A prospective, phase II, double blinded, multicentre, randomised clinical trial comparing combination gemcitabine and vandetanib therapy with gemcitabine therapy alone in locally advanced or metastatic pancreatic carcinoma
To assess whether survival times for patients receiving gemcitabine plus vandetanib are longer than for those patients receiving gemcitabine alone as first line treatment for advanced pancreatic cancer.
First MREC, 04/07/2011, ref: 11/LO/0097
Prospective phase II placebo-controlled multicentre randomised clinical trial
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
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Upper gastro-intestinal cancer, Pancreatic cancer
The planned treatment duration per patient will be until progression of disease, unacceptable toxicity or withdrawal of consent. The end of the study will be 12 months after the recruitment of the last patient. Patients who stop treatment before having developed progressive disease (PD) will be assessed every 6 weeks for response until PD occurs.Subjects will be randomised equally to two arms:
1. Arm A (standard therapeutic arm): Placebo orally once a day continuously together with Gemcitabine 1000mg/m 2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by gemcitabine 1000mg/m 2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.
2. Arm B: vandetanib orally once a day continuously at 300 mg/day together with Gemcitabine 1000mg/m 2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m 2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.
Gemcitabine administration: Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles. Vandetanib administration, 300mg/day orally continuously in the form of a white tablet. Followed up at 24 months
Primary outcome measures
1. Assessment of survival times between the two arms
2. Assess survival between subjects on arm A compared to arm B
Secondary outcome measures
1. Progression-free survival time (PFS)
2. Objective response rate
3. Disease control rate
4. Toxicity and safety
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Age > 18 years
2. Histologically or cytologically proven pancreatic ductal adenocarcinoma or undifferentiated carcinoma of the pancreas
3. Locally advanced or metastatic disease precluding curative surgical resection or definitive locally directed therapies such as chemo radiation. Patients who have relapsed following previously resected pancreatic cancer can be included.
4. Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis within 28 days prior to commencing treatment
5. Unidimensionally measurable disease as shown by CT scan, in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) guidelines (version 1.1).
6. ECOG performance status 0, 1 or 2 where the investigator feels that treatment with combination chemotherapy, for example FOLFIRINOX, is not appropriate
7. Platelets >100 x 109/l; WBC > 3 x 109/l; neutrophils > 1.5 x 109/l at entry
8. Documented Life expectancy > 3 months
9. Informed written consent
10. Male and female participants
Target number of participants
Planned Sample Size: 120; UK Sample Size: 120
Participant exclusion criteria
1. Laboratory results: Serum bilirubin >1.5x the upper limit of reference range (ULRR). Creatinine clearance < 30 mL/minute (calculated by Cockcroft-Gault formula).
Potassium, <4.0 mmol/L despite supplementation; or above the CTCAE grade 1 upper limit. Magnesium below the normal range despite supplementation, or above the CTCAE grade 1 upper limit. Serum corrected calcium above the CTCAE grade 1 upper limit. In cases where the serum calcium is below the normal range despite supplementation. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 ULRR or alkaline phosphatase (ALP) >2.5 x ULRR, or > 5x ULRR if judged by the investigator to be related to liver metastases.
2. Medical or psychiatric conditions compromising informed consent
3. Intracerebral metastases or meningeal carcinomatosis
4. Major surgery within 4 weeks or incompletely healed surgical incision before starting study therapy
5. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigators opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
6. Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart disease =2 within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia
7. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation), which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded
8. QTc prolongation with other medications that required discontinuation of that medication
9. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
10. Presence of left bundle branch block (LBBB)
11. QTc with Bazetts correction that is un-measurable, or 480 msec on screening ECG
(Note: If a subject has a QTc interval 480 msec on screening ECG, the screen ECG may be repeated twice [at least 24 hours apart]. The average QTc from the three screening ECGs must be <480 msec in order for the subject to be eligible for the study.) Patients who are receiving a drug that has a risk of inducing Torsades-de-Pointes are excluded if QTc is = 460 msec.
12. Any concurrent medication with a known risk of inducing Torsades-de-Pointes, that in the investigators opinion cannot be discontinued, are allowed; however, these patients must be monitored closely (please see section 4.2).
13. Concomitant medications that are potent inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital and St. John's Wort) of CYP3A4 function.
14. Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg).
15. Currently active diarrhoea that may affect the ability of the patient to absorb the vandetanib or tolerate diarrhoea secondary to vandetanib should that occur as a side effect.
16. Malabsorption syndrome which may impair the absorption of vandetanib (partial gastrectomy, small bowel resection), This may include previous partial gastrectomy and small bowel resection or active Crohns disease, ulcerative colitis.
17. Pregnancy or breast feeding.
18. Previous chemotherapy for locally advanced and metastatic disease. Adjuvant chemotherapy for resected pancreatic cancer will be permitted provided that chemotherapy was completed > 12 months previously.
19. Radiotherapy within the last 4 weeks prior to start of study treatment.
20. Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix or resected pancreatic cancer.
21. Chemotherapy directed at tumour apart from that described in this protocol.
22. All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom..
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
University of Liverpool
University of Liverpool (UK)
Research & Development
Funding Body Type
private sector organisation
Funding Body Subtype
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting