PALbociclib Rechallenge in horMone Receptor-posItive/HER2- Negative Advanced Breast Cancer (PALMIRA) (PALMIRA)

International,Multicenter,Randomized,Open-label, Phase II to Evaluate the Efficacy and Safety of Continuation of Palbociclib+2nd Line Endocrine Therapy in HR+/HER2- ABC Patients Who Had Clinical Benefit During 1st Line Palbociclib.

Hormone Receptor (HR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-negative advanced breast cancer (ABC)

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Advanced Breast Cancer; Hormone Receptor Positive Tumor; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Intervention / Treatment: Drug: Palbociclib; Drug: Endocrine therapy

Detailed Description

Pre- and post-menopausal women age ≥ 18 years with HR-positive and HER2-negative with ABC that had previously received first-line endocrine therapy in combination with palbociclib and had achieved clinical benefit during palbociclib-based treatment. Patients relapsing on a palbociclib-based regimen in the adjuvant setting are also eligible. Patients are not eligible if they are candidates for a local treatment with a curative intention. Evidence of either measurable and biopsiable metastatic disease (as for Response Evaluation Criteria In Solid Tumors (RECIST v.1.1)) or non-measurable disease with bone lesion is required. Pre-menopausal women must be under treatment with luteinizing hormone-releasing hormone (LHRH) analogues.

• Study Type: Interventional
• Enrollment (Actual): 198
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Besançon, France
    • Hôpital Jean Minjoz
  • Bordeaux, France
    • Polyclinique Bordeaux Nord Aquitaine
  • Dijon, France
    • centre Georges François Leclerc
  • La Roche-sur-Yon, France, 85925
    • CHD Vendée
  • Paris, France
    • Hopital Europeen Georges Pompidou
  • Paris, France
    • Hôpital Tenon AP-HP
  • Strasbourg, France, 67000
    • Centre Paul Strauss
• Germany
  • Dresden, Germany
    • University Hospital Dresden-GYN
  • Essen, Germany
    • Kliniken Essen Mitte
  • Essen, Germany
    • Universitätsklinikum Essen Frauenklinik
  • Frankfurt, Germany
    • Agaplesion Markus Krankenhaus
  • Munich, Germany
    • Technical University Munich
  • Münster, Germany
    • UKM Brustzentrum
  • Potsdam, Germany
    • Klinikum Ernst von Bergmann
  • Trier, Germany
    • Klinikum Mutterhaus der Borromäerinnen Trier
• Italy
  • Brescia, Italy
    • Ospedale Civili Brescia
  • Milano, Italy, 20141
    • Instituto Europeo di Oncologia
  • Prato, Italy
    • Oncologia Medica Ospedale di Prato
  • Roma, Italy
    • Policlinico Universitario Campus Bio-Medico
• Slovenia
  • Ljubljana, Slovenia
    • Onkološki Inštitut Ljubljana
  • Maribor, Slovenia
    • Univerzitetni klinicni center Maribor Oddelek za onkologijo
• Spain
  • A Coruña, Spain, 15009
    • Centro Oncológico de Galicia
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • H. Vall Hebrón
  • Barcelona, Spain, 08908
    • Institut Català d'Oncologia Bellvitge
  • Bilbao, Spain, 48013
    • Hospital de Basurto
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcantara
  • Girona, Spain
    • Institut Catala d'Oncologia
  • Lleida, Spain
    • Hospital Arnau de Vilanova
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28050
    • Hospital Universitario Sanchinarro
  • Madrid, Spain
    • Hospital La Paz
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Málaga
  • Palma De Mallorca, Spain, 07120
    • Hospital Universitari Son Espases
  • Reus, Spain
    • Hospital Sant Joan
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocío
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen De La Macarena
  • Valencia, Spain
    • Hospital Arnau de Vilanova de Valencia
  • Valencia, Spain
    • Hospital Universitari i Politècnic La Fe
  • Valencia, Spain, 46009
    • Instituto Valenciano de Oncologia IVO
  • Valencia, Spain, 46014
    • Hospital General Universitari de Valencia
  • Vigo, Spain, 36312
    • Hospital Álvaro Cunqueiro
  • Zaragoza, Spain
    • Hospital Miguel Servet
  • Zaragoza, Spain, 50009
    • Hospital Lozano Blesa
  • Barcelona
    • Badalona, Barcelona, Spain
      • ICO Badalona
  • Castelló
    • Castello, Castelló, Spain
      • Hospital Provincial de Castellón
  • Terrasa
    • Terrassa, Terrasa, Spain, 08191
      • Consorci Sanitari de Terrassa
• United Kingdom
  • Dartford, United Kingdom
    • Darent Valley Hospital by Dartford and Gravesham NHS Trust
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Center
  • London, United Kingdom
    • Barts Cancer Institute
  • Maidstone, United Kingdom, ME16 9QQ
    • Kent Oncology Department
  • Swansea, United Kingdom, SA127BR
    • Abertawe Bro Morgannwg University Local Health Board, Singleton Hospital
  • Truro, United Kingdom, TR1 3LQ
    • Royal Cornwall Hospital NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female patients over 18 years of age.

