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Comparison of Efficacy and Tolerability of Fulvestrant+Placebo vs Fulvestrant+Palbociclib as First Line Therapy for Postmenopausal Women With HR+ Metastatic BC Treated With 5 Years of Hormonal Therapy Remaining Disease Free More Than 12 Months After Completion or Have de Novo Metastatic Disease (FLIPPER)

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ClinicalTrials.gov Identifier: NCT02690480
Recruitment Status : Recruiting
First Posted : February 24, 2016
Last Update Posted : January 16, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group

Brief Summary:

This is an international, multicentre, double-blind, controlled, randomized phase II study comparing the efficacy and safety of fulvestrant in combination with palbociclib versus fulvestrant plus placebo in postmenopausal women with HR-positive/HER2-negative metastatic breast cancer who have received ≥5 years of endocrine therapy in the adjuvant setting as treatment for early disease and remained disease free for > 12 months following its completion or have "de novo" metastatic disease. Patients must have at least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI or plan x-ray. Patients with bone-only disease must have a lytic or mixed (lytic + blastic) lesion, which has not been previously irradiated and can be accurately assessed by CT/MRI or x-ray. Approximately 190 patients will be randomized 1:1 between the experimental arm (approximately 95 patients treated with fulvestrant plus palbociclib) and the control arm (approximately 95 patients treated with fulvestrant plus placebo).

Primary Objective:

• To compare the efficacy of fulvestrant in combination with palbociclib versus fulvestrant plus placebo in terms of the rate of Progression-Free Survival (PFS) at 1 year in postmenopausal women with HR-positive/HER2-negative metastatic breast cancer previously treated with endocrine therapy for at least 5 years and remaining disease free for more than 12 months following its completion or have "de novo" metastatic disease


Condition or disease Intervention/treatment Phase
Breast Neoplasms Drug: PD-0332991 (Palbociclib) Drug: Fulvestrant Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 190 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Parallel-group, Multicentre, Phase II Study to Compare the Efficacy and Tolerability of Fulvestrant (FaslodexTM) 500mg With Placebo and Fulvestrant (FaslodexTM) 500mg in Combination With PD-0332991 (Palbociclib) as First Line Treatment for Postmenopausal Women With Hormone Receptor-positive Metastatic Breast Cancer, Who Have Completed at Least 5 Years of Adjuvant Endocrine Therapy and Remained Disease Free for More Than 12 Months Following Its Completion or Have "de Novo" Metastatic Disease. "The FLIPPER Study"
Actual Study Start Date : February 2016
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: PD-0332991(Palbociclib)+fulvestrant(FaslodexTM)
Fulvestrant 500mg, on days 1, 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 day cycle (±3 days) in combination with Palbociclib, 125 mg, orally once daily from day 1 to day 21 followed by 7 days off treatment on every 28 days cycles.
Drug: PD-0332991 (Palbociclib)

Palbociclib, 125 mg, orally once daily from day 1 to day 21 followed by 7 days off treatment on every 28 days cycles.

Patients will continue to receive their assigned treatment until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first

Other Name: Ibrance

Drug: Fulvestrant

Fulvestrant 500mg, two 5ml intramuscular injections (one in each buttock), on days 1, 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 day cycle (±3 days)

Patients will continue to receive their assigned treatment until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first

Other Name: Faslodex

Active Comparator: Placebo+fulvestrant(FaslodexTM)
Fulvestrant 500mg on days 1, 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 day cycle (±3 days) in combination with Placebo orally once daily from day 1 to day 21 followed by 7 days off treatment on every 28 days cycles.
Drug: Fulvestrant

Fulvestrant 500mg, two 5ml intramuscular injections (one in each buttock), on days 1, 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 day cycle (±3 days)

Patients will continue to receive their assigned treatment until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first

Other Name: Faslodex

Drug: Placebo

Placebo orally once daily from day 1 to day 21 followed by 7 days off treatment on every 28 days cycles.

Patients will continue to receive their assigned treatment until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs firs





Primary Outcome Measures :
  1. Efficacy in terms of the rate of Progression-Free Survival (PFS) [ Time Frame: at 1 year ]
    assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by the investigator


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: an average of 40-44 months since FPFV (approximately Ago2019) ]
    assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by the investigator

  2. Objective Response Rate (ORR) [ Time Frame: at 1 year and to be updated with further analyses ]
    Complete Response (CR) plus Partial Response (PR) according to RECIST version 1.1

  3. Clinical Benefit Rate (CBR) [ Time Frame: at 1 year and to be updated with further analyses ]
    CR plus PR plus stable disease (SD) lasting ≥ 24 weeks (+/- 2 weeks) according to RECIST version 1.1.

  4. Overall Survival (OS). [ Time Frame: an average of 40-44 months since FPFV(approximately Ago2019). A formal analysis will be performed when at least 60% of patients have died (2021) ]
  5. 1 year and 2 year survival probabilities [ Time Frame: 1 year and 2 year ]
  6. Incidence of adverse events occurring during the study, and their relatedness to the study drug/medications (safety and tolerability). [ Time Frame: at 1 year and to be updated with further analyses ]
    Safety will be assessed by standard clinical and laboratory tests. Adverse events will be graded according to NCI-CTCAE version 4.0

  7. Patient reported outcomes of health-related quality of life based on EORTC QLQ-C30 Global Health Status/Quality of Life and Physical Function [ Time Frame: at 1 year and to be updated with further analyses ]
    Generic aspects of quality of life will be assessed. Changes (mean score) from baseline and time to deterioration will be analyzed.Health Status/QoL and Physical Function and EORTC QLQ-BR23 Breast Module from baseline

  8. Patient reported outcomes of health-related quality of life based on EORTC QLQ-BR23 Breast Module. [ Time Frame: at 1 year and to be updated with further analyses ]
    Disease-specific treatment measurements will be assessed. Changes (mean score) from baseline and time to deterioration will be analyzed.


Other Outcome Measures:
  1. Biomarker analyses [ Time Frame: Up to 5 years ]

    Identify promising biomarkers of response to fulvestrant plus palbociclib and fulvestrant plus placebo.

    • Identify promising biomarkers of primary resistance to fulvestrant plus palbociclib and fulvestrant plus placebo.
    • Identify promising biomarkers of acquired resistance to fulvestrant plus palbociclib and fulvestrant plus placebo.
    • Identify promising biomarkers to monitor response to fulvestrant plus palbociclib and fulvestrant plus placebo



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
  2. Availability of a tumor tissue sample, archival (primary tumour) or from the metastatic lesions (preferable) for the central ER, PgR and HER2 testing.
  3. Histological/cytological confirmation of breast cancer with evidence of metastatic disease (loco-regional or distant), not amenable to resection or radiation therapy with curative intent.
  4. Documented positive hormone receptor status (> or = 1% of tumour cells with oestrogen receptor [ER] and/or progesterone receptor [PgR] expression) based on central testing on the most recent tumour biopsy.
  5. Documented HER2-negative tumour based on central testing on the most recent tumour biopsy. HER2-negative tumour 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.
  6. Patients must have received at least 5 years of endocrine therapy in the adjuvant setting as treatment for early disease and remained disease free for more than 12 months following its completion or have "de novo" metastatic disease. Patients that have been scheduled 5 years with adjuvant endocrine therapy and stopped treatment, by patient's own decision, after completing at least 3 years of treatment, can be also be included as long as they have remained free of disease 3 years after discontinuing the endocrine therapy.
  7. Patients must have at least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI, plan x-ray or physical examination. Clinical lesions will only be considered measurable when they are superficial and ≥10mm diameter as assessed using callipers (e.g. skin nodules). Patients with bone-only disease must have a lytic or mixed (lytic + blastic) lesion, which has not been previously irradiated and can be accurately assessed by CT/MRI according to RECIST version 1.1.
  8. Postmenopausal patient, defined as a woman fulfilling any one of the following criteria (based on the NCCN definition of menopause [National Comprehensive Cancer Network 2008]):

    • Prior bilateral oophorectomy.
    • Age > 60 years.
    • Age ≤ 60 years and with amenorrhea for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle stimulating hormone and estradiol in the postmenopausal range.
  9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
  10. At least 18 years of age.
  11. Life expectancy ≥ 12 weeks.
  12. Adequate organ and bone marrow function:

    • ANC ≥ 1,500/mm3 (1.5x109/L);
    • Platelets ≥ 100,000/mm3 (100x109/L);
    • Haemoglobin (Hgb) ≥ 9g/dL (90g/L);
    • Serum creatinine ≤ 1.5xUpper Limit of Normal (ULN) or estimated creatinine clearance ≥ 60ml/min as calculated using the method standard for the institution;
    • Total serum bilirubin ≤ 1.5xULN (<3xULN if Gilbert´s disease);
    • AST and/or ALT ≤ 3xULN (≤5xULN if liver metastases present);
    • Alkaline Phosphatase (AP) ≤ 2.5xULN (≤5xULN if bone or liver metastases present).
  13. Patients consent to biological sample provision for biomarker exploratory analysis.
  14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

  1. Prior systemic therapy for metastatic disease. Note: patients with a local recurrent disease treated with surgery (R0) and receiving a "second hormonal adjuvant therapy for five years" will be allowed, provided they have remained disease free for more than 12 months following its completion.
  2. Have "de novo" locally advanced disease.
  3. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval.
  4. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitis spread, or any known bone marrow infiltration due to breast cancer. Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not significantly compromised as a result of disease.
  5. Treatment with a non-approved or experimental drug within 4 weeks before randomization.
  6. Prior treatment with any CDK4/6 inhibitor or fulvestrant.
  7. Current or prior malignancy within previous 5 years (other than breast cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
  8. History of:

    • Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term (>6 months) anticoagulant therapy (other than antiplatelet therapy and low dose coumarin derivatives provided that the International Normalised Ratio (INR) is less than 1.6). Hypersensitivity to active or inactive excipients of fulvestrant, palbociclib/placebo or castor oil.
    • Any severe concomitant condition which makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the trial protocol, e.g. uncontrolled cardiac disease or uncontrolled diabetes mellitus.
  9. QTc interval > 480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
  10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcaemia, hypokalaemia, hypomagnesaemia).
  11. Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of palbociclib, such as history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastro-paresis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhoea of CTCAE grade > 1.
  12. Prior hematopoietic stem cell or bone marrow transplantation.
  13. Known human immunodeficiency virus infection.
  14. Other severe acute or chronic medical or psychiatric condition 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.

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): NCT02690480


Contacts
Contact: Study Project Manager +34 916 592 870 inicio_ensayos@geicam.org
Contact: Start-Up Unit Manager +34 916 592 870 inicio_ensayos@geicam.org

Locations
Ireland
Bon Secours Hospital Recruiting
Cork, Ireland
Beaumont Hospital Withdrawn
Dublin, Ireland
Mater Misericordiae University Hospital Recruiting
Dublin, Ireland
Mater Private Hospital Withdrawn
Dublin, Ireland
St. James´s Hospital Withdrawn
Dublin, Ireland
Galway University Hospital Recruiting
Galway, Ireland
University Hospital Limerick Withdrawn
Limerick, Ireland
University Hospital Waterford Recruiting
Waterford, Ireland
Spain
Hospital Universitario Central de Asturias Recruiting
Oviedo, Asturias, Spain, 33011
Hospital Universitari Son Espases Recruiting
Palma de Mallorca, Baleares, Spain, 07120
Hospital Son Llàtzer Recruiting
Palma De Mallorca, Baleares, Spain, 07198
Hospital Universitario Mutua Terrassa Recruiting
Terrassa, Barcelona, Spain, 08221
Hospital Universitario Infanta Cristina Recruiting
Parla, Madrid, Spain, 28981
Hospital Universitario Quirón de Madrid Recruiting
Pozuelo de Alarcón, Madrid, Spain, 28223
Clínica Universidad de Navarra Withdrawn
Pamplona, Navarra, Spain, 31008
Complejo Hospitalario Universitario Vigo Recruiting
Vigo, Pontevedra, Spain, 36204
Hospital Universitario Sant Joan Reus Recruiting
Reus, Tarragona, Spain, 43204
Centro Oncológico de Galicia Recruiting
A Coruña, Spain, 15009
Hospital del Mar Recruiting
Barcelona, Spain, 08003
Hospital de la Santa Creu y Sant Pau Recruiting
Barcelona, Spain, 08026
Hospital Universitario Germans Trias i Pujol Recruiting
Barcelona, Spain, 08916
Hospital Universitario Reina Sofía Recruiting
Córdoba, Spain, 14004
Complejo Hospitalario de Jaén Recruiting
Jaen, Spain, 23007
Complejo Asistencial Universitario de León Recruiting
Leon, Spain, 24080
Hospital Universitario Ramón y Cajal Recruiting
Madrid, Spain, 28034
Hospital Clínico Universitario San Carlos Recruiting
Madrid, Spain, 28040
Hospital Universitario de Fuenlabrada Recruiting
Madrid, Spain, 28492
Hospital Regional Universitario de Málaga Recruiting
Málaga, Spain, 29011
Hospital Universitario Virgen de la Macarena Recruiting
Sevilla, Spain, 41009
Hospital Quirón Sagrado Corazón de Sevilla Recruiting
Sevilla, Spain, 41013
Hospital Universitario Vírgen del Rocío Recruiting
Sevilla, Spain, 41013
Hospital Universitario de Valme Recruiting
Sevilla, Spain, 41014
Hospital Clínico Universitario de Valencia Recruiting
Valencia, Spain, 46010
Hospital General Universitario Valencia Recruiting
Valencia, Spain, 46014
Hospital Universitario I Politècnic La Fe Recruiting
Valencia, Spain, 46026
Hospital Universitario Miguel Servet Recruiting
Zaragoza, Spain, 50009
Sponsors and Collaborators
Spanish Breast Cancer Research Group
AstraZeneca
Investigators
Study Director: Study Director Hospital del Mar

Responsible Party: Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT02690480     History of Changes
Other Study ID Numbers: GEICAM/2014-12
First Posted: February 24, 2016    Key Record Dates
Last Update Posted: January 16, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Spanish Breast Cancer Research Group:
fulvestrant
palbociclib
metastases
postmenopausal
breast cancer
hormone receptor positive

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Fulvestrant
Palbociclib
Estradiol
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Estrogens
Hormones
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action