A Phase I Trial of the Combination of AZD2014 and Weekly Paclitaxel.

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 the 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, 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
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. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.

   * 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) if no demonstrable liver metastases 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 creatinine ≤ 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

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 systemic anticancer therapy prior to the first dose of study treatment (with the exception of alopecia)
3. Known leptomeningeal involvement, brain metastases or spinal cord compression
4. Known hypersensitivity (\>Grade 2) to taxanes, drugs containing Cremophor, AZD2014 or structurally/chemically 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 (excluding placement of vascular access), 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:

    * Inhibitors (competitive): ketoconazole, itraconazole, indinavir, saquinovir, nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin, telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole, fluvoxamine (1 week minimum wash-out period), amiodarone (27 week minimum wash-out period)
    * Inhibitors (time dependent): erythromycin, clarithromycin, verapamil, ritonavir, diltiazem (2 week minimum wash-out period)
    * Inducers: phenytoin, rifampicin, St. John's Wort, carbamazepine, primidone, griseofulvin, barbiturates, troglitazone, pioglitazone, oxcarbazepine, nevirapine, efavirenz, rifabutin (3 week minimum wash-out period) and phenobarbitone (5 week minimum washout period)
11. Potent and moderate inhibitors and inducers of CYP2C8 if taken within the stated washout periods:

    * Inhibitors: Gemfibrozil, trimethoprim, glitazones, montelukast, quercetin (1 week minimum wash-out period)
    * Inducers: Rifampicin (3 week minimum wash-out period)
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 AF, 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. Inability to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation (see Appendix 5)
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 whilst on this study. 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.