Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib

Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib: A Randomized Pilot Trial With ESR1 Mutation Tested in Circulating Tumor DNA.

To assess longitudinal changes in allele frequency of ESR1 mutation in plasma in patients treated with Fulvestrant plus palbociclib compared to tamoxifen plus palbociclib

Study Overview

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

Detailed Description

The primary objectives are to assess longitudinal changes in allele frequency of ESR1 mutation in plasma in patients treated with Fulvestrant plus palbociclib compared to tamoxifen plus palbociclib.

Patients with ER+ breast cancer who had 1 to 3 prior lines of endocrine therapy and up to one line of chemotherapy for MBC, excluding fulvestrant and tamoxifen, will be randomized in a 1:1 ratio to receive fulvestrant 500mg IM Q28 days with one extra dose on Day15 of the first cycle (as a loading dose) plus palbociclib 125mg/day PO on a 21 days on/7 days off schedule or tamoxifen 20mg PO daily plus palbociclib 125mg/day PO on a 21 days on/7 days off schedule.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital UPMC

Participation Criteria

Eligibility Criteria

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

Description

For inclusion in the study subjects should fulfill the following criteria:

1. Signed informed consent

2. Patients must have histologically or cytologically confirmed invasive breast cancer that is ER+ (>1% staining) with radiographical or clinical evidence of metastatic disease

   a. Measurable and/or non-measurable disease

3. Prior therapies:

   1. Patients must have previously received an aromatase inhibitor in the adjuvant, neo-adjuvant or metastatic setting.
   2. Patients must have previously received palbociclib in the adjuvant, neo- adjuvant or metastatic setting. If patient is currently taking palbociclib at time of screening for the trial they may continue taking palbociclib.
   3. The minimum duration of AI in the adjuvant setting is 2 years.
   4. There is no minimum duration of AI in the metastatic setting or neoadjuvant setting.
   5. Patients may have been previously treated with an mTOR inhibitor or other investigational agent in addition to an aromatase inhibitor.
   6. Prior treatment with tamoxifen is allowed in the adjuvant setting provided that it was followed by a minimum of 2 years of an AI.
4. Brain metastasis is allowed if previously treated, stable and off steroids for a minimum of 56 days
5. Age > 18 years
6. Male or female breast cancer is allowed

7. Patients may be pre- or post-menopausal; pre-menopausal patients must be on ovarian suppression and must be adequately suppressed on LHRH agonists with estradiol levels in the post-menopausal range

   a. Premenopausal patients cannot be pregnant and must agree to adequate birth control in addition to ovarian suppression. Agreement by the patient and/or partner to use highly effective, nonhormonal form of contraception or two effective forms of non-hormonal contraception. Contraception use should continue during the duration of study treatment and for at least 6 months after the last dose of study treatment.

8. ECOG performance status 0-2

9. Adequate bone marrow function as indicated by the following, within 14 days of enrollment:

   1. ANC ≥ 1500 cells/mm3
   2. Platelets ≥ 100,000 cells/ mm3
   3. Hemoglobin ≥ 9 g/dL

10. Adequate liver function, as indicated by the following, within 14 days of enrollment.

    1. Total bilirubin 1.5 upper limit of normal (ULN)
    2. AST 1.5 ULN
    3. ALT ≤ 2.5 ULN
    4. Alkaline phosphatase ≤ 2.5 ULN with the following exception; ALP ≤ 5× ULN in patients with bone metastases.
11. Adequate hemostatic function as determined by PT, INR and aPTT < 1.5× ULN (unless on therapeutic coagulation, in which case the adequate level of anticoagulation will be determined by the investigator).
12. Adequate renal function, as indicated by creatinine ≤ 1.5 ULN.

Subjects should not enter the study if any of the following exclusion criteria are fulfilled

1. Prior therapy exclusions:

   1. Prior therapy with fulvestrant
   2. Prior therapy with tamoxifen in the metastatic setting
   3. More than 3 prior lines of endocrine therapy in the metastatic setting
   4. More than one prior line of chemotherapy in the metastatic setting
2. Washout of 2 weeks is required for aromatase inhibitors; washout of 4 weeks is required for, everolimus or other biological agents with the exception of Palbociclib.
3. Patients must not be receiving any other investigational agent.
4. Patients with symptomatic, untreated CNS metastases are not eligible.
5. Patients may not have significant concurrent illness, infection, pregnancy or lactation
6. Patients must not have a different active malignancy, except for skin basal cell carcinoma, skin squamous cell carcinoma and cervical intraepithelial neoplasia.

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
Active Comparator: Arm A; fulvestrant administered 500mg IM Q28 days plus palbociclib125mg/day PO on a 21 days on/7 days off schedule	Drug: Fulvestrant; 500mg IM Q28 days; Drug: Palbociclib; Tamoxifen or Fulvestrant plus palbociclib125mg/day PO on a 21 days on/7 days off schedule
Active Comparator: Arm B; Tamoxifen is administered orally, at a dose of20mg PO Qdaily plus palbociclib125mg/day PO on a 21 days on/7 days off schedule	Drug: Palbociclib; Tamoxifen or Fulvestrant plus palbociclib125mg/day PO on a 21 days on/7 days off schedule; Drug: Tamoxifen; 20mg PO Qdaily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	The duration of time from time of randomization to time of progression or death, whichever occurs first. Disease progression (PD) as defined by RECIST v1.1: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The progression of non-target lesions or the appearance of one or more new lesions is also considered progression. PFS for a subject without an event will be censored on the date of last tumor assessment. If an interval of 6 months passes without a tumor assessment, PFS will be censored at the time of the earlier tumor assessment, even if an event (progressive disease or death) is later observed.	Up to 3 years and 351 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response (BOR)	The number of patients experiencing Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) per RECIST v1.1; Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): (CR) is disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; (SD) is neither sufficient decrease (target lesions) to qualify as a PR or sufficient increase to qualify as PD. Incomplete Response/Stable Disease (SD) is the persistence of one or more non-target lesions. (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions compared to baseline sum of target lesions, or any new lesions. It also includes the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.	Up to 5 years
6-Month Clinical Benefit Rate (CBR)	The number of patients experiencing Complete Response (CR), Partial Response (PR), or Stable Disease (SD) per RECIST v1.1; Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): (CR) is disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; (SD) is neither sufficient decrease (target lesions) to qualify as a PR or sufficient increase to qualify as PD. Incomplete Response/Stable Disease (SD) is the persistence of one or more non-target lesions.	Up to 6 months
Clinical Benefit Rate (CBR)	The number of patients experiencing Complete Response (CR), Partial Response (PR), or Stable Disease (SD) per RECIST v1.1; Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): (CR) is disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; (SD) is neither sufficient decrease (target lesions) to qualify as a PR or sufficient increase to qualify as PD. Incomplete Response/Stable Disease (SD) is the persistence of one or more non-target lesions.	Up to 5 years
Overall Survival (OS)	The median length of time from the start of treatment that patients remain alive.	Up to 5 years

Collaborators and Investigators

• Sponsor: Shannon Puhalla
• Investigators: Principal Investigator: Shannon Puhalla, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2018
• Primary Completion (Actual): April 12, 2022
• Study Completion (Actual): April 30, 2024

Study Registration Dates

• First Submitted: September 1, 2016
• First Submitted That Met QC Criteria: September 21, 2016
• First Posted (Estimated): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): September 23, 2024
• Last Update Submitted That Met QC Criteria: May 24, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: ESR1 mutation
• 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: HCC 16-015

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