Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer

Inclusion Criteria:

1. Provision of fully informed consent prior to any study specific procedures.
2. Patients must be \> 19 years of age.
3. Refractory cancer patients who have failed to standard of care chemotherapy.
4. Provision of tumor sample (from either a resection or biopsy): however this criteria is optional for this study (i.e. if no biopsy sample available, not an exclusion criteria).
5. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. Especially, patients must fast (water to drink only) from at least 2 hours prior to taking a dose to at least 1 hour post-dose for all doses.
6. ECOG performance status 0-1
7. Patients must have a life expectancy ≥ 3 months from proposed first dose date.
8. At least one measurable lesion that can be accurately assessed by imaging at baseline and following up visits.
9. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment.

   Patients of child-bearing potential should be using adequate contraceptive measures (two forms of highly reliable methods) should not be breast feeding and must have a negative pregnancy test prior to start of dosing.or Patients must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
10. Male patients must be willing to use barrier contraception for the duration of the study and:

    * for one week after the last dose of study drug if the sexual partner is not of child bearing potential
    * for 6 months after last dose of study drug and in combination with a highly reliable contraceptive method for sexual partners of child-bearing potential
11. Male patients must be willing to not donate sperm for the duration of study or up to 6 months after the last dose of study drug.

Exclusion Criteria:

1. More than four prior chemotherapy regimens (excluding adjuvant chemotherapy) for cancer treatment
2. Any previous treatment with ATR inhibitors (small molecules)
3. Any previous treatment with paclitaxel (docetaxel is allowed if in physician's discretion, the tumor is not absolutely refractory to taxane)
4. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≤5 years.
5. Patients unable to swallow orally administered medication.
6. Treatment with any investigational product during the last 14 days before the enrollment (or a longer period depending on the defined characteristics of the agents used).
7. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 3 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment.
8. \- Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.

   \- Receiving, or having received, concomitant medications, herbal supplements and/or foods that significantly modulate CYP3A4 or Pgp activity (wash out periods of two weeks, but three weeks for St. John's Wort). Note these include common azole antifungals, macrolide antibiotics and other medications listed in Appendix I.
9. With the exception of alopecia, any ongoing toxicities (\>CTCAE grade 1) caused by previous cancer therapy.
10. Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks before the enrollment.
11. Resting ECG with measurable QTcF \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
12. Patients with cardiac problem as follows: uncontrolled hypertension or hypotension (BP ≥150/95 mmHg despite medical therapy, BP \<100/60 mmHg or orthostatic hypotension fall in BP \>20 mmHg) Left ventricular ejection fraction \<55% measured by echocardiography, Atrial fibrillation with a ventricular rate \>100 bpm on ECG at rest , Symptomatic heart failure (NYHA grade II-IV), Prior or current cardiomyopathy, Severe valvular heart disease, Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy), Acute coronary syndrome within 6 months prior to starting treatment
13. Female patients who are breast-feeding or child-bearing
14. Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
15. A diagnosis of ataxia telangiectasia
16. Inadequate bone marrow and impaired hepatic or renal function as demonstrated by any of the following laboratory values:

    * Haemoglobin \< 9.0 g/dL (transfusion allowed)
    * Absolute neutrophil count (ANC) \<1.5 x 109/L
    * White blood cells (WBC) ≤ 3 x 109/L
    * Platelet count \< 100 x 109/L (transfusion allowed)
    * Albumin \< 33g/L
    * Total bilirubin \< 1.5 x institutional upper limit of normal (ULN)
    * AST (SGOT)/ALT (SGPT) \> 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be \> 5x ULN
    * Serum creatinine \> 1.5 x institutional ULN
    * Glomerular filtration rate (GFR) \< 45 mL/min, as assessed using the standard methodology at the investigating centre (i.e. cockcroft-Gault, MDRD or CKD-EPI formulae, EDTA clearance or 24 h urine collection)
    * Haematuria: +++ on microscopy or dipstick
    * INR ≥ 1.5 or other evidence of impaired hepatic synthesis function
17. Previous allogenic bone marrow transplant
18. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection