Testing the Effects of Palbociclib and Fulvestrant or Letrozole for Patients 70 years of Age and Older with Metastatic Breast Cancer

Status: closed to accrual

This phase II trial studies the side effects and how well palbociclib and letrozole or fulvestrant works in treating patients aged 70 and older with estrogen receptor positive, HER2 negative breast cancer that has spread to other places in the body (metastatic). Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as letrozole or fulvestrant, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if giving palbociclib and letrozole or fulvestrant may work better in treating patients aged 70 and older with breast cancer.

Inclusion Criteria

Documentation of disease: estrogen receptor positive and/or progesterone receptor (PR) positive, HER2 negative metastatic breast cancer; histologic confirmation is required
Measurable disease or non-measurable disease
Planning to begin palbociclib for metastatic disease; one prior line of endocrine therapy and/or chemotherapy for metastatic disease is allowed; patients may begin or have already begun endocrine therapy before they start palbociclib treatment, but no more than two weeks prior to registration
No prior therapy with a CDK inhibitor
Resolution of all acute toxic effects of prior therapy or surgical procedures to CTCAE grade =< 1 (except alopecia) or to baseline toxicities prior to previous therapy or surgical procedures, prior to registration
No untreated brain metastases; patients with treated brain metastases must have completed treatment with steroids to be eligible
No known interstitial lung disease
No second malignancies other than non-melanoma skin cancers or cervical carcinoma in situ; however, patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for >= 3 years
No active infection requiring treatment with antibiotics
Patients must be able to swallow and retain oral medication
Patient Age: ≥ 70 years
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
Patients must be able to read and comprehend English or Spanish
Absolute neutrophil count (ANC) >= 1500/mm^3 (1.5 x 10^9/L)
Platelet count >= 100,000/mm^3 (100 x 10^9/L)
Creatinine clearance >= 30 ml/min calculated using the Cockcroft-Gault formula
Total serum bilirubin =< 1.5 upper limit of normal (ULN) (< 3 ULN if Gilbert’s disease)
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x ULN (=< 5.0 x ULN if liver metastases present)
Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN if bone or liver metastases present)

PRIMARY OBJECTIVE:

I. To estimate the safety and tolerability (adverse event rate) of the combination of palbociclib and letrozole or fulvestrant in adults age 70 or older with estrogen receptor-positive, HER2-negative metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To describe the full toxicity profile including all grade 2 and higher adverse events (per National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0), specifically estimating the rate of grade 2 and higher myelosuppression (neutropenia, leukopenia, thrombocytopenia, and anemia), neutropenic fever, gastrointestinal (GI) side effects (nausea, diarrhea, decreased appetite, vomiting, mucositis-oral), fatigue, neuropathy, and thromboembolism.

II. To describe rates of dose reductions, dose holds, and hospitalizations.

III. To estimate median time to treatment failure, including progression free survival and overall survival.

IV. To estimate the rate of adherence to palbociclib, letrozole and fulvestrant.

V. To explore factors other than chronologic age that can affect toxicity rates as identified using a cancer-specific geriatric assessment.

VI. To describe the results of the Was It Worth It (WIWI) Questionnaire and the Overall Treatment Utility (OTU).

VII. To determine the degree of agreement between patient-reported adverse events (AEs) using Patient Reported Outcomes (PRO)-CTCAE measures and those reported using traditional collections for AEs.

VIII. To examine the association between sarcopenia and the development of toxicity and adverse events.

CORRELATIVE SCIENCE OBJECTIVES:

I. To explore the association between baseline chronic inflammatory mediator levels and development of adverse events.

II. To explore the association between baseline chronic inflammatory mediator levels and treatment modification.

III. To explore the association between baseline chronic inflammatory mediator levels and baseline physical function as assessed by the cancer-specific geriatric assessment.

IV. To explore the association between baseline chronic inflammatory mediator levels and decline in physical function as assessed by the cancer-specific geriatric assessment.

V. To explore the correlation between inherited single nucleotide polymorphisms (SNPs) in cell cycle pathway genes and in genes that metabolize palbociclib and treatment efficacy and toxicity (clinical outcomes) in elderly patients undergoing combined endocrine therapy plus palbociclib for estrogen receptor positive, HER2 negative metastatic breast cancer.

VI. To explore whether genes in CYP19A, CYP2A6 and ESR1 will also correlate with treatment efficacy and toxicity (clinical outcomes) in elderly patients undergoing combined endocrine therapy plus palbociclib for estrogen receptor positive, HER2 negative metastatic breast cancer.

VII. To refine a population pharmacokinetic model using nonlinear mixed effects modeling (NONMEM) for palbociclib based on that of Sun and Wang (European Society for Medical Oncology [ESMO] poster presentation 462P 2014) taking account of relevant intrinsic and extrinsic factors.

VIII. To determine the intrapatient and interpatient variability of palbociclib exposure (area under the curve [AUC]) in older breast cancer patients receiving palbociclib plus letrozole/fulvestrant.

IX. To explore the exposure (AUC/maximum concentration [Cmax]) toxicity (neutropenia, thrombocytopenia) relationship for palbociclib when combined with letrozole/fulvestrant in older breast cancer patients.

OUTLINE:

Patients receive palbociclib orally (PO) once daily (QD) on days 1-21. Patients also receive letrozole PO QD on days 1-28 or fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles per Doctor of Medicine (MD) discretion. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients additionally undergo blood sample collection, bone scan, computed tomography (CT) or positron emission tomography (PET) on study.

After completion of study treatment, patients are followed up every year for up to 5 years.

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Testing the Effects of Palbociclib and Fulvestrant or Letrozole for Patients 70 years of Age and Older with Metastatic Breast Cancer

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