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Breast NeoplasmsPhase 2FLIPPERNCT02690480

Fulvestrant (F)+Placebo vs F+Palbociclib First Line for Postmenopausal Hormone Receptor+ Advanced Breast Cancer

A Phase 2 study testing PD-0332991 (Palbociclib) and Fulvestrant in people with Breast Neoplasms, run by Spanish Breast Cancer Research Group at 32 sites in 2 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Neoplasms
What is being tested?
PD-0332991 (Palbociclib) and Fulvestrant
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
189 participants
Where
32 sitesin 2 countries
Study dates
17 Feb 2016to Dec 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
  • Availability of a tumor tissue sample, archival (primary tumour) or from the metastatic lesions (preferable) for the central ER, PgR and HER2 testing.
  • 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.
  • 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.
  • 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.
  • 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.
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  • 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.
  • 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.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
  • At least 18 years of age.
  • Life expectancy ≥ 12 weeks.
  • 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).
  • Patients consent to biological sample provision for biomarker exploratory analysis.
  • Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Who cannot join

  • 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.
  • Have "de novo" locally advanced disease.
  • 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.
  • 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.
  • Treatment with a non-approved or experimental drug within 4 weeks before randomization.
  • Prior treatment with any CDK4/6 inhibitor or fulvestrant.
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  • 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).
  • 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.
  • 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.
  • Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcaemia, hypokalaemia, hypomagnesaemia).
  • 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.
  • Prior hematopoietic stem cell or bone marrow transplantation.
  • Known human immunodeficiency virus infection.
  • 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.

Trial locations and contacts

32 sites in 2 countries.

32 sites in 2 countries

Spain27 sites

  • Centro Oncológico de Galicia

    A Coruña, 15009

  • Hospital del Mar

    Barcelona, 08003

  • Hospital de la Santa Creu y Sant Pau

    Barcelona, 08026

  • Hospital Universitario Germans Trias i Pujol

    Barcelona, 08916

  • Hospital Universitario Reina Sofía

    Córdoba, 14004

  • Complejo Hospitalario de Jaén

    Jaén, 23007

  • Complejo Asistencial Universitario de León

    León, 24080

  • Hospital Universitario Ramón y Cajal

    Madrid, 28034

  • Hospital Clínico Universitario San Carlos

    Madrid, 28040

  • Hospital Universitario de Fuenlabrada

    Madrid, 28492

  • Hospital Regional Universitario de Málaga

    Málaga, 29011

  • Hospital Universitario Central de Asturias

    Oviedo, Principality of Asturias, 33011

  • Hospital Universitari Son Espases

    Palma de Mallorca, Balearic Islands, 07120

  • Hospital Son Llàtzer

    Palma de Mallorca, Balearic Islands, 07198

  • Hospital Universitario Infanta Cristina

    Parla, Madrid, 28981

  • Hospital Universitario Quirón de Madrid

    Pozuelo de Alarcón, Madrid, 28223

  • Hospital Universitario Sant Joan Reus

    Reus, Tarragona, 43204

  • Hospital Universitario Virgen de la Macarena

    Seville, 41009

  • Hospital Quirón Sagrado Corazón de Sevilla

    Seville, 41013

  • Hospital Universitario Vírgen del Rocío

    Seville, 41013

  • Hospital Universitario de Valme

    Seville, 41014

  • Hospital Universitario Mutua Terrassa

    Terrassa, Barcelona, 08221

  • Hospital Clínico Universitario de Valencia

    Valencia, 46010

  • Hospital General Universitario Valencia

    Valencia, 46014

  • Hospital Universitario I Politècnic La Fe

    Valencia, 46026

  • Complejo Hospitalario Universitario Vigo

    Vigo, Pontevedra, 36204

  • Hospital Universitario Miguel Servet

    Zaragoza, 50009

Other trials in Spain

Ireland5 sites

  • Bon Secours Hospital

    Cork

  • Beaumont Hospital

    Dublin

  • Mater Misericordiae University Hospital

    Dublin

  • Galway University Hospital

    Galway

  • University Hospital Waterford

    Waterford

Other trials in Ireland

About this study

Official title: Phase II Study to Compare Fulvestrant (F) 500mg Plus Placebo vs F 500mg Plus Palbociclib as First Line Treatment for Postmenopausal Women With Hormone Receptor Positive Advanced Breast Cancer Sensitive to Endocrine Therapy. GEICAM/2014-12

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.

Read the detailed description

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
Being tested
PD-0332991 (Palbociclib), Fulvestrant, Placebo
Keywords
fulvestrant, palbociclib, metastases, postmenopausal, breast cancer, hormone receptor positive
Medical subject headings
Breast Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PD-0332991 (Palbociclib)Drug

    Also called Ibrance

    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

  • FulvestrantDrug

    Also called Faslodex

    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

  • PlaceboDrug

    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

Study groups in NCT02690480
Study groupRoleWhat they receive
PD-0332991(Palbociclib)+fulvestrant(FaslodexTM)ExperimentalFulvestrant 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.
Receives: Drug: PD-0332991 (Palbociclib); Drug: Fulvestrant
Placebo+fulvestrant(FaslodexTM)Active comparatorFulvestrant 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.
Receives: Drug: Fulvestrant; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Efficacy in terms of the rate of Progression-Free Survival (PFS)

    assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by the investigator

    Measured: at 1 year

Secondary outcomes (8)

  1. Progression-Free Survival (PFS)

    the time from the date of randomization to the first documented progressive disease, using RECIST version 1.1, or death from any cause, whichever occurs first

    Measured: an average of 40-44 months since FPFV (approximately Ago2019)

  2. Objective Response Rate (ORR)

    the percentage of patients with a complete or partial response out of the patients who had measurable disease at baseline.

    Measured: at 1 year and to be updated with further analyses

  3. Clinical Benefit Rate (CBR)

    Complete Response (CR) plus Partial Response (PR) plus stable disease (SD) lasting ≥ 24 weeks (+/- 2 weeks) according to RECIST version 1.1.

    Measured: at 1 year and to be updated with further analyses

  4. Overall Survival (OS).

    the time from the date of randomization to the date of death from any cause.

    Measured: 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

    the percentage of patients without death from any cause out of the randomised patients (calculated using the Kaplan-Meier technique).

    Measured: 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).

    Safety will be assessed by standard clinical and laboratory tests. Adverse events will be graded according to NCI-CTCAE version 4.0

    Measured: at 1 year and to be updated with further analyses

  7. Patient reported outcomes of health-related quality of life based on EORTC QLQ-C30 Global Health Status/Quality of Life and Physical Function

    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

    Measured: at 1 year and to be updated with further analyses

  8. Patient reported outcomes of health-related quality of life based on EORTC QLQ-BR23 Breast Module.

    Disease-specific treatment measurements will be assessed. Changes (mean score) from baseline and time to deterioration will be analyzed.

    Measured: at 1 year and to be updated with further analyses

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Feb 2016 (estimated)
  2. Study start17 Feb 2016
  3. Primary completion11 Jan 2020
  4. Study completionDec 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
189 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02690480
Sponsor's protocol ID
GEICAM/2014-12
Other IDs
2015-002437-21, 2015
Acronym
FLIPPER
Status last verified
Feb 2020
First submitted
5 Jan 2016
Last updated
5 Feb 2020
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Tibau A, Martinez MT, Ramos M, De La Cruz-Merino L, Santaballa A, O'Connor M, Martinez-Janez N, Moreno F, Fernandez I, Virizuela JA, Alarcon J, de La Haba-Rodriguez J, Sanchez-Rovira P, Albacar CR, Bueno Muino C, Kelly C, Casas M, Bezares S, Rosell L, Albanell J. Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Ther Adv Med Oncol. 2023 Jan 19;15:17588359221148921. doi: 10.1177/17588359221148921. eCollection 2023.

    PubMed 36743520

  • Albanell J, Martinez MT, Ramos M, O'Connor M, de la Cruz-Merino L, Santaballa A, Martinez-Janez N, Moreno F, Fernandez I, Alarcon J, Virizuela JA, de la Haba-Rodriguez J, Sanchez-Rovira P, Gonzalez-Cortijo L, Margeli M, Sanchez-Munoz A, Anton A, Casas M, Bezares S, Rojo F. Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER). Eur J Cancer. 2022 Jan;161:26-37. doi: 10.1016/j.ejca.2021.11.010. Epub 2021 Dec 11.

    PubMed 34902765

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing PD-0332991 (Palbociclib) and Fulvestrant in people with Breast Neoplasms, run by Spanish Breast Cancer Research Group at 32 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 5 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 32 sites in Spain, Ireland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy in terms of the rate of Progression-Free Survival (PFS) (time frame: at 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02690480, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2020.

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