A Modular Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ascending Doses of Ceralasertib in combination with Cytotoxic Chemotherapy and/or DNA Damage Repair/Novel Anti-cancer Agents in Patients with Advanced Solid Malignancies

This is a modular, phase I/ phase 1 b, open-label, multicentre study of ceralasertib
administered orally in combination with cytotoxic chemotherapy regimens and/or novel
anti-cancer agents, to patients with advanced malignancies. The study design allows an
investigation of optimal combination dose of ceralasertib with other anti-cancer treatments,
with intensive safety monitoring to ensure the safety of the patients. The initial
combination to be investigated is ceralasertib with carboplatin. The second combination to be
investigated is ceralasertib with Olaparib. The third combination to be investigated is
ceralasertib with durvalumab. The fourth module will investigate the effect of food on
ceralasertib absorption and the effect of ceralasertib on ECG parameter. The fifth module to
be investigated is ceralasertib with AZD5305.

Principal Inclusion criteria:

- Aged at least 18

- The presence of a solid malignant tumour that is not considered appropriate for
further standard treatment

- Module 2 Part B study expansions, and Module 3: patients must have a tumour at least 1
cm in size that can be measured using a CT or MRI scan

- Module 2 Part B All (except B5): No previous treatment with PARP inhibitor.

- Module 2 Part B1 Study expansion: advanced gastric adenocarcinoma (including GEJ)
patients with ATM deficient tumours

- Module 2 Part B2 Study expansion: advanced gastric adenocarcinoma (including GEJ)
patients with ATM proficient tumours

- Module 2 Part B3 Study expansion: Second or thrid line HER2 negative breast cancer

- Module 2 Part B4 Study expansion: Second or third line triple negative breast cancer
(TNBC)

- Module 2 Part B5 Study expansion: BRCAm or RAD51C/Dm or PALB2m or HRD positive status
ovarian cancer patient who are Platinum Sensitive Relapsed and have previously
progressed on a licensed PARPi

- Module 3: advanced recurrent or metastatic non-small cell lung cancer, or head and
neck squamous cell carcinoma

- Module 4: any advanced solid tumours except gastric, gastro-oesophageal, oesophageal
or colorectal cancer with a small bowel resection

- Module 4: Ability to comply with an overnight fast of at least 10 hours prior to
dosing and 4 hours after dosing as mandated, and ability to eat a high fat meal as
mandated

- Module 5 All: Ovarian fallopian tube or primary peritonial cancer, previous treatment
with PARP inhibitor, platinum-sensitive relapsed ovarian cancer

- Module 5 Part B: known or suspected BRCA mutation, PALB2 mutation, RAD51C/D mutation
or HRD positive status

Principal exclusion criteria

- A diagnosis of ataxia telangiectasia

- Prior exposure to an ATR inhibitor

- Bad reaction to ceralasertib

- Module 2: Contra-indicated for treatment with olaparib

- Module 3: Contra-indicated for treatment with durvalumab

- Module 4: Mean resting corrected QT interval (QTc) >470 msec or history of familial
long QT syndrome.

- Module 4: Patients with type I or type II diabetes

- Module 5: Known hypersensitivity to PARP including AZD5305