E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced solid tumours, lymphomas and endometrial carcinoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014733 |
E.1.2 | Term | Endometrial cancer |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065143 |
E.1.2 | Term | Malignant solid tumour |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025632 |
E.1.2 | Term | Malignant lymphoma |
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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 |
To assess the safety and tolerability of AZD8055 in patients with advanced solid tumours or lymphomas (including 20 patients with endometrial carcinoma in Part B). |
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E.2.2 | Secondary objectives of the trial |
1. To determine the pharmacokinetics of AZD8055 following both single and multiple oral dosing of AZD8055 in patients with advanced solid tumours or lymphomas (including 20 patients with endometrial carcinoma in Part B). 2. To obtain a preliminary evaluation of the role of renal excretion in the disposition of AZD8055. 3. To evaluate phosphorylation levels of biomarkers such as AKT following treatment with AZD8055. 4. To investigate possible relationships between plasma AZD8055 concentrations/exposure and changes in safety and PD parameters. 5. To give an early indication of efficacy by evaluation of tumour size. 6. To determine inhibition of tumour glucose uptake by assessment with FDG-PET.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of signed written informed consent 2. Male or female, aged 18 years or older 3. Cancer which is refractory to standard therapies, or for which no standard therapies exist, or for which the investigator feels no other active therapy is required for the duration of the study. Inclusion is irrespective of stage of disease. 4. Histological or cytological confirmation of an advanced, solid, malignant tumour or lymphoma. Patients with endometrial carcinosarcomas can be included in the study but will be analysed in the non-endometrial sub group in Part B. 5. WHO performance status 0-2 (those with performance status 2 must have been stable with no deterioration over the previous 2 weeks) 6. Evidence of post-menopausal status, permanent or surgically sterile, or negative serum or urine pregnancy test for female patients of child-bearing potential. Women will be considered post menopausal if they are over 50 years old and have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments. Permanent sterilisation includes hysterectomy and/or bilateral oopherectomy and/or bilateral salpingectomy but excludes bilateral tubal occlusion. Tubal occlusion is considered a highly effective method of birth control but does not absolutely exclude the possibility of pregnancy. (The term occlusion refers to both occluding and ligating techniques that do not physically remove the oviducts). Women who have undergone tubal occlusion should be managed as if they are of child-bearing potential (eg undergo pregnancy testing as required by the study). Females of reproductive potential are required to use reliable contraception (see Section 3.3.4) 7. For Parts A and B of the study, patients with measurable and non-measurable disease (according to RECIST criteria) can be recruited.
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E.4 | Principal exclusion criteria |
1. Laboratory values as listed below: (SI Units) - ANC <1.5x109/L - Platelets <100x109/L - Haemoglobin (Hb) <9.0 g/dL - AST (SGOT) or ALT (SGPT) >2.5 x ULN if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases, total bilirubin (TBL) >1.5 x ULN if no demonstrable liver metastases or >3 x ULN in the presence of liver metastases - Serum creatinine >1.5 x ULN or creatinine clearance ≤50 mL/min (measured or calculated by Cockcroft-Gault method) - Clinically relevant and treatment resistant abnormalities in potassium, sodium, calcium (corrected for plasma albumin) or magnesium - Proteinuria +1 on dipstick analysis or >500 mg/24 hours 2. Endometrial cancer who have isolated recurrences of their disease (vaginal, pelvic or para-aortic) that are amenable to potentially curative treatment with radiation therapy or surgery 3. Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, corticosteroids or other investigational anti-cancer therapy within 21 days of entering the trial (not including palliative radiotherapy at focal sites). Patients must have also recovered from previous chemo-associated toxicities to Grade 0-1. 4. Treatment with any haemopoietic growth factors (eg G-CSF, GM-CSF) within 2 weeks prior to receiving study drug 5. Active spinal cord compression as evidenced by clinical signs and/or oedema or progressive growth demonstrated by imaging unless treated and stable off steroids for at least 1 month prior to study treatment 6. History of peripheral neuropathy, pre-existing leg weakness or muscle diseases 7. Family history of myopathy 8. Past history or current evidence of brain metastases 9. Evidence of severe or uncontrolled systemic conditions (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardise compliance with the protocol 10. Patients with pre existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis 11. Impaired oral glucose tolerance test (OGTT) as defined by fasting glucose >109 mg/dL (6.1 mmol/L) and postprandial glucose 2h level >140mg/dL (>7.8 mmol/L). 12. Manifest Diabetes Type I and II or Erythrocyte-HbA1c >6.5% 13. Uncontrolled hypercholesterolaemia or hypertriglyceridaemia (fasting state) despite lipid-lowering therapy 14. Evidence of active infection or active bleeding diatheses 15. Experience of any of the following in the preceding 12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction (MI), angina pectoris, congestive heart failure NYHA Grade 2, uncontrolled hypertension (BP>150/90 mmHg despite maximal medical management), ventricular arrhythmias requiring continuous therapy, supraventricular arrhythmias including AF, which are uncontrolled, haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding 16. Abnormal echocardiogram at baseline (LVEF < 55% and shortening fraction SF <15%) 17. Torsades de Pointes, currently or within 2 weeks of study entry 18. Patients with mean QTc interval >450ms from 3 ECGs using Fridericia's correction at both screening visit and predose on the first day of dosing 19. Patients taking concomitant medications known to prolong QT interval or with factors that increase the risk of QT prolongation or arrhythmic events (heart failure, hyperkalaemia, personal or family history of long QT syndrome) 20. Uncontrolled severe thyroid hyperfunction or hypofunction. 21. History of neurocardiogenic syncope 22. Recent major surgery within 4 weeks prior to study entry (excluding the placement of vascular access), or minor surgery within 2 weeks of entry into the study 23. Patients with documented cases of HIV or hepatitis B or C 24. Involvement in the planning or conduct of study (AstraZeneca staff and staff at the study site) 25. Previous enrolment into the present study 26. Patients receiving potent and moderate inhibitors and inducers of CYP3A4 if they are taken within the stated washout periods (see protocol) 27. Any other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with study participation or study drug administration or could interfere with the interpretation of the study results and, in the judgment of the investigator, would make a patient inappropriate for entry 28. Refractory nausea and vomiting, chronic gastrointestinal diseases (eg inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption 29. See Appendix E/I for exclusion criteria from the optional host genetic research/buccal biopsies 30. Investigator's clinical judgement that the patient should not participate in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability: Assessed by incidence and severity of adverse events (CTCAE Version 3.0), vital signs, general organ function, clinical chemistry (including liver function test), haematology and urinalysis, coagulation, glucose management, ECG and echocardiography, nervous and musculoskeletal system examination. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
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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30 days after the last patient discontinues study treatment |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |