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

NCT ID: NCT02690480

Last Updated: 2020-02-05

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 189 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-17
• Study Completion Date: 2023-12-31

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.

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

Conditions

Breast Neoplasms

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

PD-0332991 (Palbociclib)

Intervention Type: DRUG

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

Fulvestrant

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Fulvestrant

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Ibrance; Faslodex

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Spanish Breast Cancer Research Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Hospital del Mar

Locations

Bon Secours Hospital

Cork, , Ireland

Beaumont Hospital

Dublin, , Ireland

Mater Misericordiae University Hospital

Dublin, , Ireland

Galway University Hospital

Galway, , Ireland

University Hospital Waterford

Waterford, , Ireland

Hospital Universitari Son Espases

Palma de Mallorca, Balearic Islands, Spain

Hospital Son Llàtzer

Palma de Mallorca, Balearic Islands, Spain

Hospital Universitario Mutua Terrassa

Terrassa, Barcelona, Spain

Hospital Universitario Infanta Cristina

Parla, Madrid, Spain

Hospital Universitario Quirón de Madrid

Pozuelo de Alarcón, Madrid, Spain

Complejo Hospitalario Universitario Vigo

Vigo, Pontevedra, Spain

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, Spain

Hospital Universitario Sant Joan Reus

Reus, Tarragona, Spain

Centro Oncológico de Galicia

A Coruña, , Spain

Hospital del Mar

Barcelona, , Spain

Hospital de la Santa Creu y Sant Pau

Barcelona, , Spain

Hospital Universitario Germans Trias i Pujol

Barcelona, , Spain

Hospital Universitario Reina Sofía

Córdoba, , Spain

Complejo Hospitalario de Jaén

Jaén, , Spain

Complejo Asistencial Universitario de León

León, , Spain

Hospital Universitario Ramón y Cajal

Madrid, , Spain

Hospital Clínico Universitario San Carlos

Madrid, , Spain

Hospital Universitario de Fuenlabrada

Madrid, , Spain

Hospital Regional Universitario de Málaga

Málaga, , Spain

Hospital Universitario Virgen de la Macarena

Seville, , Spain

Hospital Quirón Sagrado Corazón de Sevilla

Seville, , Spain

Hospital Universitario Vírgen del Rocío

Seville, , Spain

Hospital Universitario de Valme

Seville, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Hospital General Universitario Valencia

Valencia, , Spain

Hospital Universitario I Politècnic La Fe

Valencia, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Countries

Ireland; Spain

References

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.

Reference Type: DERIVED

PMID: 36743520 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34902765 (View on PubMed)

Other Identifiers

2015-002437-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GEICAM/2014-12

Identifier Type: -

Identifier Source: org_study_id