Overview
FORTITUDE is a translational research study that aims to collect serial multi-site needle biopsy samples of tumour tissue and blood from metastatic breast cancer patients. Cancer biopsies are generally performed when cancer is diagnosed and are sometimes repeated when the cancer is suspected to have spread but this is not mandatory. However, studies have shown that cancers change with time and evolve to become resistant to therapy. The purpose of this study is to assess the feasibility of biopsies of multiple cancer sites across different time points during treatment and understand how cancers evolve and change throughout treatment. The findings of this study could pave the way for using cancer biopsies more frequently in the clinic to pick up changes in cancer behaviour that could influence treatment choice. The samples collected from this study will be used for molecular and genetic research to increase our understanding of how metastatic breast cancer changes during treatment and will enable us to develop new cancer treatments and new ways of monitoring response to cancer therapies.
Description
Breast cancer is the most frequently diagnosed cancer in women and is the second leading cause of female cancer death in the UK. Metastatic breast cancer has a historical five-year survival of 26% in England, although there is considerable variation by histology, with the poorest outcomes observed in patients with triple negative breast cancer (TNBC). Therapeutic approaches are chosen based on tumour clinical and pathological features, including oestrogen hormone receptor (ER) and human epidermal growth factor receptor 2 (HER2) status, however, patients with advanced disease almost inevitably develop therapy resistance and disease progression.
Next generation sequencing technologies have allowed us to understand the biology of breast cancer at a previously unprecedented depth. While the molecular landscape of early breast cancer has been extensively investigated, our understanding of the molecular basis of metastatic breast cancer remains more limited. In the clinic, metastatic breast cancer tissue is often biopsied once, from a single site, at the time of diagnosis. This biopsy sampling method is under-representative of the total disease burden and does not take into consideration the fact that metastatic disease is heterogeneous and evolves during the course of the disease.
The development of a method to serially sample multiple disease sites that is acceptable to patients will allow comprehensive evaluation of the heterogeneity of their disease and allow a deeper understanding of tumour heterogeneity, the mechanisms underlying treatment resistance as well as the biological processes governing metastatic behaviour. This will enable us to develop new cancer treatments and new ways of monitoring response to cancer therapies.
FORTITUDE will evaluate established standard of care biopsy techniques (fine needle biopsy and core needle biopsy) in a serial and multisite approach in patients with metastatic breast cancer or with locally advanced but inoperable breast cancer. Tumour tissue will be acquired at:
- Baseline (mandatory), defined as:
- At diagnosis of locally advanced but inoperable breast cancer or metastatic disease OR
- In patients with established locally advanced but inoperable breast cancer or metastatic disease who require re-biopsy for clinical reasons
- At every diagnosis of disease progression (optional)
No more than a total of four lesions will be biopsied in one sitting, with a maximum of three anatomical sites targeted (and no more than two solid organs). When tissue sampling is required as part of clinical care, patients will be invited to undergo additional serial multisite sampling. The sampling scheme will be repeated at subsequent relevant time points. This will be coupled with blood sampling when clinically indicated, including prior to each cycle of systemic therapy, and on disease progression. Furthermore, any cerebrospinal, ascitic and pleural fluid drained as part of clinical care can also be collected and profiled within this study.
Eligibility
Inclusion Criteria:
- Histologically confirmed CD20-positive marginal zone lymphoma (MZL) that has not received systemic therapy.
- MZL that has progressed or relapsed after prior local therapy (local therapy includes surgery, radiotherapy, Helicobacter pylori eradication, and hepatitis C treatment) or is not amenable to local therapy.
- Age ≥18 years.
- Presence of an indication for treatment as determined by the investigator or patient's willingness to receive treatment.
- Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.
- Adequate organ function as defined below:
- Hematology: Hemoglobin (HB) ≥60 g/L, platelets (PLT) ≥50×10⁹/L, neutrophils (NE) ≥1.0×10⁹/L (Note: Subjects with cytopenia due to lymphoma bone marrow involvement are not restricted by this criterion).
- Cardiac: Left ventricular ejection fraction (LVEF) ≥50% as determined by echocardiogram.
- Renal: Creatinine ≤1.5×upper limit of normal (ULN) or creatinine clearance ≥30 ml/min.
- Hepatic: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN.
- Women of childbearing potential must have a negative pregnancy test. Both male and female patients must agree to use effective contraception during the treatment period and for 2 years thereafter.
- Life expectancy of more than 3 months.
- Voluntary provision of written informed consent.
Exclusion Criteria:
- Underwent major surgery or severe trauma within 2 weeks prior to enrollment, or has not yet recovered from significant adverse effects.
- Has other malignancies currently or within the past 3 years, excluding those that have been cured (such as basal or squamous cell carcinoma of the skin, superficial bladder cancer, prostatic intraepithelial neoplasia, and cervical carcinoma in situ).
- Has a history of stroke or intracranial hemorrhage within the past 3 months.
- Requires anticoagulation with warfarin or equivalent vitamin K antagonist.
- Has evidence of any comorbidities or medical conditions that may interfere with the conduct of the study or place the patient at significant risk, including but not limited to severe cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia, or unstable angina) and/or severe pulmonary disease (e.g., severe obstructive pulmonary disease and a history of symptomatic bronchospasm).
- Is infected with human immunodeficiency virus, or has uncontrollable active hepatitis C virus or hepatitis B virus infection.
- Has uncontrollable active infection.
- Is pregnant or breastfeeding.
- Has any life-threatening disease, medical condition, or organ dysfunction that may jeopardize the safety of the patient, as determined by the investigator.
- Has any condition that may interfere with the absorption or metabolism of orelabrutinib or place the study results at unnecessary risk.
- Has central nervous system involvement by marginal zone lymphoma or evidence of disease transformation.
- Has any condition that the investigator judges may interfere with the patient's full participation in the study; any condition that poses significant risk to the patient; or any condition that may interfere with the interpretation of study data.