Patient case: 50-year-old male with prostate cancer; genetic feature: ATM deletion

Clinical trial: Ascending Doses of AZD6738 in Combination With Chemotherapy and/or Novel Anti Cancer Agents

Summary: This is a modular, phase I/ phase 1 b, open-label, multicentre study of AZD6738 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 AZD6738 with other anti-cancer treatments, with intensive safety monitoring to ensure the safety of the patients. The initial combination to be investigated is AZD6738 with carboplatin. The second combination to be investigated is AZD6738 with Olaparib. The third combination to be investigated is AZD6738 with MEDI4736.

Detailed description: This is a modular, phase I, 2 part, open-label, multicentre study of AZD6738, administered orally, in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced/metastatic solid malignancies. The study design allows an escalation of the dose of AZD6738 in combination with the standard dose and schedule of either cytotoxic chemotherapies and/or novel anti-cancer agents, with intensive safety monitoring to ensure the safety of the patients. There are two parts to each combination module of this study; part A, dose escalation and an optional part B, cohort expansions in particular patient groups. The initial combination module will be with Carboplatin (module 1). The second combination will be with Olaparib (module 2). The third combination will be with MEDI4736 (module 3). The option to start further combination modules will be the decision of the Safety Review Committee (SRC), based on emerging preclinical data and, safety and tolerability information from the initial combination. Combinations of AZD6738 with novel anti-cancer agents may also be explored. Once a minimally biologically active dose of AZD6738, for that combination module, has been identified from part A of that module, the SRC may decide to commence part B if deemed to be necessary. This may include cohort expansions of specific patient groups to explore preliminary anti-tumour activity or the effect of food or particular drug combinations on drug pharmacokinetics.

Eligibility: Principal Inclusion criteria:
  -  Aged at least 18
  -  The presence of a solid malignant tumour that is not considered appropriate for further standard treatment
  -  Module 1 and 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 1 Part B Study expansion: second line lung adenocarcinoma with ATM deficient tumours.
  -  Module 2 Part B All - 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
  -  Module2 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 3: advanced recurrent or metastatic non-small cell lung cancer, or head and neck squamous cell carcinoma
  Principal exclusion criteria
  -  A diagnosis of ataxia telangiectasia
  -  Prior exposure to an ATR inhibitor
  -  Bad reaction to AZD6738
  -  Module 1: Contra-indicated for treatment with carboplatin
  -  Module 2: Contra-indicated for treatment with olaparib
  -  Module 3: Contra-indicated for treatment with MEDI4736

Relevance to patient case: not relevant