| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 |
| To establish the maximum tolerated dose and recommended dose of intermittent and once weekly AZD2014 administration in combination with weekly paclitaxel in patients with solid tumours. |
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| E.2.2 | Secondary objectives of the trial |
| - To investigate the effect of paclitaxel on the pharmacokinetic (PK - how the body handles the drug) profile of AZD2014. - To investigate the pharmacodynamic (PD - what the drug does to the body) profile of AZD2014 in combination with weekly paclitaxel. - To document any tumour shrinkage or clinical response to AZD2014 in combination with paclitaxel. - To study genetic abnormalities in the patients' tumour and see if these correlate to a response to AZD2014 in combination with paclitaxel. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Histologically or cytologically proven solid tumour, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient, or where treatment with paclitaxel is an appropriate treatment option. Patients enrolled in the expansion phase must have recurrent ovarian, fallopian tube or primary peritoneal cancer only. 2. Patients who have had conventional treatment and where paclitaxel is appropriate. In instances where paclitaxel is appropriate but he patients has not already received it the patient may be enrolled after discussion between the referring oncologist and Principal Investigator. 3.Life expectancy of at least 12 weeks 4.ECOG performance status of 0-1 5.Females should be using adequate contraceptive measures (see restrictions below), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR Female patients must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation 6.Male patients should be willing to use barrier contraception i.e., condoms 7.Measurable or evaluable disease. Patients enrolled in the expansion phase should have measurable disease by RECIST v1.1 criteria. 8.Haematological and biochemical indices within the ranges shown below: Haemoglobin (Hb)≥ 9.0 g/dL Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5 x (ULN or ≤ 5 times ULN in the presence of liver metastases Alkaline phosphatase (ALP)< 5 x ULN Creatinine Clearance ≥ 50 mL/min (uncorrected value) OR Serum creatiine ≤ 1.5 x ULN Fasting glucose ≤ 125 mg/dL (7 mmol/L) Erythrocyte-HbA1c ≤ 59 mmol/mol 9.18 years or over 10.Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up |
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| E.4 | Principal exclusion criteria |
| 1.Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy, or immunotherapy during the previous 3 weeks (4 weeks for investigational medicinal products and 6 weeks for nitrosoureas and Mitomycin-C) before treatment. N.B. Exceptions to this are patients receiving weekly taxol as standard of care who have not had a partial or complete response after 6 to 12 weekly doses. Those patients should discontinue their weekly taxol treatment and may be enrolled to the dose expansion phase without a wash out period. 2.CTCAE Grade 1 or higher toxicities from previous anticancer therapy (except alopecia) 3.Known leptomeningeal involvement, brain metastases or spinal cord compression 4.Known hypersensitivity (>Grade 2) to taxanes, drugs containing Cremophor, AZD2014 or similar drugs 5.Unresolved bowel obstruction 6.Current refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014 7.Patients with Diabetes Type I or uncontrolled Type II (HbA1c >59 mmol/mol assessed locally) as judged by the investigator 8. Major surgery within 4 weeks prior to entry to the study or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered 9.Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH. 10.Potent and moderate inhibitors and inducers of CYP3A4/5 if taken within the stated washout periods (see protocol for details) 11.Potent and moderate inhibitors and inducers of CYP2C8 if taken within the stated washout periods (see protocol for details) 12. At high medical risk because of non-malignant systemic disease including active uncontrolled infection e.g. interstitial lung disease, severe hepatic impairment, uncontrolled chronic renal disease 13.Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 14.Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: - coronary artery bypass graft - angioplasty - vascular stent - myocardial infarction (MI) - uncontrolled angina pectoris - congestive heart failure NYHA Grade 2 - ventricular arrhythmias requiring continuous therapy - supraventricular arrhythmias including atrial fibrillation, which are uncontrolled - Torsades de Pointes - haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding 15.Resting ECG with measurable QTc interval of >470ms msec at 2 or more time points within a 24 hour period. 16.Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome), or unexplained sudden death under 40 years of age 17.Left ventricular (LV) dysfunction (LVEF outside institutional range of normal) by MUGA or Echocardiogram. 18.Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for three years or more and are deemed at negligible risk for recurrence, are eligible for the trial. 19.Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks of starting trial 20.Patients participating in or planning to participate in another interventional clinical trial. Participation in an observational trial is acceptable. 21.Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To establish the maximum tolerated dose of AZD2014 in combination with paclitaxel of an intermittent and BD once weekly dosing schedule in combination in patients with solid tumours by determining a dose at which no more than one patient out of up to six patients at the same dose level experience a probable drug-related dose limiting toxicity. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation of the safety and tolerability of AZD2014 in combination with paclitaxel over the first cycle (49 days )of treatment. A safety review meeting will be carried out after recruitment of each dosing cohort of 3 patients throughout the study. In addition, there will be forthnightly safety meetings throughout the study. |
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| E.5.2 | Secondary end point(s) |
| Determining the PK parameters for AZD2014 and paclitaxel derived from determining their plasma concentrations using validated assays. Determining the pAkt/Akt, pGSKbeta/TGSKbeta3 and pS6 kinase/S6 kinase ratios in platelet-rich plasma and tumour biopsies pre and post administration of AZD2014 in combination with paclitaxel and apoptosis markers (m30 and m65). Determining disease response by RECIST criteria version 1.1, GCIC CA125 criteria and change in tumour size. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety and tolerability of combination treatment will be assessed by the Safety Review Committee and PK/PD data will be reviewed as part of that. Response assessment will be carried out for patients that have received at least 1 cycles of treatment and have a baseline disease assessment. A status of complete response (CR) or partial response (PR) will be confirmed by repeat measurements performed no less than four weeks after the response criteria are met. |
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | Yes |
| 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 | 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
| 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 | 3 |
| 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 | 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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| The end of the study is defined as the last visit of the last patient participating in 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 | 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 |
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