PRICKLE

Pancreatic Resectability in Cancers with Known Limited Extension

Research summary

In the absence of resectability, pancreatic ductal adenocarcinoma (PDAC) is almost uniformly lethal; therefore there is a great need to optimize novel therapeutic approaches. Only around 10-20% of patients present with operable disease and with the addition of adjuvant chemotherapy, 5-yr survival in this group is 29%. At presentation, 50-60% of patients are diagnosed with metastatic disease and with palliative gemcitabine-based chemotherapy show a median survival of 5.7 months. More recently, combination chemotherapy using Fluorouracil/Oxaliplatin/ Leucovorin/ Irinotecan (FOLFIRINOX) has resulted in improved overall survival (OS: 11.1m vs. 6.8m) in the advanced setting over gemcitabine alone. However, toxicity, particularly febrile neutropenia requiring hospitalisation, was a major concern, raising doubts over the feasibility of delivering this regimen to the general population of patients with advanced pancreatic cancer.

Inoperable locally advanced pancreatic cancer (LAPC) accounts for 30-40% of advanced disease and is generally determined by vascular encasement, which is not amenable to surgical resection and vascular reconstruction. It shares a poor prognosis with median survival of around 9 months. The optimal management for LAPC is controversial, with gemcitabine-based chemotherapy or chemoradiotherapy resulting in a median survival in the range of 10-13 months. Resectability in LAPC patients is associated with poor long-term survival, even with use of adjuvant chemotherapy, due to considerable rates of local recurrence and high probability of involved resection margins (R1). In addition to nodal status, R1 resection strongly predicts early recurrence and short survival. Given the high likelihood of positive resection margins and thus poor outcomes, there is a strong argument against primary surgery in this group.

The long-term goal is to improve survival of patients with unresectable pancreatic cancer by permitting local control through resection and treatment of micrometastatic disease. The study population of LAPC patients in this study will be stringently defined by preset criteria and prospectively assessed for resectability by independent assessors. Detailed exploratory imaging and histological analysis of responding and non-responding tumours will be assessed through repeat biopsies, elastography and dynamic contrast enhancement studies of primary pancreatic tumours. Novel magnetic resonance imaging (MRI) techniques including dynamic-contrast enhanced (DCE)-MRI and diffusion-weighted (DW) - MRI will be employed to assess how non-invasive imaging can compare to EUS imaging correlates for tumour and stroma. No selection of patients based on SPARC expression will be attempted for this study. We will instead be monitoring changes in CDA activity with treatment, and assessing whether baseline CDA immunohistochemical staining of tumour can identify those patients who derive clinical benefit. Alongside CDA, novel biomarker analysis will be attempted in the pre-, peri- and post-operative period using ctDNA23-25 evaluating serial sets of blood samples with matched fresh tissue following neo-adjuvant therapy or in the relapse setting.

We propose that the tumour shrinkage (response) seen in Stage IV pancreatic cancer patients as a result of ABX/GEM may translate to a realistic prospect of downstaging borderline unresectable LAPC tumours sufficiently to enable resection. Notionally, even in the absence of a classical partial response by RECIST criteria (≥30% reduction in sum of longest diameters) a beneficial outcome may arise from any tumour shrinkage sufficient to permit the tumour to be separated from major vessels thus rendering it resectable. Such an outcome may significantly alter the poor survival outcomes in this group of patients. The PRICKLE clinical study paradigm is useful for evaluating novel agents and combinations that show impressive activity in the pre-clinical or advanced setting and offers an opportunity for detailed correlative translational studies to evaluate activities of therapy.

This is a single-centre, non-randomised, phase 2a, single arm, Simon two-stage design trial of nab-paclitaxel and gemcitabine (ABX/GEM) in patients with histological documentation of pancreatic ductal adenocarcinoma (PDAC) who are determined by central radiological review to have “category 2” borderline unresectable LAPC. We will investigate the feasibility of administering ABX/GEM in terms of safety and efficacy, and will study activity both in terms of radiological response and the feasibility of downstaging patients to “category 1” status, in order to attempt resection after up to 6 cycles of combination treatment. In addition to adding to data on the safety and tolerability of this combination, peri- and post-operative morbidity following this treatment will be evaluated. As part of the trial, detailed correlative studies will be undertaken to evaluate the mechanism of action of the combination, at a tissue level, a circulating biomarker level and a radiological level.

clinicaltrials.gov

Main inclusion criteria

  • Patients with borderline unresectable advanced pancreatic adenocarcinoma, defined as Category 2 by central radiological review.

  • Aged 18 years or over at the time of signing the informed consent form.

  • Documented histological or cytological diagnosis of pancreatic ductal adenocarcinoma.

  • ECOG performance status 0-1.

  • Life expectancy of at least 12 weeks.

  • Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.

  • Adequate haematological function defined by:

    • Absolute neutrophil count (ANC) ≥1,500 cells/mm3 (1.5 x 109/L).

    • Haemoglobin ≥8.0 g/dL (80 g/L) (may be increased to this level with transfusion as long as there is no evidence of active bleeding).

    • Platelets ≥100x 109/L

  • Adequate renal function defined by serum creatinine≤1.5 x ULN or calculated creatinine clearance by Cockcroft-Gault of ≥50 ml/min.

  • Adequate hepatic function defined by:

    • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN)

    • Total bilirubin ≤1.5 x ULN

  • Patients may have endoscopic or radiologic stenting to treat biliary obstruction. If so, bilirubin must return to ≤1.5 x ULN prior to enrolment.

  • Received no prior therapy for their disease.

  • Measurable disease by RECIST 1.1 criteria. Tumour assessments and measurements must be done within 28 days before the patient receives the first dose of ABX/GEM.

  • All Women of Child Bearing Potential (WoCBP) and all sexually active male patients must agree to use effective contraception methods throughout the study and for 6 months after the final dose of trial drug.

Main exclusion criteria

  • Patients with metastatic PDAC, or disease which is amenable to resection with curative intent. These include tumours which are defined as Category 1 or 3 by central radiological review

  • Other invasive malignancies diagnosed within the last 5 years, with the exceptions of adequately treated localized cured prostate cancer, in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for three years or more and are deemed at negligible risk for recurrence, are eligible for the trial

  • Known allergy or hypersensitivity to ABX or GEM

  • Routine use of oral anti-oxidant supplements: beta-carotene, selenium, lutein, zeaxanthin, lycopene, pycnogenol, fernblock, omega-3S, vitamin C, vitamin E, astaxanthin. If recent use, a washout period of 5 half-lives is required

  • Patients with pre-existent ischemic heart disease particularly those under active treatment for coronary disease, will be excluded from Sonuvue dynamic contrast enhanced ultrasound investigation due to sporadic reports of cardiac ischemia in this population. They will be eligible for the rest of the study, as long as their cardiac status does not preclude surgery

  • 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 study. Examples include, but are not limited to:

    • Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation who are not appropriately anti-coagulated or have had a NCI CTCAE (version 4.0) Grade 2 or greater bleeding episode in the 4 weeks before Day 1

    • Patients taking warfarin, unless it is possible for the patient to be switched to a low molecular weight heparin for the duration of the study

    • Patients with a significant history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months

    • ACirrhotic liver disease, ongoing alcohol abuse, or known chronic active or acute hepatitis B, or hepatitis C

    • Known infection with HIV

  • Women, who are pregnant, plan to become pregnant or are lactating (during the study or for up to 6 months after the last dose)

Funders and sponsors

Chief investigator

Dr Bristi Basu

Contact details

Cancer Theme Email: [email protected]