2. Pre-menopausal women provided they are being treated with a LHRH analogue for at least 28 days (if shorter, post-menopausal levels of serum estradiol/Follicle-stimulating hormone (FSH) must be confirmed analytically) prior to study entry or post- menopausal women as defined by any of the following criteria:

   1. Age ≥60 years;
   2. Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and/or FSH level within the laboratory's reference range for postmenopausal females;
   3. Documented bilateral oophorectomy.
3. Eastern Cooperative Oncology Group (ECOG) performance status lower or equal to 1.
4. Life expectancy greater or equal to 12 weeks.
5. Histologically proven diagnosed of ABC not amenable to curative treatment.
6. Documented recurrent ER-positive and/or progesterone receptor (PgR)-positive (with ≥1% positive stained cells (according to NCCN National Comprehensive Cancer Network and ASCO American Society of Clinical Oncology guidelines) and HER2-negative (0-1+ by immunohistochemistry (IHC) or 2+ and negative by in situ hybridization (ISH) test) breast cancer in the advanced setting.
7. Radiological or clinical evidence of disease progression on first- line combination of palbociclib plus endocrine therapy (aromatase inhibitor (AI) or fulvestrant). Patients previously treated with the combination of palbociclib and tamoxifen will be excluded.
8. Patients have achieved clinical benefit criteria to a first-line palbociclib-based endocrine regimen (defined as at least stable disease ≥ 24 weeks or partial or complete response confirmed or unconfirmed).
9. Patients must have been treated with a stable minimum dose of 75 mg palbociclib during the last 2 cycles of the prior palbociclib-based regimen.
10. Last dose of palbociclib administered not later than 8 weeks and not earlier than 7 days from study entry, with the exception of patients relapsing on a palbociclib-based regimen in the adjuvant setting.
11. Patients should not have been treated in the advanced setting with at least one of these endocrine therapy options: either fulvestrant or AI.
12. Patients must have measurable disease or evaluable disease according to RECIST criteria v.1.1. Patients with only bone lesions are eligible.
13. Willingness and ability to provide tumor biopsy (if feasible) both at the time of the inclusion and after disease progression in order to perform exploratory studies. If not feasible, patient eligibility should be evaluated by a Sponsor's qualified designee.
14. Patients agree to collection of blood samples (liquid biopsy) at the time of inclusion, after 2 weeks of treatment, and upon progression or study termination.
15. Adequate organ function: (Hematological, hepatic and renal)
16. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
17. Patients have been informed about the nature of study, and have agreed to participate in the study, and signed the informed consent form prior to participation in any study-related activities.
18. Resolution of all acute toxic effects of prior anti-cancer therapy to grade 1

Exclusion Criteria:

1. HR or HER2 unknown disease.
2. HER2-positive disease based on local laboratory results (performed by IHC / ISH test).
3. Locally ABC candidate for curative treatment.
4. Formal contraindication to endocrine therapy defined as visceral crisis and rapidly or symptomatic progressive visceral disease.
5. Prior therapy with any other CDK4/6 inhibitor different from palbociclib.
6. 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 and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
7. Patients are currently receiving food or drugs known to be strong inducers or inhibitors of CYP3A4.
8. Current or prior malignancy which could affect compliance with the protocol or interpretation of results. Patients with curatively- treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinoma in situ, among others, are generally eligible.
9. No other systemic therapy for metastatic disease including chemotherapy, immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine therapy excluding first-line palbociclib-based regimen.
10. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 2 weeks of start of study drug, or patients who have not recovered from the side effects of any major surgery, or patients who may require major surgery during the study.
11. Radiotherapy or limited-field palliative radiotherapy within 7 days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated.
12. Use of concurrent investigational agents or other concomitant anticancer therapies.
13. Active bleeding diathesis, previous history of bleeding diathesis, or chronic anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
14. Serious concomitant systemic disorder (e.g., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
15. Unable to swallow capsules or tablets.
16. History of malabsorption syndrome or other condition that would interfere with enteral absorption.

17. Any of the following within 6 months of randomization:

    myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI-CTCAE v.5.0 grade ≥2, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.

18. Uncontrolled electrolyte disorders of NCI-CTCAE v.5.0 grade ≥ 2.
19. Known hypersensitivity to palbociclib or any of its excipients.

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: Interventional Arm (Arm A); Patients will receive palbociclib capsules orally once daily (QD) (at 100mg or 125mg depending on previous treatment dose) for 21 days every four weeks in combination with endocrine therapy (letrozole or fulvestrant).	Drug: Palbociclib; Palbociclib capsules orally once daily (QD) (at 100mg or 125mg depending on previous treatment dose) for 21 days every four weeks; Other Names: IBRANCE; Drug: Endocrine therapy; Endocrine therapy alone (letrozole or fulvestrant); Other Names: letrozole; fulvestrant
Active Comparator: Control Arm (Arm B); Patients will receive endocrine therapy (letrozole or fulvestrant).	Drug: Endocrine therapy; Endocrine therapy alone (letrozole or fulvestrant); Other Names: letrozole; fulvestrant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS (Progression-free survival)	From a clinical point of view, the primary endpoint for this study is the PFS (progression-free survival) - defined as the period of time from randomization until objective tumor progression or death - assessed by RECIST criteria v.1.1, of continuation of palbociclib treatment combined with second-line endocrine therapy (letrozole or fulvestrant) versus endocrine therapy in pre- and post- menopausal women with HR-positive/HER2-negative ABC.	Baseline up to 29 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety AEs	Patient safety and adverse events (AEs) will be evaluated using the NCI-CTCAE v.5.0. Grade 3 and 4 AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the different treatment arms.	Baseline up to 29 months
Efficacy (ORR)	To compare the objective response rate (ORR), the duration of response (DoR), the time to response (TTR), the clinical benefit rate (CBR), the time to progression (TTP), and the overall survival (OS) of palbociclib plus second-line endocrine therapy (letrozole or fulvestrant) versus endocrine therapy alone	Baseline up to 29 months
Efficacy (Quality of Life)	To compare the patient reported global Quality of Life (QOL), functioning and symptoms of palbociclib plus second-line endocrine therapy (letrozole or fulvestrant) versus endocrine therapy alone.	Baseline up to 42 months
Efficacy of subgroup analysis	To perform subgroup analysis for primary and secondary endpoints in stratified groups of patients.	Baseline up to 42 months
Compare efficacy	To compare the time to first chemotherapy of palbociclib plus second-line endocrine therapy (letrozole or fulvestrant) versus endocrine therapy alone.	Baseline up to 42 months
Exploratory objectives (molecular markers)	To explore potential molecular markers of sensitivity and/or resistance for the combination and endocrine therapy alone, according to, but not limited to, the results obtained from the BioPER trial (NCT03184090).	Baseline up to 42 months
Exploratory objectives (intrinsic molecular subtypes)	To explore correlations between the intrinsic molecular subtypes and efficacy/safety findings in patients with HR-positive/HER2- negative ABC.	Baseline up to 42 months

Collaborators and Investigators

• Sponsor: MedSIR
• Collaborators: Pfizer
• Investigators: Principal Investigator: José Perez, MedSIR

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2019
• Primary Completion (Actual): November 30, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: January 15, 2019
• First Submitted That Met QC Criteria: January 16, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: breast cancer; HER2; advanced; ABC; estrogen receptor; progesterone receptor; HR
• 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; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Letrozole; Fulvestrant; Palbociclib
• Other Study ID Numbers: MedOPP068; 2017-002781-48 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study Leaflet V2_20190115 with study design, primary objetive, inclusion criteria and exclusion criteria
• IPD Sharing Time Frame: During recruitment period
• IPD Sharing Access Criteria: Oncology department
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No