A Trial of Early Detection of Molecular Relapse With Circulating Tumour DNA Tracking and Treatment With Palbociclib Plus Fulvestrant Versus Standard Endocrine Therapy in Patients With ER Positive HER2 Negative Breast Cancer

NCT04985266 | Recruiting Phase 2 DMC

• 1 other identifier: CCR5316
• Study Type: interventional
• Target: 1,100
• Locations: 2 countries
• Sites: 49

Brief Summary

Detection of molecular relapse with circulating tumour DNA analysis can identify which patients with ER positive breast cancer are relapsing on adjuvant endocrine therapy. This trial will aim to demonstrate that palbociclib and fulvestrant, can defer or prevent relapse in patients with ctDNA detected molecular relapse. The TRAK-ER trial will have two phases, a ctDNA surveillance phase and a randomised therapy trial in patients with positive ctDNA. The TRAK-ER trial will establish a ctDNA screening programme for patients with ER positive breast cancer receiving adjuvant endocrine therapy with at least a further three years of standard adjuvant endocrine therapy planned. Patients recruited into the TRAK-ER study will have high-risk clinical features to identify patients at higher risk of future relapse. ctDNA assays will be used to identify which people are at very high risk of relapse (i.e. those with a positive ctDNA result), and randomise this high risk population between standard endocrine therapy versus palbociclib plus fulvestrant for up to two years.

Conditions

ER+ Breast Cancer; HER2-negative Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Incidence of positive ctDNA result during surveillance (Surveillance phase)

  Test during the surveillance phase detects presence of ctDNA

  Up to 36 months from entry to study

• Incidence of positive ctDNA result at first test (Surveillance phase)

  Test during the surveillance phase detects presence of ctDNA in the first test

  Start of study

• Relapse free survival (Treatment phase)

  Time from randomization to invasive local/regional recurrence (including ipsilateral invasive breast recurrence) or distant recurrence or death from any cause. Patients with second primary invasive cancers (breast or non-breast) would be censored at time of detection.

  60 months from randomisation

Secondary Outcomes (10)

• Frequency and Severity of adverse events

  up to 24 months from randomisation

• Overall survival

  up to 60 months from randomisation

• Invasive disease free survival

  up to 60 months from randomisation

• Distant recurrence free survival

  up to 60 months from randomisation

• EQ-5D-5L quality of life assessment: Mobility element

  up to 24 months from randomisation

Study Arms (2)

Standard endocrine therapy

ACTIVE COMPARATOR

Standard endocrine therapy will continue for up to 24 months on trial. Standard endocrine therapies include tamoxifen, and aromatase inhibitors (letrozole, anastrazole, exemestane).

Drug: Tamoxifen; Drug: Letrozole; Drug: Exemestane; Drug: Anastrozole

Palbociclib and fulvestrant

EXPERIMENTAL

Treatment with palbociclib plus fulvestrant will continue for a maximum of 24 months. Palbociclib will be given orally once a day on days 1-21 of each 28 day cycle. Fulvestrant 500 mg will be administered on cycle 1 days 1 and 15, cycle 2 day 1 and then every 28 days thereafter (plus or minus 3 days) as two intramuscular injections of 250mg fulvestrant at each visit.

Drug: Palbociclib 125Mg Tab; Drug: Fulvestrant injection

Interventions

Palbociclib 125Mg Tab DRUG

Palbociclib Tablets, 125 mg orally once daily, beginning on Cycle 1, on Days 1-21 of each 28-day cycle.

Palbociclib and fulvestrant

Fulvestrant injection DRUG

Fulvestrant Intramuscular injections, 500 mg as two injection of 250mg fulvestrant in 5ml solution at each visit. No fulvestrant dose reductions are permitted. Administered on days 1, 15 (plus or minus 3 days), 29 (plus or minus 3 days), and every 28 (plus or minus 3 days) days thereafter.

