This study will investigate the use of a new drug targeting the DNA repair pathway AZD6738, an ATR inhibitor). Many tumours have lost important DNA repair functions and rely more heavily on a few remaining repair pathways to survive. Preclinical studies indicate that, in these tumours, preventing the function of the remaining pathways will lead to tumour cell death, while sparing normal cells. This study aims to investigate the safety and tolerability of the new drug in patients with advanced cancer, as well as in combination with palliative radiotherapy, where the drug may increase the effectiveness of radiotherapy by preventing repair of the radiationinduced DNA damage. As the drug has only been given to a small number of patients, the study will focus on safety and finding the correct dose to proceed to further studies, although preliminary signs of drug activity will also be examined.

The initial part of the study will administer increasing doses of the drug to groups of patients with advanced cancer who have no standard anticancer treatment options available. Testing will establish whether the drug levels in the body and tumour are adequate for the drug to have an effect, and any toxicity will be assessed. After the recommended dose is established, the recommended dose schedule will be stablished by trialing different schedules. Participants will be tested to see if their tumours lack the main DNA repair pathway (those who are predicted to have a better response to this drug). Finally, the drug will be given to patients with advanced cancer who require a course of radiotherapy for symptom control - the drug will be tested at different doses and with different doses of radiotherapy.

Side effects will be monitored and tests will establish whether the drug is enhancing the radiotherapy effect in the tumours or normal tissues.

Inclusion Criteria:

• Histologically or cytologically documented solid tumour refractory to conventional treatment
• Evidence of measurable or evaluable disease by RECIST 1.1
• Age must be 18 years or over.
• ECOG performance status 0-1 (part A); 0-2 (parts B and C)
• Life expectancy of at least 3 months.
• Patients must have normal organ and bone marrow function measured within 7 days prior to administration of study treatment as defined below:
• Signed informed consent indicating that the subject is aware of the neoplastic nature of their disease and have been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
• Willing and able to comply with scheduled visits, tissue sampling, treatment plan, and laboratory tests.
• Able to swallow, absorb and retain oral medication.

Exclusion Criteria:

• Therapy with any other investigational medical product (IMP) concurrently or within 28 days prior to signing of consent.
• Pregnant or breast-feeding women.
• Ability to become pregnant (or already pregnant or lactating).
• Clinically significant cardiac disease including:
• Known HIV positive or active hepatitis B or C infection
• Uncontrolled active infection
• Symptomatic and progressive or steroid-requiring brain metastases or leptomeningeal disease involvement.
• Uncontrolled hypertension requiring clinical intervention, hypertension requiring 2 or more antihypertensive agents
• Dementia or altered mental status that would prohibit informed consent.
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Principal Investigator, would make the subject inappropriate for this study.