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

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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:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Description
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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.

Condition or disease Intervention/treatment Phase
Estrogen Receptor-positive Breast Cancer HER2/Neu Negative Stage IV Breast Cancer AJCC v6 and v7 Drug: Palbociclib Drug: Letrozole Drug: Fulvestrant Other: Questionnaire Administration Other: Quality-of-Life Assessment Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 93 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 15, 2018
Actual Primary Completion Date : September 8, 2020
Estimated Study Completion Date : August 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
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.
 Drug: Palbociclib
Given PO

Drug: Letrozole
Given PO

Drug: Fulvestrant
Given IM

Other: Questionnaire Administration
Ancillary studies

Other: Quality-of-Life Assessment
Ancillary studies


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Overall Survival (OS) [ Time Frame: Up to 5 years ]
    Distributions of overall survival (OS) times will be estimated using Kaplan-Meier methodology.

  8. 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.

  9. 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.

  10. 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.


Eligibility Criteria
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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03633331


Locations
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Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Investigators
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Study Chair: Mina Sedrak, MD, MS City of Hope Comprehensive Cancer Center
  Study Documents (Full-Text)

Documents provided by Alliance for Clinical Trials in Oncology:
Study Protocol, Statistical Analysis Plan, and Informed Consent Form  [PDF] May 29, 2020

More Information
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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT03633331    
Other Study ID Numbers: A171601
NCI-2017-01596 ( Registry Identifier: NCI Clinical Trial Reporting Program )
First Posted: August 16, 2018    Key Record Dates
Results First Posted: October 15, 2021
Last Update Posted: October 15, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Fulvestrant
Palbociclib
Antineoplastic Agents
Aromatase Inhibitors
 Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Protein Kinase Inhibitors