E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with advanced solid tumour |
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MedDRA Classification |
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 |
Part A:The primary objective of Part A of this study is to compare the PK parameters (AUC and Cmax) of AZD2171 obtained following single oral doses of 45 mg to patients in the fed and fasted state. Part B:The primary objective of Part B of this study is to compare the safety and tolerability of AZD2171 when given as either a fixed daily dose of 45 mg or an individualised dose escalation plan. |
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E.2.2 | Secondary objectives of the trial |
Part A: To determine the PK parameters (area under the curve from time 0 to the last measurable time point [AUC(0-t)], time to reach peak or maximum concentration or maximum response following drug administration [tmax], terminal phase half life [t1/2λz], terminal elimination rate constant [λz] and apparent total body clearance of drug from plasma [CL/F]) of AZD2171 in the fed and fasted state. To determine the effect of a single dose of AZD2171 on the QTc interval.
Part B: The secondary objectives of Part B of the study are: To compare the efficacy of AZD2171 monotherapy using either a fixed daily dose of 45 mg or an individualised dose escalation plan (best overall RECIST response rates, measurable tumour burden and measurement of serological markers). To determine the effect of multiple doses of AZD2171 on the QTc interval. To determine the steady state PK of AZD2171.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
For inclusion in the study, patients must fulfil all of the following criteria: Provision of written informed consent. Males or females aged 18 years or older. Histological or cytological confirmation of advanced solid tumour, which is refractory to standard therapies or for which no standard therapy exists and for which there is a rationale for the therapeutic use of a VEGFR tyrosine kinase inhibitor. World Health Organisation (WHO) performance status 0 2. Life expectancy ≥12 weeks. One or more measurable lesions at least 10 mm in the longest diameter by spiral computed tomography scan or 20 mm with conventional techniques (as defined by RECIST). Ability to consume a Food and Drug Administration high fat breakfast (see Appendix D). Patients considered by the investigator to be suitable for orally administered treatment. For inclusion in the genetic research component of this study, patients must fulfil the following criterion: Provision of informed consent for genetic research If a patient declines to participate in the genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent to these aspects. For inclusion in the DC MRI research component of this study, patients must fulfil the following criterion: Presence of liver metastases or tumours (2 10 cm) or, in the absence of liver lesions, other tumour sites deemed assessable by the investigator (2 10 cm) by DCE MRI. If a patient declines to participate in the DCE MRI research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent to these aspects.
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E.4 | Principal exclusion criteria |
Any of the following is regarded as a criterion for exclusion from the study: Untreated unstable brain or meningeal metastases. Patients with radiological evidence of stable brain metastases are eligible providing that they are asymptomatic and either: do not require corticosteroids or have been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count ≤1.5 x 109/L or platelet count ≤100 x 109/L or requiring regular blood transfusions to maintain haemoglobin >9 g/dL. Serum bilirubin ≥1.5 x upper limit of reference range (ULRR). Alanine amino transferase (ALT) or aspartate aminotransferase (AST) ≥2.5 x ULRR. If liver metastases are present, ALT or AST >5 x ULRR. Serum creatinine >1.5 x ULRR or a creatinine clearance of ≤50 mL/min calculated by Cockcroft-Gault. Greater than +1 proteinuria on 2 consecutive dipsticks taken no less than 1 week apart or if urinary protein >1.5 g in a 24 hour urine collection. Patients with a history of poorly controlled hypertension with resting BP >150/100 mmHg in the presence or absence of a stable regimen of hypertensive therapy. Measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2 minute intervals and averaged. If the first 2 diastolic readings differ by more than 5 mmHg, an additional reading should be obtained and averaged. Any evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated respiratory, cardiac including arrhythmias, hepatic or renal disease), including the known risk of the patient transmitting HIV or hepatitis B or C via infected blood. Any unresolved toxicity > CTC grade 1 from previous anti-cancer therapy (including radiotherapy) except alopecia (if applicable). For haemoglobin, refer to exclusion criteria number 2. Mean QTc with Bazetts correction (QTcB) >470msec in screening ECG or history of familial long QT syndrome: a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval >450 ms) a history of additional risk factors for Torsade de pointes (eg, heart failure, hypokalemia, family history of long QT syndrome). The use of concomitant medications that prolong the QT/QTc interval. Significant haemorrhage (>30 mL bleeding/episode in previous 3 months) or haemoptysis (>5 mL fresh blood in previous 4 weeks). Recent (<14 days) major surgery prior to entry into the study or a surgical incision that is not fully healed. Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication. Known hypersensitivity to AZD2171 or any of its excipients. Other concomitant anti-cancer therapy, except steroids or luteinising hormone releasing hormone agonist therapy for prostate cancer (eg, Zoladex). Known severe hypersensitivity to beta-blockers or calcium-channel blockers. History of other malignancies within 5 years except for adequately treated basal or squamous cell skin cancer or carcinoma in situ. History of central nervous system disorders or uncontrolled seizures. History of significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of AZD2171. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site) Previous enrolment or randomisation of treatment in the present study. Treatment with an investigational (non-registered) drug within 30 days prior to starting AZD2171. Concomitant use of any medication that may significantly affect hepatic cytochrome P450 drug metabolising activity by way of enzyme induction (eg, phenytoin) or inhibition (eg, ketoconazole, ritonavir, erythromycin) within 2 weeks if the first dose of AZD2171 and throughout the study period in Part A of the study only. Any of the following is regarded as a criterion for exclusion from the DCE MRI research component of the study: Ineligibility for MRI scanning (metal implants such as cochlear implants, cardiac pacemakers, heart valves, aneurysm clips and metal fragments in eyes).
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A of the study Primary outcome variable: Single dose AZD2171 PK parameters (AUC and Cmax) in the fed and fasted state.
Part B of the study Primary outcome variables: Maximum well tolerated dose for 6 weeks without treatment breaks or dose reductions Total dose received over the initial 16 weeks AEs Vital signs (BP and heart rate) Electrocardiograms (ECG) Laboratory findings (clinical chemistry, haematology, urinalysis)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.5 | 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 | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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The end of the study is defined as the date 16 weeks after the last patient has entered Part B of the study. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |