Systemic Therapy and Chemoradiation in Advanced Localised Pancreatic Cancer - 2

Study Overview
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Brief Summary
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This study will evaluate the role of increasing radiotherapy dose and addition of nelfinavir to chemoradiotherapy (CRT) in patients with inoperable pancreatic cancer that has not spread beyond the pancreas. Currently in the United Kingdom (UK), either chemotherapy alone or chemotherapy followed by CRT can be used in the management of inoperable pancreatic cancer that has not spread. CRT consists of 25-30 radiotherapy treatments in combination with chemotherapy. Although this treatment is effective in controlling local symptoms and slowing down the pace of cancer, in most cases it is unable to shrink it enough to make it operable. Some of the reasons for this could be the lack of oxygen and lack of blood flow within the tumour making it resistant to the effects of CRT. This study will investigate whether increasing the dose of radiotherapy, or increasing the oxygen and blood supply to the tumour by giving nelfinavir, or a combination of both, can improve outcomes. We also want to know what the additional toxicities from such intensive approaches are. All participants will initially receive 12 weeks of chemotherapy, and those with stable or responding disease will receive further study treatment. The treatment allocation to 1 of the 5 options outlined below will be done at random by computer and neither the doctor nor the patient can choose the treatment option. The process of randomisation ensures that all treatment arms are equally balanced in terms of patient and tumour characteristics, and to reduce the possibility of bias. The study will consist of 2 stages. In the 1st stage we aim to find the right dose of nelfinavir to combine with CRT, and this will require around 27 participants of whom up to 18 will receive nelfinavir together with CRT. In the 2nd stage, we want to find out the benefits of this approach over and above standard treatments and therefore we will recruit the order of 262 participants and allocate 170 to 1 of the 5 following treatment arms: Arm A: Nelfinavir together with CRT Arm B: CRT (without nelfinavir) Arm C: Nelfinavir together with CRT (but using a higher than conventional dose of radiotherapy) Arm D: CRT without nelfinavir (but using a higher than conventional dose of radiotherapy) Arm E: Chemotherapy alone (without radiotherapy) Participants who are ineligible or refuse randomisation will be treated as per local standard but will remain in the study for follow up at 26, 39 and 52 weeks. Their data will contribute to an Overall Survival (OS) analysis.

Official Title
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A Multi-centre Randomised Study of Induction Chemotherapy Followed by Capecitabine (+/-Nelfinavir) With High or Standard Dose Radiotherapy for Locally Advanced Non-metastatic Pancreatic Cancer

Conditions
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Pancreatic Neoplasms (Locally Advanced Non-metastatic)

Intervention / Treatment
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* Drug: nab-paclitaxel
* Radiation: 60Gy in 30#
* Radiation: 50.4Gy in 28#
* Drug: Nelfinavir
* Drug: Capecitabine
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 1. Aged 18 years or over Histologically or cytologically proven carcinoma of the pancreas Locally advanced, non-metastatic inoperable disease as per NCCN criteria (APPENDIX 2). The following types of interventions are allowed: Palliative bypass procedure Common bile duct stenting Primary pancreatic lesion 6 cm or less in diameter (taken from scan results) WHO PS 0-1 (APPENDIX 1) Adequate haematological function: neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L and haemoglobin ≥100g/L Adequate liver function tests: Serum bilirubin ≤1.5 x ULN. In participants who have had a recent biliary drain and whose bilirubin is improving, a value of ≤3 x ULN is acceptable, however treatment should not start unless Bilirubin is ≤1.5 x ULN. AST and/or ALT ≤ 3 x ULN. Adequate renal function (GFR ≥ 50ml/min (Cockcroft & Gault - APPENDIX 3)) Written informed consent obtained Women of child-bearing potential must have negative serum or urine pregnancy test within 14 days prior to registration, must agree to use a highly effective contraception method during GEMABX treatment and for 30 days after last administration of GEMABX and to use an acceptable contraception method during chemoradiotherapy and for 6 months after completion of all treatment. Male patients must be surgically sterile or must agree to use a condom during GEMABX treatment and for 90 days after last administration of GEMABX, and to use a condom during chemoradiotherapy and for three months after completion of chemoradiotherapy. Exclusion criteria: Primary resectable cancer of the pancreas. Distant metastases Pregnant or breast-feeding patients. Any evidence of severe uncontrolled systemic diseases including uncontrolled coronary artery disease, myocardial infarction or stroke within the last 6 months, any major systemic or psychiatric co-morbidities or any other considerations that the PI judges might impact on patient safety or protocol compliance and achievement of the study aims. Previous malignancies in the preceding 3 years except for: In situ cancer of the uterine cervix Adequately treated basal cell skin carcinoma Adequately treated early stage non-pancreatic malignancy in complete remission for at least 3 years Renal abnormalities including adult polycystic kidney disease or hydronephrosis or ipsilateral single kidney (i.e. functioning right kidney for head tumours; left kidney for tail tumours) that may preclude upper abdominal radiotherapy without damaging functional kidneys. Previous RT to upper abdomen Recurrent cancer following definitive pancreatic surgery Lymphoma or neuroendocrine tumours of the pancreas Known haemophilia A and B, chronic hepatitis type B or C. Other experimental treatment 6 weeks or less prior to registration into this study (including chemothera¬py and immunotherapy). Known hypersensitivity to any of the IMPs or any of their excipients. Known dihydropyrimidine dehydrogenase (DPD) deficiency Known galactose intolerance, Lapp-lactose deficiency or glucose-galactose malabsorption History of severe unexpected reaction to fluoropyrimidine therapies If the following concomitant medications cannot be discontinued temporarily during the CRT phase then the patients cannot enter the trial: Sorivudine and analogues e.g. brivudine Methotrexate. Allopurinol and dipyridamole Known HIV positive disease (but routine screening for HIV is not required)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15. | Drug: nab-paclitaxel<br>* Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state<br>* Other names: Abraxane;Radiation: 50.4Gy in 28#<br> <br> Drug: Nelfinavir<br>* VIRACEPT® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease.<br>* Other names: Viracept;Drug: Capecitabine<br>* Given in combination with gemcitabine, known as GemCap.<br>Drug: Gemcitabine<br>* Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion<br>* Other names: GEMZAR;|
| Experimental: Arm B<br>12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 50.4Gy in 28# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15. | Drug: nab-paclitaxel<br>* Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state<br>* Other names: Abraxane;Radiation: 50.4Gy in 28#<br> <br> Drug: Capecitabine<br>* Given in combination with gemcitabine, known as GemCap.<br>Drug: Gemcitabine<br>* Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion<br>* Other names: GEMZAR;|
| Experimental: Arm C<br>12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 60Gy in 30# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15 | Drug: nab-paclitaxel<br>* Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state<br>* Other names: Abraxane;Radiation: 60Gy in 30#<br> <br> Drug: Nelfinavir<br>* VIRACEPT® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease.<br>* Other names: Viracept;Drug: Gemcitabine<br>* Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion<br>* Other names: GEMZAR;|
| Experimental: Arm D<br>12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 60Gy in 30# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15. | Drug: nab-paclitaxel<br>* Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state<br>* Other names: Abraxane;Radiation: 60Gy in 30#<br> <br> Drug: Gemcitabine<br>* Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion<br>* Other names: GEMZAR;|
| Experimental: Arm E<br>6 cycles of GEMABX* *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15. | Drug: nab-paclitaxel<br>* Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion<br>* Other names: GEMZAR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 12 months | 
| Progression free survival |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Common Toxicity Criteria for Adverse Effects (CTCAE) v 4.02 | 12 months | 
| Quality of life | European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ) - C30 and PAN26 for pancreatic cancer. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chemoradiotherapy, nelfinavir, abraxane, gemcitabine, radiotherapy, capecitabine