Systemic Therapy and Chemoradiation in Advanced Localised Pancreatic Cancer - 2

• Status: Unknown status
• Trial end date: 2020-08-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Oxford
• Collaborators: Cancer Research UK; Celgene
• Treatments: Albumin-Bound Paclitaxel; Capecitabine; Gemcitabine; Nelfinavir; Paclitaxel

Criteria

Inclusion criteria:

1. 1. Aged 18 years or over

2. Histologically or cytologically proven carcinoma of the pancreas

3. Locally advanced, non-metastatic inoperable disease as per NCCN criteria (APPENDIX 2). The following types of interventions are allowed:

1. Palliative bypass procedure

2. Common bile duct stenting

4. Primary pancreatic lesion 6 cm or less in diameter (taken from scan results)

5. WHO PS 0-1 (APPENDIX 1)

6. Adequate haematological function: neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L and haemoglobin ≥100g/L

7. Adequate liver function tests:

1. 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.

2. AST and/or ALT ≤ 3 x ULN.

8. Adequate renal function (GFR ≥ 50ml/min (Cockcroft & Gault - APPENDIX 3))

9. Written informed consent obtained

10. 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.

11. 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:

1. Primary resectable cancer of the pancreas.

2. Distant metastases

3. Pregnant or breast-feeding patients.

4. 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.

5. Previous malignancies in the preceding 3 years except for:

1. In situ cancer of the uterine cervix

2. Adequately treated basal cell skin carcinoma

3. Adequately treated early stage non-pancreatic malignancy in complete remission for at least 3 years

6. 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.

7. Previous RT to upper abdomen

8. Recurrent cancer following definitive pancreatic surgery

9. Lymphoma or neuroendocrine tumours of the pancreas

10. Known haemophilia A and B, chronic hepatitis type B or C.

11. Other experimental treatment 6 weeks or less prior to registration into this study (including chemothera¬py and immunotherapy).

12. Known hypersensitivity to any of the IMPs or any of their excipients.

13. Known dihydropyrimidine dehydrogenase (DPD) deficiency

14. Known galactose intolerance, Lapp-lactose deficiency or glucose-galactose malabsorption

15. History of severe unexpected reaction to fluoropyrimidine therapies

16. If the following concomitant medications cannot be discontinued temporarily during the CRT phase then the patients cannot enter the trial:

1. Sorivudine and analogues e.g. brivudine

2. Methotrexate.

3. Allopurinol and dipyridamole

17. Known HIV positive disease (but routine screening for HIV is not required)