This biomarker study has been designed to assess the effects of different agents in both tumour tissue and peripheral samples to help inform the best combinations of DDR agents with immuno-oncology (IO) therapies. In the first instance 2 DDR agents will be assessed separately as monotherapy. Additional arms may be added later to evaluate other DDR agents and/or DDR and immunotherapy agents in combination or in sequence. The primary objective of the study is to investigate immune activation due to DDR inhibition by assessing tumour and blood samples of patients treated with study investigational agent(s).
Patients are dosed for a minimum of nine days with drug. Surgery or biopsy can then take place at any time between Day 10 and Day 21 (depending on when it can be scheduled), but must occur with 24 hrs following three consecutive treatment days. During the treatment period, safety assessments must be completed at least weekly. Follow-up will be completed after surgical resection or biopsy has been completed and can be part of standard post-surgery follow-up. If this follow-up visit occurs prior to 30 days after the final dose, a further visit or telephone call must be conducted to assess that any toxicity has resolved and to check for late toxicity.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Ceralasertib is an oral agent and will be dosed at 160 mg. Ceralasertib tablets should be taken at the same time each day, approximately 12 hours apart (maximum ± 2 hour window) with one glass of water. Ceralasertib is a potent, selective inhibitor of the serine/threonine-specific protein kinase, ataxia telangiectasia and Rad3-related protein (ATR), with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members.
Olaparib is available as a green film-coated tablet containing 100 mg or 150 mg of Olaparib. Patients will be administered Olaparib orally twice daily at 300 mg bid. The Olaprib tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water. Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5'diphosphoribose \[poly (ADP ribose)\] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anti-cancer agents.
Research Site
Pittsburgh, Pennsylvania, United States
Research Site
Toulouse, France
Research Site
Changhua, Taiwan
Research Site
Taipei, Taiwan
Conversion of an immunologically based 25-gene signature from a prognostically unfavourable state to a prognostically favourable state.
To investigate prognosis-correlated immune activation due to DDR inhibition by monitoring the induction of immunologically relevant genes in tumours of patients treated with study investigational agent(s)
Time frame: From baseline through Day 31 (Follow up)
Transition from a low tumour infiltrating leukocyte (TIL) state (poor prognosis) to a high TIL state (favourable prognosis) shown by TIL enumeration and an increase in CD8+ T-cells
To investigate the prevalence and localization of TILs associated with prognosis.
Time frame: From baseline through Day 31 (Follow up)
Transition from a low TIL infiltrative state (poor prognosis) to a high TIL infiltrative state (favourable prognosis) shown by TIL enumeration and an increase in CD3+ T-cells
To investigate the prevalence and localization of tumour infiltrating leukocytes (TILs) associated with prognosis.
Time frame: From baseline through Day 31 (Follow up)
Number of patients with adverse events (AE) / serious adverse events (SAE)
Assessment of the safety for each DDR agent in terms of the incidences of the AEs
Time frame: From time of signature of informed consent throughout the treatment period and including the follow-up period
Vital signs
Assessment of the safety for each DDR agent in terms of the Vital signs
Time frame: From screening until Day 15 (+ 2 days)
Clinical chemistry/haematology
Assessment of the safety for each DDR agent in terms of the clinical chemistry / haematology assessments
Time frame: From screening until Day 15 (+ 2 days)
Number of patients with abnormal findings in Electrocardiograms (ECG)
Assessment of the safety for each DDR agent in terms of the ECG changes. A 12-lead ECG will be performed in triplicate at screening and at a time convenient during the visits (single ECG only required at subsequent visits).
Time frame: At screening and Day 1
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