A Study of Palbociclib in Combination With Fulvestrant or Tamoxifen as Treatment for Metastatic Breast Cancer

Palbociclib in Combination With Fulvestrant or Tamoxifen as Treatment for Hormone Receptor Positive Metastatic Breast Cancer Previously Exposed to Inhibitors of the PI3K Pathway: A Phase II Study With Pharmacodynamics Markers

This phase II trial studies the side effects of palbociclib when given together with fulvestrant or tamoxifen citrate in treating patients with hormone receptor positive breast cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or 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. Hormone therapy using fulvestrant or tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving palbociclib together with fulvestrant or tamoxifen citrate may work better in treating hormone receptor positive breast cancer.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer; Hormone Receptor Positive
• Intervention / Treatment: Drug: Palbociclib; Drug: Tamoxifen; Drug: Fulvestrant

Detailed Description

Patients will be randomly allocated in a 1:1 ratio to take either 100 mg or 125 mg of palbociclib. Randomized treatment assignments will be made by permuted blocks, generated by our collaborating statistician at Dana-Farber Cancer Institute.

PRIMARY OBJECTIVES:

I. To evaluate the incidence of grade 3/4 neutropenia in patients with hormone receptor positive (HR+) advanced breast cancer previously exposed to chemotherapy, treated with fulvestrant or tamoxifen (tamoxifen citrate) in combination with palbociclib at a dose of 100mg or 125mg.

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival with 100 mg and 125 mg dosing of palbociclib.

II. To evaluate inhibition of retinoblastoma (RB) phosphorylation in tumor and in skin at 100 mg and 125 mg dosing of palbociclib.

III. To evaluate the correlation between inhibition of RB phosphorylation in skin and tumor.

IV. To evaluate the correlation between inhibition of RB phosphorylation and progression-free survival (PFS).

V. To evaluate the objective response and clinical benefit rate of palbociclib given at 100 mg or 125 mg.

VI. To evaluate the toxicity associated with palbociclib given at 100 mg and 125 mg in combination with fulvestrant or tamoxifen.

VII. To evaluate markers of resistance to palbociclib and fulvestrant or tamoxifen in circulating plasma tumor deoxyribonucleic acid (DNA) (ptDNA).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive low-dose palbociclib orally (PO) on days 1-21. Patients also receive tamoxifen citrate PO on days 1-28 or fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and then on day 1 only in subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive high-dose palbociclib PO on days 1-21. Patients also receive tamoxifen citrate PO on days 1-28 or fulvestrant IM on days 1 and 15 of cycle 1 and then on day 1 only in subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Tennessee
    • Nashville, Tennessee, United States, 37240
      • Vanderbilt University
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically proven diagnosis of breast cancer with evidence of metastatic or locally advanced disease, not amenable to resection or radiation therapy with curative intent.
• Patients 18 years of age or older, Female patients should be either:
• Postmenopausal, as defined by at least one of the following criteria:
• Age >=60 years;
• Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause;
• Documented bilateral oophorectomy;
• Medically confirmed ovarian failure.

OR

• Pre/peri-menopausal, ie, not meeting the criteria for being postmenopausal who are also receiving ongoing treatment with Luteinizing hormone-releasing hormone (LHRH) agonists (goserelin or leuprolide). The first injection should occur at least two weeks before study start.
• Documentation of ER-positive and/or PR-positive tumor (≥1% positive stained cells) based on most recent tumor biopsy (unless bone-only disease,discuss with study PI if results are discordant) utilizing an assay consistent with local standards.
• Documented human epidermal growth factor receptor 2 negative (HER2-) tumor based on local testing on most recent tumor biopsy: HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio <2 or for single probe assessment a HER2 copy number <4.
• Must have received prior treatment with an Mechanistic target of rapamycin (mTOR) or phosphatidylinositol 3-kinase (PI3K) inhibitor
• Up to 2 prior lines of chemotherapy are allowed in the metastatic setting.
• Any number of lines of prior hormone therapy are allowed
• Patients with clear progression on either tamoxifen or fulvestrant should receive the alternate agent. Patients with clear progression on both drugs are not eligible.
• Ability to have a skin and tumor biopsy. Patients without accessible tumor for biopsy will be considered on a case by case basis.
• Patients who cannot be biopsied will not be replaced (although up to 5 ineligible/inevaluable patients can be replaced)
• A patient without biopsy amenable tumor must be cleared by the PI of the study; up to 10 patients without biopsy amenable tumor will be allowed in each arm of the study.
• Patients without accessible tumor for biopsy must provide archived tumor from the most recent biopsy available
• Bone marrow, hepatic, and renal function as follows:

Adequate bone marrow function:

• leukocytes > 2500/mL
• absolute neutrophil count > 1,000/mL
• platelets > 100,000/mL"

Adequate hepatic function:

• total bilirubin within normal institutional limits (unless Gilbert's disease with elevated indirect bilirubin only)
• aspartate aminotransferase (AST) / (serum glutamic-oxaloacetic transaminase (SGOT) < 2.5 X institutional upper limit of normal
• alanine aminotransferase (ALT) / (serum glutamic-pyruvic transaminase (SGPT) < 2.5 X institutional upper limit of normal
• Adequate renal function:
• creatinine within normal institutional limits
• Measurable or evaluable disease as defined by RECIST version 1.1. Tumor lesions previously irradiated or subjected to other loco-regional therapy will only be deemed measurable if progression at the treated site after completion of therapy is clearly documented.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Resolution of acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade <=1 (except alopecia)
• Ability to understand a written informed consent document, and the willingness to sign it

Exclusion Criteria:

• Prior treatment with any cyclin-dependent kinase (CDK) inhibitor, and/or both fulvestrant and tamoxifen in the metastatic setting with clear progression.
• Patients with advanced/metastatic, symptomatic, visceral spread, at risk of life-threatening complications in the short term by investigator assessment.
• Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization .
• Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers (for examples, see the prohibited medications section), and drugs that are known to prolong the QT interval. See prohibited meds in appendix 5.
• Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 2 weeks before randomization.
• Any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
• QTc interval >480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.

QTc (Bazett) = QT/√RR

• Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, symptomatic congestive heart failure, or cerebrovascular accident excluding transient ischemic attack.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of palbociclib, such as history of GI surgery with may result in intestinal blind loops and patients with clinically significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhea of CTCAE v4.0 Grade >1.
• Prior hematopoietic stem cell or bone marrow transplantation.
• Abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants (that cannot be safely held for biopsy) that would preclude tumor and skin biopsies.
• For fulvestrant: Ongoing anticoagulation that would preclude an IM injection
• For tamoxifen: Documented hypercoagulable state not receiving anticoagulation
• Known or possible hypersensitivity to palbociclib (CTCAE v4.0).
• Known human immunodeficiency virus infection.
• Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Participation in other studies involving investigational drug(s) (Phases 1-4) within 2 weeks before randomization the current study.
• Women should not become pregnant or breastfeed whilst on this study. Birth control methods are acceptable and will be discussed with study participants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Palbociclib 100mg and, fulvestrant or tamoxifen; Palbociclib dose 100mg, and either fulvestrant (500 mg IM on days 1 and 15 in the first 28 days, then every 28 days thereafter) or tamoxifen (20 mg PO daily by physician choice)	Drug: Palbociclib; Given orally (PO); Other Names: Ibrance; Drug: Tamoxifen; Given orally (PO); Other Names: Tamoxifen 20mg; Drug: Fulvestrant; Given by intramuscular (IM) injection.; Other Names: Faslodex
Experimental: Palbociclib 125mg and, fulvestrant or tamoxifen; Palbociclib dose 125mg and either fulvestrant (500 mg IM on days 1 and 15 in the first 28 days, then every 28 days thereafter) or tamoxifen (20 mg PO daily by physician choice)	Drug: Palbociclib; Given orally (PO); Other Names: Ibrance; Drug: Tamoxifen; Given orally (PO); Other Names: Tamoxifen 20mg; Drug: Fulvestrant; Given by intramuscular (IM) injection.; Other Names: Faslodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Grade 3 or 4 Neutropenia	Grade 3/4 neutropenia as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 in patients with prior exposure to 1-3 lines of chemotherapy for metastatic breast cancer	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS defined as the interval from study entry to the first documented evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter (SLD) of target lesions, taking as reference the smallest sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or the appearance of one or more new lesions. Patients who remain progression-free at the time of analysis will be censored at their last date of follow-up.	Up to 24 months
Proportion of Participants With Demonstrated Clinical Benefit	Defined as the proportion of patients whose best overall response, according to RECIST, is either complete response (CR), a partial response (PR) or stable disease (SD) at 24 weeks. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.	24 weeks
Proportion of Participants With an Objective Response	Defined as the proportion of patients whose best overall response, according to RECIST, is either complete response (CR), a partial response (PR) at 24 weeks. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.	24 weeks
Median Change in Percent Positive Cells From Baseline of Ki-67	Median change in percent positive cells of Ki-67 from baseline will be reported with IQR	Up to 24 months
Median Change in Percent Positive Cells From Baseline of Total-Rb	Median change in percent positive cells of Total-Rb from baseline will be reported with interquartile range (IQR)	Up to 24 months
Median Change in Percent Positive Cells From Baseline of pS780-Rb	Median change in percent positive cells of pS780-Rb from baseline will be reported with IQR	Up to 24 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Dana-Farber Cancer Institute; Translational Breast Cancer Research Consortium
• Investigators: Principal Investigator: Hope S Rugo, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2015
• Primary Completion (Actual): January 31, 2021
• Study Completion (Actual): January 31, 2021

Study Registration Dates

• First Submitted: February 10, 2015
• First Submitted That Met QC Criteria: March 9, 2015
• First Posted (Estimate): March 10, 2015

Study Record Updates

• Last Update Posted (Actual): March 16, 2022
• Last Update Submitted That Met QC Criteria: February 16, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Estrogen Receptor Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Fulvestrant; Palbociclib; Tamoxifen
• Other Study ID Numbers: 147522; NCI-2015-01791 (Registry Identifier: Clinical Trials Reporting Program)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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.: No