Scheduling nab-paclItaxEl with GEmcitabine

Research summary

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 32,500 deaths per year in Europe. In the absence of resectable disease, it is almost uniformly lethal. Only around 10-20% of patients present with operable disease and with the addition of adjuvant chemotherapy, 5-year survival in this group is 29%. At presentation, 50-60% of patients are diagnosed with metastatic disease. There is a great need to improve upon current treatment.

Metastatic PDAC carries a poor prognosis. Gemcitabine (GEM) is the international standard of care with a median survival of 5.7 months. Recently, the combination chemotherapy regimen FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) was reported to generate a superior progression-free survival (median PFS: 6.4 versus 3.3 months) and overall survival (median OS: 11.1 versus 6.8 months) in metastatic PDAC compared with GEM alone. Despite optimism arising from these results, the population in this trial was highly selected in having a high proportion of patients with tumours located in the tail and body rather than, more commonly, head of pancreas and a low number of patients with indwelling biliary stents. There were 46% of patients who experienced grade 3/4 neutropaenia. This regimen is unlikely to be tolerated by all patients with metastatic PDAC. Prospective trials are ongoing or in development to further evaluate either standard or modified, FOLFIRINOX, in both operable and inoperable disease. There is clearly a need for other treatment options for these patients.

Metastatic PDAC carries a poor prognosis. Two combination chemotherapy regimens have been shown to improve overall survival over the standard single-agent GEM. The FOLFIRINOX regimen is suitable for a highly selected patient population and associated with significant drug-related side effects. The concomitant ABX/GEM regimen was reported to be less toxic than FOLFIRINOX. Studies in mouse models of PDAC suggest that delivery of ABX 24 hours prior to GEM might result in higher intra-tumoural GEM concentrations. Thus, scheduling of these two drugs may be critical to optimising clinical benefit.

SIEGE is a multi-centre, randomised open-label two-arm phase II trial. It is designed to investigate two different schedules of ABX combined with GEM (concomitant ABX/GEM and sequential ABX/GEM) as first-line treatment for metastatic PDAC patients. Progression-free survival is the primary endpoint. Research tumour and blood samples will be collected prospectively. This is a multi-centre trial with 23 participating sites across the UK. SIEGE is centrally co-ordinated at the Cambridge Clinical Trials Unit – Cancer Theme (CCTU-CT). The plan is to recruit at least 146 patients. The duration of treatment is expected to be 24 weeks (6 cycles of 4-weekly chemotherapy). After completion of 6 cycles of treatment, patients who benefit from the treatment may continue the same regimen until the protocol-defined disease progression or beyond at the investigator’s discretion. A minimum of one-year follow-up from the date of randomisation is required for all surviving patients.

Main inclusion criteria

  1. Aged ≥ 18 years old
  2. Signed informed consent and ability to comply with the protocol
  3. Histologically or cytologically confirmed metastatic PDAC
  4. Radiologically confirmed stage IV disease and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; baseline tumour assessments and measurements must be done within 28 days prior to randomisation
  5. Karnofsky performance status ≥70%
  6. Life expectancy >12 weeks from the date of screening assessment
  7. Adequate bone marrow function:

    1. Absolute neutrophil count (ANC) ≥1.5 x 109 /L
    2. Haemoglobin (Hb) ≥ 100 g/L
    3. Platelets ≥100 x 109 /L
    4. White blood cell count (WBC) ≥ 3 x 109 /L
  8. Adequate liver function:

    1. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x upper limit of normal range (ULN)
    2. Total bilirubin <1.5 x ULN
  9. Adequate renal function defined as a serum creatinine ≤1.5 x ULN or calculated creatinine clearance by Cockcroft-Gault of ≥50 mL/min

  10. Received no prior systemic therapy for metastatic disease
  11. Prior adjuvant chemotherapy (with GEM or any other drug/s) is allowed if completed at least 6 months previously
  12. Prior radiotherapy is allowed as long as there is measurable disease which has not been irradiated
  13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, completion of QoL and HE questionnaires and other study procedures
  14. Confirmation of tumour tissue sample collected within 12 weeks prior to randomisation and blood to be taken prior to randomisation
  15. Women of child-bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if age ≤55 years or 12 months if age >55 years, must have a negative serum or urine pregnancy test within 14 days prior to randomisation
  16. All WCBP and all sexually active male patients must agree to use effective contraception methods throughout the study and for 30 days after the final dose of study drug for WCBP and for up to 6 months after treatment for male patients

Main exclusion criteria

The presence of any of the following will exclude patients:

  1. Patients with operable or locally advanced PDAC
  2. Other invasive malignancies diagnosed within the last 5 years, except non-melanoma skin cancer and localized cured prostate cancer
  3. Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial. Examples include, but are not limited to:

    1. Patients who have had a venous thromboembolic event who are not appropriately anticoagulated or have had a significant bleeding episode in the 3 weeks prior to randomisation
    2. Patients with symptoms of severe chronic obstructive airways disease or significant shortness of breath at rest AND have an FEV1<1.0 L within the last 6 months
    3. Patients with a history of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, cystic fibrosis or bronchiectasis
    4. Patients with uncontrolled ischaemic heart or other cardiovascular event (myocardial infarction (MI), new angina, stroke transient ischaemic attack (TIA), or new congestive cardiac failure (CCF)) within the last 6 months
    5. Patients with stable but significant cardiovascular disease defined by heart failure (New York Heart Association Functional Classification (NYHF) III or IV, see Appendix 3) or frequent angina
    6. Presence of active infection
    7. Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C
    8. Known allergy or hypersensitivity to GEM or ABX
  4. Women who are pregnant, plan to become pregnant or are lactating

  5. Routine use of any of the following will exclude patients:

    1. Oral anti-oxidant supplements: beta-carotene, selenium, lutein, zeaxanthin, lycopene, pycnogenol, fernblock, omega-3S, vitamin C, vitamin E, astaxanthin

Funders and sponsors

Chief investigator

Dr Pippa Corrie

Contact details

Cancer Theme Email: [email protected]