Palbociclib and fulvestrant

Tamoxifen DRUG

As per clinical guidelines

Standard endocrine therapy

Letrozole DRUG

As per clinical guidelines

Standard endocrine therapy

Exemestane DRUG

As per clinical guidelines

Standard endocrine therapy

Anastrozole DRUG

As per clinical guidelines

Standard endocrine therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to participate in the trial and to donation of tissue and blood samples
• Male or female patients aged 18 years or older
• ECOG performance status 0, 1 or 2 (see https://ecog-acrin.org/resources/ecog-performance-status)
• Histologically proven primary ER+ (Allred score 6/8 or greater, or stain in ≥10% of cancer cells) and HER2- (immunohistochemistry 0/1+ and/or negative by in situ hybridization) breast cancer as determined by local laboratory
• Patients with high risk early stage breast cancer according to at least one of the following criteria:
• Primary surgery (no other treatment prior to surgery) A. Four or more involved axillary lymph nodes or positive supraclavicular lymph node at diagnosis, or
• B. Tumour size \> 5 cm, regardless of lymph node status, or
• C. 1-3 involved axillary lymph nodes and at least one of the following; i) Tumour size \> 3 cm, ii) histological grade 3 iii) high genomic risk defined as Oncotype Dx Recurrence Score \>=26, Prosigna score \>=60, EPclin risk score \>=4.0, or Mammaprint high risk category, or
• Neoadjuvant chemotherapy (chemotherapy prior to surgery)
• D. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy
• E. Lymph node negative and tumour size \> 3 cm after chemotherapy
• Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) Use the primary surgery criteria - staging tumour size and lymph node status may be either the pathological staging after endocrine therapy or on the initial clinical staging prior to neoadjuvant therapy
• Available tissue from one archival tumour tissue sample (either from diagnostic biopsy, primary surgery or where available residual disease post-neoadjuvant chemotherapy)
• No evidence of macroscopic distant metastatic disease or incurable locally advanced disease on staging scans conducted at any time since initial diagnosis.
• Patients receiving standard endocrine therapy with aromatase inhibitors (letrozole, anastrazole, exemestane), tamoxifen, or combination of such for a minimum of 6 months\* and maximum of 7 years duration with an additional three years of endocrine therapy planned. Pre- or peri-menopausal patients may also receive GnRH analogues.

You may not qualify if:

• Any concurrent or planned treatment for the current diagnosis of breast cancer other than adjuvant endocrine therapy or a bisphosphonate.
• Patients with prior exposure to a CDK 4/6 inhibitor as part of standard of care may enrol only after at least 12 months from completing CDK4/6 therapy.
• Prior exposure to therapeutic dose of fulvestrant is not permitted. One subtherapeutic dose of fulvestrant is permitted.
• Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ
• Patients previously entered into a therapeutic trial where experimental therapy is continued post-surgery. Patients who have entered a clinical trial of a CDK4/6 inhibitor in the adjuvant setting are not eligible. Patients who received a CDK4/6 inhibitor only before an operation, with no post-operative adjuvant use, are eligible.
• Treatment with an unlicensed or investigational product within 4 weeks prior registration to trial
• Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities, which in the opinion of the Investigator should not exclude the patient) from related side effects of any prior antineoplastic therapy, not including side-effects of endocrine therapy
• Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral medication (e.g. Crohn's disease, ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection)
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol.
• Clinically significant uncontrolled heart disease including any of the following:
• History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry
• Symptomatic congestive heart failure
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
• Cardiac arrhythmia.
• History of pneumonitis, interstitial lung disease or pulmonary fibrosis

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Pfizer: collaborator
• AstraZeneca: collaborator
• Institute of Cancer Research, United Kingdom: collaborator
• UNICANCER: collaborator
• Gustave Roussy, Cancer Campus, Grand Paris: collaborator
• Invitae Corporation: collaborator

Study Sites (49)

Institut de Cancérologie de l'Ouest

Angers, 49055, France

RECRUITING

Centre Hospitalier Annecy Genevois_Site d'Annecy

Annecy, 90074, France

RECRUITING

Institut du Cancer Avignon Sainte Catherine

Avignon, 84000, France

RECRUITING

Centre Hospitalier Simone Veil de Blois

Blois, 41016, France

RECRUITING

Institut Bergonié

Bordeaux, France

RECRUITING

Centre Jean Perrin

Clermont-Ferrand, 63011, France

RECRUITING

Centre George François Leclerc

Dijon, 21079, France

RECRUITING

Groupe Hospitalier Mutualiste de Grenoble

Grenoble, 38000, France

RECRUITING

Clinique Chénieux

Limoges, 87000, France

RECRUITING

Centre Hospitalier Universitaire de Limoges

Limoges, 87042, France

RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Institut Paoli Calmettes

Marseille, 13273, France

RECRUITING

Institut de Cancérologie de l'Ouest

Nantes, 44805, France

RECRUITING

Centre Antoine Lacassagne

Nice, 06189, France

RECRUITING

Gustave Roussy Cancer Campus

Paris, 94800, France

RECRUITING

Hôpital Américain de Paris

Paris, France

WITHDRAWN

Institut Godinot

Reims, 51726, France

RECRUITING

Centre Eugène Marquis

Rennes, 25042, France

RECRUITING

Centre Henri Becquerel

Rouen, 76038, France

RECRUITING

CHU de Saint Etienne-Institut de Cancérologie

Saint-Priest-en-Jarez, 42270, France

RECRUITING

Institut Claudius Regaud

Toulouse, 31059, France

RECRUITING

Barnet Hospital

London, Barnet, EN5 3DJ, United Kingdom

NOT YET RECRUITING

Royal Cornwall Hospitals NHS Trust

Truro, Cornwall, TR1 3LJ, United Kingdom

RECRUITING

University Hospitals Dorset: Royal Bournemouth Hospital

Bournemouth, BH7 7DW, United Kingdom

RECRUITING

Royal Sussex Hospital

Brighton, BN2 5BE, United Kingdom

NOT YET RECRUITING

Bristol Haematology and Oncology Centre

Bristol, BS2 8ED, United Kingdom

RECRUITING

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

RECRUITING

Velindre University NHS Trust

Cardiff, CF14 2TL, United Kingdom

RECRUITING

Darlington Memorial Hospital

Darlington, United Kingdom

NOT YET RECRUITING

Western General

Edinburgh, EH4 2XU, United Kingdom

RECRUITING

Royal Devon and Exeter Hospital

Exeter, EX2 5DW, United Kingdom

RECRUITING

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

NOT YET RECRUITING

North West Anglia NHS Foundation Trust: Hinchingbrooke Hospital

Huntingdon, PE29 6NT, United Kingdom

RECRUITING

St James's University Hospital

Leeds, LS9 7FT, United Kingdom

NOT YET RECRUITING

The Clatterbridge Cancer Centre NHS Foundation Trust

Liverpool, United Kingdom

RECRUITING

Barts Health NHS Trust

London, EC1A 7BE, United Kingdom

RECRUITING

Mount Vernon Hospital

London, HA6 2RN, United Kingdom

RECRUITING

University College London Hospital

London, NW1 2BU, United Kingdom

RECRUITING

The Royal Free Hospital

London, NW3 2QG, United Kingdom

RECRUITING

The Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

RECRUITING

Maidstone Hospital

Maidstone, ME16 9QQ, United Kingdom

NOT YET RECRUITING

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

RECRUITING

Nottingham University Hopsitals NHS Trust

Nottingham, NG5 1PB, United Kingdom

RECRUITING

Oxford Cancer & Haematology Centre, Churchill Hospital,

Oxford, OX3 7LE, United Kingdom

RECRUITING

North West Anglia NHS Foundation Trust: Peterborough Hospital

Peterborough, PE3 9GZ, United Kingdom

RECRUITING

Derriford Hospital - UHPNT

Plymouth, PL6 8DH, United Kingdom

RECRUITING

University Hospitals Dorset: Poole Hospital

Poole, BH15 2JB, United Kingdom

RECRUITING

Weston Park Hospital

Sheffield, S10 2SJ, United Kingdom

RECRUITING

Somerset NHS Foundation Trust

Taunton, TA1 5DA, United Kingdom

RECRUITING

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MeSH Terms

Interventions

palbociclib; Fulvestrant; Tamoxifen; Letrozole; exemestane; Anastrozole

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Nicholas Turner

  Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Project Manager

CONTACT

020 7808 2887; trak-er@rmh.nhs.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2021
• First Posted: August 2, 2021
• Study Start: March 30, 2022
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2030
• Last Updated: December 5, 2024

Record last verified: 2024-12

Locations

FR (21); GB (28)