Scheduling Nab-paclitaxel With Gemcitabine (SIEGE)

Randomised Phase II Trial to Investigate Two Different Schedules of Nab-paclitaxel (Abraxane) Combined With Gemcitabine as First Line Treatment for Metastatic Pancreatic Ductal Adenocarcinoma

Metastatic pancreatic cancer is difficult to treat. Until recently, most patients would be offered treatment with a chemotherapy drug called gemcitabine. However, a large international trial showed that combining gemcitabine with a drug called nab-paclitaxel (or abraxane) was more effective compared with gemcitabine alone. The purpose of this study is to compare two different ways of combining gemcitabine with abraxane. Conventionally, both drugs are given on the same day via a drip into a vein in the arm but research suggests that giving abraxane 24 hours in advance of gemcitabine could possibly be more beneficial.

In this study, blood and tumour samples will be collected and analysed to try to confirm what has been seen in the laboratory studies. In addition, the investigators wish to find out whether certain tumour characteristics (called biomarkers) can be used to predict for response to chemotherapy.

Study Overview

• Status: Completed
• Conditions: Pancreatic Adenocarcinoma Metastatic
• Intervention / Treatment: Drug: Gemcitabine; Drug: Abraxane (nab-paclitaxel)

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Bangor, United Kingdom
    • Ysbyty Gwynedd
  • Belfast, United Kingdom, BT9 7AB
    • Belfast City Hospital
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital
  • Bristol, United Kingdom
    • Bristol Haematology & Oncology Centre
  • Cardiff, United Kingdom
    • Velindre Cancer Centre
  • Colchester, United Kingdom, CO4 5JL
    • Colchester Hospital
  • Coventry, United Kingdom, CV2 2DX
    • University Hospitals Coventry & Warwickshire
  • Edinburgh, United Kingdom
    • Edinburgh Cancer Research Centre
  • Glasgow, United Kingdom
    • The Beatson Oncology Centre
  • Guildford, United Kingdom
    • The Royal Surrey County Hospital
  • Leeds, United Kingdom
    • St James' Institute of Oncology
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • Liverpool, United Kingdom
    • Clatterbridge Cancer Centre
  • London, United Kingdom, EC1A 7BE
    • Barts Health NHS Trust
  • London, United Kingdom
    • University College London Hospital
  • London, United Kingdom
    • Hammersmith Hospital
  • London, United Kingdom
    • The Royal Free Hospital
  • Manchester, United Kingdom
    • The Christie Hospital
  • Oxford, United Kingdom
    • Churchill Hospital
  • Sheffield, United Kingdom
    • Weston Park Hospital
  • Truro, United Kingdom
    • Royal Cornwall Hospital
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Cambridge University Hospitals NHS Foundation Trust
    • Peterborough, Cambridgeshire, United Kingdom, PE3 9GZ
      • Peterborough City Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged ≥ 18 years old
• Signed informed consent and ability to comply with the protocol
• Histologically or cytologically confirmed metastatic PDAC
• 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
• Karnofsky performance status ≥70%
• Life expectancy >12 weeks from the date of screening assessment

• Adequate bone marrow function

  • Absolute neutrophil count (ANC) ≥1.5 x 109 /L
  • Haemoglobin (Hb) ≥ 100 g/L
  • Platelets ≥100 x 109 /L
  • White blood cell count (WBC) ≥ 3 x 109 /L

• Adequate liver function

  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x upper limit of normal range (ULN)
  • Total bilirubin <1.5 x ULN
• Adequate renal function defined as a serum creatinine ≤1.5 x ULN or calculated creatinine clearance by Cockcroft-Gault of ≥50 mL/min
• Received no prior systemic therapy for metastatic disease
• Prior adjuvant chemotherapy (with GEM or any other drug/s) is allowed if completed at least 6 months previously
• Prior radiotherapy is allowed as long as there is measurable disease which has not been irradiated
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, completion of QoL and HE questionnaires and other study procedures
• Confirmation of tumour tissue sample collected within 12 weeks prior to randomisation and blood to be taken prior to randomisation
• 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
• 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

Exclusion Criteria:

• Patients with operable or locally advanced PDAC
• Other invasive malignancies diagnosed within the last 5 years, except non-melanoma skin cancer and localized cured prostate cancer

• 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:

  • 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
  • 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
  • Patients with a history of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, cystic fibrosis or bronchiectasis
  • 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
  • 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
  • Presence of active infection
  • Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C
  • Known allergy or hypersensitivity to GEM or ABX
• Women who are pregnant, plan to become pregnant or are lactating

• Routine use of any of the following will exclude patients:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Concomitant; Intravenous Abraxane125 mg/m2 30-minute infusion followed immediately by intravenous Gemcitabine 1000 mg/m2 30-minute infusion will be administered on days 1, 8 and 15 of a 4-week cycle.	Drug: Gemcitabine; Drug: Abraxane (nab-paclitaxel)
ACTIVE_COMPARATOR: Sequential; Intravenous Abraxane 125 mg/m2 30-minute infusion will be administered on days 1, 8 and 15 of a 4-week cycle. Intravenous Gemcitabine 1000 mg/m2 30-minute infusion will be administered on days 2, 9 and 16 of a 4-week cycle. Gemcitabine must be delivered 24 +/- 2 hours after commencing Abraxane infusion.	Drug: Gemcitabine; Drug: Abraxane (nab-paclitaxel)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	The primary objective of the trial is to investigate the outcome of sequential administration of nab-paclitaxel combined with gemcitabine (ABX/GEM, 24 hours apart) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) in terms of progression-free survival.	From participant randomisation to the point at which disease progression is reported (i.e. 12 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Safety	Adverse Events (including Serious Adverse Events), abnormal laboratory test results and performance status	1 year after end of treatment visit
Treatment Efficacy	response to treatment assessed using radiological RECIST criteria	8 weeks

Collaborators and Investigators

• Sponsor: CCTU- Cancer Theme
• Collaborators: Celgene
• Investigators: Principal Investigator: Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital

Publications and helpful links

General Publications

• Corrie PG, Qian W, Basu B, Valle JW, Falk S, Lwuji C, Wasan H, Palmer D, Scott-Brown M, Wadsley J, Arif S, Bridgewater J, Propper D, Gillmore R, Gopinathan A, Skells R, Bundi P, Brais R, Dalchau K, Bax L, Chhabra A, Machin A, Dayim A, McAdam K, Cummins S, Wall L, Ellis R, Anthoney A, Evans J, Ma YT, Isherwood C, Neesse A, Tuveson D, Jodrell DI. Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma. Br J Cancer. 2020 Jun;122(12):1760-1768. doi: 10.1038/s41416-020-0846-2. Epub 2020 Apr 30.

Helpful Links

• University of Cambridge Pancreatic Cancer Centre

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ACTUAL): June 1, 2016
• Study Completion (ACTUAL): June 1, 2016

Study Registration Dates

• First Submitted: May 1, 2014
• First Submitted That Met QC Criteria: May 17, 2018
• First Posted (ACTUAL): May 18, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 16, 2019
• Last Update Submitted That Met QC Criteria: July 15, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Gemcitabine; Paclitaxel; Albumin-Bound Paclitaxel
• Other Study ID Numbers: SIEGE (AX-PANC-PI-0101)