Trial

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