ARTemis

Avastin® Randomised Trial with neo-adjuvant chemotherapy for patients with early breast cancer

Research summary

Worldwide breast cancer poses a major healthcare problem. Considerable improvements in the treatment of the disease both in the adjuvant and in the metastatic setting have contributed to recent reductions in mortality. Although much of this progress has been made through large adjuvant randomised treatment trials, progress is slow because prolonged recruitment and follow up periods are required to measure treatment benefit in adjuvant trials. By contrast, clinical trials in the neo-adjuvant setting promise faster progress, because the endpoint of improved pathological complete response at the time of surgery has been shown to correlate well with later improvement in disease-free survival for those in whom it is achieved. In addition, neo-adjuvant chemotherapy offers additional advantages to the individual patient, improving the rates of conservative surgery, and has therefore become a standard of care for higher risk or larger tumours for which mastectomy might otherwise be indicated. Nevertheless, pathological complete response rates with standard chemotherapy regimens remain relatively low and further improvements would be valuable.

Bevacizumab (Avastin®) is a new humanised monoclonal antibody which targets vascular endothelial growth factor (VEGF) and thereby the neo-angiogenic process in cancer. Bevacizumab has shown promising antitumour effect when given concurrently with taxane-based chemotherapy in breast cancer. ARTemis will address three central hypotheses:

  1. A short course of pre-operative bevacizumab in combination with chemotherapy will improve the pathological complete response to neo-adjuvant treatment for HER2-negative breast cancer patients, and thereby improve their chances of breast conservation, as well as improving disease-free and overall survival.
  2. The existence of independent molecular signatures of response to chemotherapy and to bevacizumab with chemotherapy, which can be detected in paraffin-embedded or fresh frozen tumour tissue. Cost-effective utilisation of bevacizumab in combination with chemotherapy for NHS patients in future will require the use of these signatures to select optimal therapy.
  3. The use of bevacizumab in combination with chemotherapy for NHS patients in future will require a demonstration of cost-effectiveness, and data on the impact of bevacizumab on quality of life will be critical to any such future health assessment.

ARTemis is a phase III, randomised trial to determine whether the addition to neo-adjuvant chemotherapy of antiangiogenic agent bevacizumab is more effective than standard chemotherapy alone in terms of short-term and long-term outcome in patients presenting with HER2-negative early breast cancer. Associated translational science will use prospective molecular profiling and candidate gene analysis on paraffin-embedded and fresh tissue to define molecular predictors of response/ resistance to bevacizumab and chemotherapy. A quality of life sub-study will collect data critical to any future health assessment of bevacizumab in this indication.

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Main inclusion criteria

  • Patient with histological diagnosis of HER2 negative invasive breast cancer.

  • Unifocal tumour:

    • T2 or T3 tumours (>20mm diameter on ultrasound*; see Appendix 3).

    • T4 tumour of any size with direct extension to (a) chest wall or (b) skin.

OR

  • Inflammatory carcinoma with tumour of any size.

OR

  • Other Locally Advanced disease:

    • Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (>20mm diameter on ultrasound*,or clinical N2 or N3, see appendix 3) and primary breast tumour of any diameter.

    • Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (>20mm diameter on ultrasound*, or clinical N2 or N3, see appendix 3), without a primary breast tumour, identified the presence of breast cancer in a Lymph Node (LN) must be histopathologically confirmed by LN biopsy (trucut or whole LN).

OR

  • Multifocal tumour:

    • The sum of each tumours’ maximum diameter must be >20mm on ultrasound* (total radiological tumour size >20mm in the breast only, i.e. excluding axilla).

  • Patients with bilateral disease are eligible to enter the trial provided that one of the breast diseases meets the above criteria.

  • Any hormone receptor status.

  • Patient fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician:

    • Patient must have adequate bone marrow, hepatic, and renal function^.

  • Patient must not have clinically significant cardiac abnormalities and must not have had a previous myocardial infarction during the 6 months prior to recruitment. Cardiac function should be assessed by physical examination and baseline measurement MUST be made of LVEF by MUGA scan or ECHOcardiogram. LVEF must be within the normal range as defined locally by the treating centre (usually at least 50%).

  • ECOG performance status of 0, 1, or 2 (see Appendix 2).

  • No previous or concomitant chemotherapy or biological agents.

  • No previous diagnosis of other malignancy unless:

    • managed by surgical treatment with or without radiotherapy or endocrine therapy, and disease-free for 5 years

    • OR

    • previous basal cell carcinoma

    • previous cervical carcinoma in situ, or other in situ malignancy without invasion

    • contralateral ductal carcinoma in situ of the breast treated by surgery with or without radiotherapy

    • ipsilateral ductal carcinoma in situ of the breast treated by surgery only

  • Non-pregnant and non-lactating, with no intention of pregnancy during chemotherapy, and prepared to adopt adequate barrier contraceptive measures if there is any possibility of pregnancy (males and females).

  • No concomitant medical or psychiatric problems that might prevent completion of treatment or follow-up. 18 years or older

  • Male or female

  • Written informed consent for the trial.

  • Randomisation is recommended within 4 weeks of diagnostic biopsy and chemotherapy should start within 1 week after randomisation. Authorisation must be sought from the Trial Coordinators before randomisation if there is any delay outside of these time frames.

  • Availability of slides and paraffin-embedded tumour blocks from pre-chemotherapy biopsy and from surgical specimen is required.


^Recommendations:

  • Hepatic function:

    • AST/ALT 1.5 x ULN (If <2 x ULN, contact TMG for randomisation authorisation)

    • Alkaline phosphatase 2 x ULN

    • Bilirubin within normal range. If AST/ALT and Alkaline phosphatase are within normal limits then isolated elevation of bilirubin to 3 ULN and a presumptive diagnosis of Gilbert’s syndrome is permitted.

  • Renal function: Creatinine ≤1.5 x ULN (see Appendix 4 for Cockroft and Gault formula)

  • Bone marrow function: Hb >10g/dL; WBC >3 109/L; platelets >100 x 109/L

  • Prothrombin time (PT) and Partial thromboplastin time (PTT/ aPTT): 1.5 x ULN.

*Ultrasound measurements are mandatory for completion of trial CRFs however, if a more accurate radiological test (MRI, spiral CT) is performed at baseline and shows >20mm measurement where the US is ≤20mm, please contact the ARTemis trial office for confirmation of eligibility.

Main exclusion criteria

  1. HER2 positive invasive breast cancer (IHC 3+ or FISH positive).

  2. T0 and T1 tumours in absence of large (total tumour size >20mm) or fixed axillary nodes (see Appendix 3).

  3. Evidence of metastatic disease.

  4. Prior diagnosis of ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, arterial or

  5. venous thromboembolic disease, cardiac failure.

  6. Prior diagnosis of gastroduodenal ulcer, symptomatic diverticulitis, inflammatory bowel disease.

  7. Bleeding diathesis.

  8. On full therapeutic dose of anti-coagulants, or aspirin >325mg/day, clopidogrel >75mg/day or corticosteroids

  9. Uncontrolled hypertension defined by a systolic pressure >150mmHg or diastolic pressure >90mmHg, with or

  10. without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or

  11. adjustment of antihypertensive medication lowers pressure to meet entry criteria.

  12. Presence of active uncontrolled infection.

  13. History of nephritic or nephrotic syndrome.

  14. Major surgical procedure or traumatic injury within 28 days prior to randomisation.

  15. Any evidence of other disease which in the opinion of the investigator places the patient at high risk of

  16. treatment related complication.

  17. Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent

  18. completion of treatment or follow-up.

  19. Non-healing wound, or peptic ulcer, or bone fracture.

  20. On LHRH-agonists for ER strongly positive disease



Chief investigator

Dr Helena Earl

Contact details

Cancer Theme Email: cctu-cancer@addenbrookes.co.uk