TRAK-ER_A randomised 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The Royal Marsden NHS Foundation Trust

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Jan 2023 → ongoing

Decision date (initial)

2024-10-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517414-15-00

EudraCT number

2020-004022-36

ClinicalTrials.gov

NCT04985266

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

Surveillance Phase:
To assess the incidence of ctDNA detection in patients with ER positive HER2 negative breast cancer.

Treatment Phase:
To assess whether palbociclib plus fulvestrant improves relapse free survival compared to standard endocrine therapy in patients with ER positive HER2 negative breast cancer with detectable circulating tumour DNA during adjuvant endocrine therapy.

Conditions and MedDRA coding

ER positive HER2 negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Written informed consent to participate in the trial and to donation of tissue and blood samples
2. Male or female patients aged 18 years or older
3. ECOG performance status 0, 1 or 2 (see https://ecog-acrin.org/resources/ecog-performance-status)
4. 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
5. 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
6. Available tissue from one archival tumour tissue sample (either from diagnostic biopsy, primary surgery or where available residual disease post-neoadjuvant chemotherapy)
7. No evidence of macroscopic distant metastatic disease or incurable locally advanced disease on staging scans conducted at any time since initial diagnosis.
8. 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. * patients may enrol during the first 6 months of standard endocrine therapy, and wait until at least 6 months of endocrine therapy has been received prior to starting ctDNA surveillance. Patients who have previously started and have permanently discontinued standard endocrine therapy cannot be enrolled in the trial.
9. Patients must have had surgery achieving clear margins (as per local guidelines)
10. Female and male patients of reproductive potential must be willing to use an adequate method of contraception for the first three years of the trial, if randomised to standard endocrine therapy for the duration of trial treatment through to at least 4 weeks after the last dose of trial treatment, and if randomised to fulvestrant and palbociclib to 2 years after the last dose of fulvestrant (see section 4.6). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
11. Patients willing to have frequent blood tests.

Exclusion criteria 17

1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than adjuvant endocrine therapy or a bisphosphonate.
2. 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.
3. Prior exposure to therapeutic dose of fulvestrant is not permitted. One subtherapeutic dose of fulvestrant is permitted.
4. 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
5. 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.
6. Treatment with an unlicensed or investigational product within 4 weeks prior registration to trial
7. 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
8. 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)
9. 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.
10. Clinically significant uncontrolled heart disease including any of the following: a. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry b. Symptomatic congestive heart failure c. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome. d. Cardiac arrhythmia.
11. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
12. Known history of Human Immunodeficiency Virus (HIV) (testing not required as part of study screening)
13. Known active Hepatitis B or Hepatitis C (testing not required as part of study screening)
14. Females who are known to be pregnant or breastfeeding
15. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting factor deficiency), other known abnormalities in coagulation or treatment with anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted.
16. Child-Pugh class C hepatic impairment or creatinine clearance < 30ml/min.
17. Patient with bilateral tumours, or unilateral multifocal cancers with multiple separate primary cancers.(Multifocal cancer that reflects a single primary cancer, in the opinion of the investigator, are eligible)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Surveillance Phase: • ctDNA detection – Total ctDNA detection and breakdown by incidence at first ctDNA test verses incidence at subsequent ctDNA tests
2. Treatment Phase: • Relapse free survival – 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.

Secondary endpoints 11

1. • Relapse free interval – Time from randomisation to invasive local/regional recurrence (including ipsilateral invasive breast recurrence) or distant invasive recurrence. All deaths and second primary invasive cancers (breast or non-breast) would be censored at time of detection.
2. • Invasive disease free survival – Time from randomisation to invasive local/regional recurrence (including ipsilateral invasive breast recurrence), new breast cancer (ipsilateral or contralateral) or distant recurrence or death from any cause. Patients with non-invasive recurrences or second primary invasive cancers (non-breast) would be censored at time of detection.
3. • Distant recurrence free survival - Time from randomization to distant invasive breast cancer recurrence or death from any cause. Patients with new contralateral invasive breast cancers or second primary invasive non-breast cancers would be censored at time of detection.
4. • Overall survival – Time from randomisation to death from any cause.
5. • ctDNA clearance – Absence of detectable ctDNA and disease recurrence at 24 weeks. Additional timepoints will be assessed in exploratory analysis (e.g. 52 weeks).
6. • Safety and tolerability – Assessed by Adverse Events (AEs) as per CTCAE v5 and quality of life as measured with EQ-5D-5L and EORTC C30 and BR23 questionnaires
7. • Overt advanced disease (metastatic disease or incurable locally advanced disease) at time of ctDNA detection at the time of first ctDNA detection, and subsequent ctDNA tests.
8. • Isolated local recurrence (recurrence in ipslilateral breast or ipsilateral regional lymph nodes treatable with potentially curative intent) at the time at time of ctDNA detection at the time of first ctDNA detection, and subsequent ctDNA tests.
9. • Proportion of recurrences detected by ctDNA – the proportion of recurrences that have ctDNA detected prior to recurrence compared to the total number of recurrences during the period of ctDNA surveillance.
10. • Level of ctDNA detection – the allele fraction of ctDNA at the time of first ctDNA detection.
11. • Lead time to recurrence on standard of care – the time from the date of ctDNA detection to invasive local/regional recurrence (including ipsilateral invasive breast recurrence) in the standard of care endocrine therapy group. All deaths and second primary invasive cancers (breast or non-breast) would be censored.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The Royal Marsden NHS Foundation Trust

Sponsor organisation

The Royal Marsden NHS Foundation Trust

Address

Fulham Road

City

London

Postcode

SW3 6JJ

Country

United Kingdom

Scientific contact point

Organisation

The Royal Marsden NHS Foundation Trust

Contact name

TRAK-ER Lead Project Team

Public contact point

Organisation

The Royal Marsden NHS Foundation Trust

Contact name

TRAK-ER Lead Project Team

Locations

1 EU/EEA country · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications