Palbociclib and Letrozole or Fulvestrant in Treating Patients With Estrogen Receptor Positive, HER2 Negative Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT03633331
• Recruitment Status: Active, not recruiting
• First Posted: August 16, 2018
• Results First Posted: October 15, 2021
• Last Update Posted: October 15, 2021
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: August 7, 2018
• First Posted Date: August 16, 2018
• Results First Submitted Date: September 17, 2021
• Results First Posted Date: October 15, 2021
• Last Update Posted Date: October 15, 2021
• Actual Study Start Date: August 15, 2018
• Actual Primary Completion Date: September 8, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 17, 2021)

Incidence of Adverse Events [ Time Frame: 6 months ]

Defined as the proportion of patients with documentation of grade 3 - 5 toxicity (regardless of attribution using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 criteria). A 95% binomial confidence interval for single proportions will be constructed for the severe toxicity rate during treatment. Univariate relationships between the primary endpoint and various pre-treatment patient characteristics such as anemia, self-assessed functional status, or social support will be described via cross-tabulation and Fisher's exact testing. Exploratory logistic regression modeling, with limited generalizability due to the modest sample size, will be used to assess the relative contributions of these variables impact the likelihood of developing a severe toxicity during treatment. The strength of this association will be expressed in terms of an odds ratio and its associated 95% confidence interval.

Original Primary Outcome Measures (submitted: August 15, 2018)

Incidence of adverse events [ Time Frame: Up to 1 year ]

Defined as the proportion of patients with documentation of grade 3 - 5 toxicity (regardless of attribution using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 criteria). A 95% binomial confidence interval for single proportions will be constructed for the severe toxicity rate during treatment. Univariate relationships between the primary endpoint and various pre-treatment patient characteristics such as anemia, self-assessed functional status, or social support will be described via cross-tabulation and Fisher's exact testing. Exploratory logistic regression modeling, with limited generalizability due to the modest sample size, will be used to assess the relative contributions of these variables impact the likelihood of developing a severe toxicity during treatment. The strength of this association will be expressed in terms of an odds ratio and its associated 95% confidence interval.

Current Secondary Outcome Measures (submitted: September 17, 2021)

• Incidence of Drug Toxicities - Measured by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v. 5.0 [ Time Frame: Up to 1 year ]
  Measured by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v. 5.0
• Dose Reduction, Dose Hold, and Hospitalization Reasons [ Time Frame: Up to 1 year ]
  A 95% binomial confidence interval for single proportions will be constructed for the percentage of patients that had at least one dose reduction, dose hold, or hospitalization within the first year of treatment.
• Time to Treatment Failure (and Reason for Coming Off Study - Toxicity, Patient Preference, Progression) [ Time Frame: Up to 5 years ]
  Distributions time to treatment failure will be estimated using Kaplan-Meier methodology. Treatment failure is defined as a severe adverse event, disease progression or patient refusal to continue assigned treatment. Any reason that treatment is discontinued to time to treatment failure and not censor patients will be included. The reason for treatment discontinuation will be captured.
• Palbociclib Adherence Rate [ Time Frame: Up to 12 weeks ]
  Patients to be included in the analysis cohort will be those patients who have taken one or more doses of the study treatment. Those patients will be considered adherent to study treatment. For each of the first 3 cycles, an estimate of the proportion of patients who meet the criteria for adherence and its corresponding 95% confidence interval will be determined.
• Response Rate as Determined by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 1 year ]
  The response rate is defined as the proportion of patients whose disease status met Response Evaluation Criteria in Solid Tumors (RECIST) criteria for complete response (CR) or partial response (PR) on 2 consecutive evaluations at least 8 weeks apart. A 95% binomial confidence interval for the response rate will be constructed.
• Progression Free Survival (PFS) [ Time Frame: From start of treatment to the first of the following disease events: local/regional/distant recurrence, invasive contralateral breast disease, second primary or death due to any cause, assessed up to 5 years ]
  Distributions of progression free survival (PFS) times will be estimated using Kaplan-Meier methodology.
• Overall Survival (OS) [ Time Frame: Up to 5 years ]
  Distributions of overall survival (OS) times will be estimated using Kaplan-Meier methodology.
• Overall Treatment Utility (OTU) Results [ Time Frame: Up to 1 year ]
  OTU is a novel composite endpoint developed by investigators of the FOCUS2 trial to assess the outcome of palliative chemotherapy. The patient will be given either an overall score of "good", "intermediate", or "poor". A 95% binomial confidence interval will be constructed for the percentage of patients that scored "good" on the OTU.
• Sarcopenia Analysis [ Time Frame: Up to 1 year ]
  Will examine variables associated with skeletal muscle loss during treatment and whether skeletal muscle loss during treatment is associated with the presence of grade 3-5 toxicity and adverse events. Sarcopenia will be treated as a binary variable using the Skeletal Muscle Index (SMI) (SMI < 41 cm^2/m^2 vs. SMI > 41 cm^2/m^2) and differences in grades chemotherapy toxicity and adverse events will be analyzed using two group t-tests and fisher's exact test. The number of patients with and without sarcopenia grouped by patients with or without grade 3+ Adverse Events (AE's) will be also be reported.
• Quality of Life as Measured by the European Quality of Life Five Dimension Three Level Questionnaire (EQ-5D-3L) [ Time Frame: Up to 1 year ]
  European Quality of Life Five Dimension Three Level Questionnaire (EQ-5D-3L) is comprised of 5 dimensions. Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, no problems, some problems, extreme problems. The EQ-5D-3L can be converted to a single summary index. The median and range of this total score will be reported.

Original Secondary Outcome Measures (submitted: August 15, 2018)

• Incidence of drug toxicities - Measured by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v. 5.0 [ Time Frame: Up to 1 year ]
  Measured by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v. 5.0
• Dose reduction, dose hold, and hospitalization reasons [ Time Frame: Up to 1 year ]
  A 95% binomial confidence interval for single proportions will be constructed for the percentage of patients that had at least one dose reduction, dose hold, or hospitalization within the first year of treatment.
• Time to treatment failure (and reason for coming off study - toxicity, patient preference, progression) [ Time Frame: Up to 5 years ]
  Distributions time to treatment failure will be estimated using Kaplan-Meier methodology. Treatment failure is defined as a severe adverse event, disease progression or patient refusal to continue assigned treatment. Any reason that treatment is discontinued to time to treatment failure and not censor patients will be included. The reason for treatment discontinuation will be captured.
• Palbociclib adherence rate [ Time Frame: Up to 12 weeks ]
  Patients to be included in the analysis cohort will be those patients who have taken one or more doses of the study treatment. Those patients will be considered adherent to study treatment. For each of the first 3 cycles, an estimate of the proportion of patients who meet the criteria for adherence and its corresponding 95% confidence interval will be determined.
• Response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 1 year ]
  The response rate is defined as the proportion of patients whose disease status met Response Evaluation Criteria in Solid Tumors (RECIST) criteria for complete response (CR) or partial response (PR) on 2 consecutive evaluations at least 8 weeks apart. A 95% binomial confidence interval for the response rate will be constructed.
• Progression free survival (PFS) [ Time Frame: From start of treatment to the first of the following disease events: local/regional/distant recurrence, invasive contralateral breast disease, second primary or death due to any cause, assessed up to 5 years ]
  Distributions of progression free survival (PFS) times will be estimated using Kaplan-Meier methodology.
• Overall survival (OS) [ Time Frame: Up to 5 years ]
  Distributions of overall survival (OS) times will be estimated using Kaplan-Meier methodology.
• Overall Treatment Utility (OTU) results [ Time Frame: Up to 1 year ]
  OTU is a novel composite endpoint developed by investigators of the FOCUS2 trial to assess the outcome of palliative chemotherapy. The patient will be given either an overall score of "good", "intermediate", or "poor". A 95% binomial confidence interval will be constructed for the percentage of patients that scored "good" on the OTU.
• Sarcopenia analysis [ Time Frame: Up to 1 year ]
  Will examine variables associated with skeletal muscle loss during treatment and whether skeletal muscle loss during treatment is associated with the presence of grade 3-5 toxicity and adverse events. Sarcopenia will be treated as a binary variable using the Skeletal Muscle Index (SMI) (SMI < 41 cm^2/m^2 vs. SMI > 41 cm^2/m^2) and differences in grades chemotherapy toxicity and adverse events will be analyzed using two group t-tests and fisher's exact test. The number of patients with and without sarcopenia grouped by patients with or without grade 3+ Adverse Events (AE's) will be also be reported.
• Quality of life as measured by the European Quality of Life Five Dimension Three Level Questionnaire (EQ-5D-3L) [ Time Frame: Up to 1 year ]
  European Quality of Life Five Dimension Three Level Questionnaire (EQ-5D-3L) is comprised of 5 dimensions. Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, no problems, some problems, extreme problems. The EQ-5D-3L can be converted to a single summary index. The median and range of this total score will be reported.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Palbociclib and Letrozole or Fulvestrant in Treating Patients With Estrogen Receptor Positive, HER2 Negative Metastatic Breast Cancer
• Official Title: A Phase II Trial Assessing the Tolerability of Palbociclib in Combination With Letrozole or Fulvestrant in Patients Aged 70 and Older With Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer
• Brief Summary: This phase II trial studies the side effects and how well palbociclib and letrozole or fulvestrant works in treating patients aged 70 years and older with estrogen receptor positive, HER2 negative breast cancer that has spread to other places in the body. 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. Giving palbociclib and letrozole or fulvestrant may work better in treating patients with breast cancer. The trial will explore factors other than chronologic age that can affect toxicity rates as identified using a cancer-specific geriatric assessment.

Detailed Description

PRIMARY OBJECTIVES:

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 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.

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 course 1 and on day 1 of subsequent courses per Doctor of Medicine (MD) discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Estrogen Receptor-positive Breast Cancer
• HER2/Neu Negative
• Stage IV Breast Cancer AJCC v6 and v7

Intervention

• Drug: Palbociclib
  Given PO
• Drug: Letrozole
  Given PO
• Drug: Fulvestrant
  Given IM
• Other: Questionnaire Administration
  Ancillary studies
• Other: Quality-of-Life Assessment
  Ancillary studies

Study Arms

Experimental: Treatment (palbociclib, letrozole or fulvestrant)

Patients receive palbociclib PO QD on days 1-21. Patients also receive letrozole PO QD on days 1-28 or fulvestrant IM on days 1 and 15 of course 1 and on day 1 of subsequent courses per MD discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions:

• Drug: Palbociclib
• Drug: Letrozole
• Drug: Fulvestrant
• Other: Questionnaire Administration
• Other: Quality-of-Life Assessment

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 4, 2020): 93
• Original Estimated Enrollment (submitted: August 15, 2018): 88
• Estimated Study Completion Date: August 2024
• Actual Primary Completion Date: September 8, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
• 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 70 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03633331
• Other Study ID Numbers: A171601; NCI-2017-01596 ( Registry Identifier: NCI Clinical Trial Reporting Program )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Mina Sedrak, MD, MS; City of Hope Comprehensive Cancer Center

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: September 2021