| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced non-metastatic pancreatic cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced pancreatic cancer that has not spread around the body |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033606 |
| E.1.2 | Term | Pancreatic cancer non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objective of Stage 1 was to determine the Maximum Tolerated Dose (MTD) of nelfinavir to be administered alongside chemoradiotherapy and therefore to establish the dose of nelfinavir to be taken forward into Stage 2.
There are 2 co-principal research objectives of Stage 2 which are:
1. Does increasing radiotherapy dose schedule from 50.4Gy (in 28 fractions) to 60Gy (in 30 fractions) improve the overall survival (OS) in LAPC?
2. Does the addition of nelfinavir to chemoradiotherapy improve progression free survival (PFS) in locally advanced non-metastatic pancreatic cancer?
The aim is to select the best chemoradiotherapy regimen/s that can be taken forward to compare against chemotherapy alone in order to define the best treatment for this group of patients.
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| E.2.2 | Secondary objectives of the trial |
Stage 2: Secondary objectives:
1. To evaluate safety, overall survival and resection rates and compliance with the addition of nelfinavir to CRT
2. To study the effect of increasing radiotherapy dose schedule on progression free survival, 12 month overall survival rate, resection rates and safety
3. To assess the quality of life for each arm.
4. To measure CA19-9 level, 1 year local control rate for each arm
5. To determine disease response rate for each arm
Stage 2: Exploratory objective:
1. To evaluate the proportion and time to receive subsequent treatment for each arm
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| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Functional imaging cohort
a) To demonstrate feasibility of conducting multiparametric MRI at multiple time points in patients with pancreatic cancer
b) Image differential changes in perfusion within patients on treatment of LAPC using DCE-MRI
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| E.3 | Principal inclusion criteria |
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. The following types of interventions are allowed:
a. Palliative bypass procedure
b. Common bile duct stenting
4. Primary pancreatic lesion 6cm or less in diameter (taken from scan results)
5. WHO PS 0-1
6. Adequate haematological function: neutrophils ≥1.5 x 109/L and platelets ≥100 x 109/L
7. Adequate liver function tests:
a. Serum bilirubin ≤1.5 x ULN. In participants who have had a recent biliary drain and whose bilirubin is descending, a value of ≤3 x ULN is acceptable, however treatment should not start unless Bilirubin is ≤1.5 x ULN.
b. AST and/or ALT ≤ 3 x ULN
8. Adequate renal function: GFR ≥ 40 mL/min using a validated creatinine clearance calculation (e.g. Cockcroft-Gault (Appendix 3) or, Wright formula, or as per local standard).
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 6 months 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 6 months after last administration of GEMABX, and to use a condom during chemoradiotherapy and for three months after completion of chemoradiotherapy or whichever date comes last.
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| E.4 | Principal exclusion criteria |
If any of the following criteria apply, patients cannot be included in the trial:
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 six 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 three years except for:
a. In situ cancer of the uterine cervix
b. Adequately treated basal cell skin carcinoma
c. Adequately treated early stage non-pancreatic malignancy in complete remission for at least three years
6. Renal abnormalities including adult polycystic kidney disease or hydronephrosis or ipsilateral single kidney (ie 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 six weeks or less prior to registration into this study (including chemotherapy and immunotherapy).
12. Known hypersensitivity to any of the IMPs or any of their excipients e.g. hypersensitivity to products containing albumin
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 as they interact with Capecitabine:
a. Sorivudine and analogues e.g. brivudine
b. Methotrexate.
c. Allopurinol and dipyridamole
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1: The Maximum Tolerated Dose (MTD) to be administered alongside chemoradiotherapy in Stage 2 and safety.
Stage 2: Co-primary outcome measures:
1. Concurrent biological question (-nelfinavir vs +nelfinavir): Progression free Survival (PFS) (time from registration to event) (progression or death if death occurred without progression). Patients who are not assessed to have disease progression and are not observed to die during the course of the trial will be censored at the last known progression free follow-up date).
2. RT dose question (50.4Gy vs 60Gy): 12 month overall survival (OS) (time from registration to event (death by any cause); patients who are not observed to die during the course of the trial will be censored at the last known date alive prior to end of trial date)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Stage 1: week 26; Stage 2: 1. From date of registration until the date of first disease progression or 2. date of death from any cause, assessed up to 12 months after the last patient is registered. |
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| E.5.2 | Secondary end point(s) |
• Toxicity (-nelfinavir vs +nelfinavir; 50.4Gy vs 60Gy): will be scored using the NCI CTCAE v4.03 at registration, during treatment, post treatment and during follow up of randomised participants. Serious adverse events will be collected “real-time”
• Chemotherapy treatment compliance (-nelfinavir vs +nelfinavir)
• Overall Survival (-nelfinavir vs +nelfinavir): Time from registration to death by any cause and those still alive will be censored at time last known alive
• 12 month Overall survival rate: number of participants who survive at 12 months (50.4Gy vs. 60Gy)
• Surgical resection (of primary tumour) rate (-nelfinavir vs +nelfinavir; 50.4Gy vs 60Gy)
• Progression-free survival (time to event (progression)) (50.4Gy vs 60Gy)
• Quality of life will be assessed by the EORTC QLQ-C30 and PAN26 and EQ-5D questionnaires
• CA19-9 level: in units per ml
• 1 year Local Control rate
• Disease response at each CT scan based on RECIST v1.1: complete response, partial response, progressive disease, stable disease
Exploratory outcome measures
Subsequent treatment: proportion of patients receiving subsequent treatment, and time to 1st subsequent treatment for each arm
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage 1 assessments same as Arm A Stage 2
Toxicity
Arms A-D weeks 1, 5, 9, 13, CRT week 1-6 Post-CRT +1, +3, +6, +18, +28 weeks
Arms A and C nelfinavir induction week
Overall survival
All patients time of registration to week 28 follow-up visit
Quality of Life
Arms A-D: weeks 1, CRT week 1, Post- CRT, +1, +6, +18, +28 weeks
CA19-9
Arms A-D week 1, 5, 9, 13, CRT week 1. Post-CRT +6, +18, +28 weeks
Disease progression
Spiral/ multi-slice CT (all patients) screening, cycle 3 week 3/4 , EOT +6 , +18, +28
Subsequent treatment collected |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 24 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS
For the purposes of the Research Ethics Committee (REC) and regulatory authority approval, the trial end date is deemed to be the date of the last data capture which is the point at which all the data has been entered and queries resolved |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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