Study to Assess the Safety and Preliminary Efficacy of AZD0156 at Increasing Doses Alone or in Combination With Other Anti-cancer Treatment in Patients With Advanced Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether AZD0156 is safe, what is the best dose to give, and how it is processed by the body when given alone or in combination with other agents. The study will also collect some initial information about how effective it is.

Detailed Description
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The study will consist of a number of study modules, each evaluating the safety and tolerability of AZD0156 with a specific combination agent. The combination option may require an initial monotherapy dose escalation to gain an understanding of pharmacokinetics, safety and tolerability before initiating dose escalation in combination. An oral formulation of AZD0156 will be used. Module 1 explores AZD0156 in combination with olaparib Module 2 explores AZD0156 in combination with irinotecan/FOLFIRI Additional modules may be added to explore AZD0156 as a monotherapy or in combination with other agents and may be in different tumour types. Expansion cohorts may enroll additional patients to explore further the safety, tolerability, pharmacokinetics and biological activity at selected dose(s) or alternate dosing schedules, and to get a preliminary assessment of efficacy . Module 1 includes an expansion cohort in locally advanced/metastatic tumours including but not limited to gastric adenocarcinoma Module 2 includes an expansion cohort in colorectal cancer

Official Title
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A Phase I, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Ascending Doses of AZD0156 Monotherapy or in Combination With Either Cytotoxic Chemotherapies or Novel Anti-Cancer Agents in Patients With Advanced Malignancies

Conditions
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Advanced Solid Tumours

Intervention / Treatment
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* Drug: AZD0156
* Drug: Olaparib
* Drug: irinotecan
* Drug: Fluorouracil
* Drug: Folinic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for all parts of the study Confirmation of locally advanced/metastatic cancer. Refractory or resistant to standard therapy, or have no effective standard Aged at least 18 yrs Reasonable health (performance status 0 or 1), stable over the previous 2 weeks Females who can have children must use contraception; have a negative pregnancy test, & not be breast feeding Sexually active male patients must use contraception for duration of study and for 3 months afterwards Inclusion criteria for Part B only Tumour(s) that can be measured by CT or MRI, at least 1cm in size Inclusion Part B Confirmation of metastatic/locally advanced cancer of specific tumour type which failed to respond to standard treatments Exclusion criteria for all parts of the study Prior treatment with an ATM inhibitor Past medical history of an inflammatory type(interstitial) lung disease or current inflammatory lung disease Radiotherapy within the last 4 weeks, except palliative radiotherapy for bone pain relief Prior treatment with drugs that may cause lung damage Poor of lung function History/presence of muscle weakness or abnormal blood tests relating to muscle function Cancer affecting the spinal cord and/or brain unless asymptomatic and stable Any evidence of severe or uncontrolled diseases, active bleeding,kidney transplant, or active infection including liver infections (hepatitis B, hepatitis C) and human immunodeficiency virus (HIV). Evidence of severe lung infections Receiving, or having received during the four weeks prior to starting study treatment other chemotherapy treatment for your cancer Treatment with certain doses of steroids during the two weeks prior to starting study treatment A known sensitivity to AZD0156 or any of its components Treatment with any unapproved medicine within 28 days prior to starting study treatment Receiving, or having received medications, herbal supplements and/or foods that significantly affect how your liver works Low numbers of certain blood cells If your liver and kidney aren't working normally If your heart isn't working normally or you have a strong family history of certain heart diseases Other cancers within the past 3 years, except for certain types of cervical and skin cancers Sickness and vomiting, digestive diseases or previous significant bowel removal Patients with uncontrolled fitting Infections requiring treatment Other severe and/or uncontrolled medical conditions in addition to your cancer A blockage in your digestive system or severe bleeding from the stomach within 4 weeks before your take medication on the stuy Patients with acute leukaemia or certain bone marrow diseases Patients with a known sensitivity to olaparib or its components (Module 1), or components of FOLFIRI (Module 2) Any previous treatment with drugs that work like olaparib. (Module 1 Only)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety and Tolerability<br>All patients will receive AZD0156 as a monotherapy or in combination with either olaparib, cytotoxic chemotherapies, or novel anti-cancer agents to assess safety and tolerability | Drug: AZD0156<br>* All patients will receive AZD0156 as a monotherapy or in combination to assess safety and tolerability.<br>Drug: Olaparib<br>* Module 1 combination with olaparib<br>* Other names: AZD2281, Lynparza;Drug: irinotecan<br>* Module 2 combination with irinotecan/FOLFIRI<br>* Other names: Camptosar;Drug: Fluorouracil<br>* Module 2 combination with irinotecan/FOLFIRI<br>* Other names: 5-FU, Adrucil;Drug: Folinic Acid<br>* Module 2 combination with irinotecan/FOLFIRI<br>* Other names: leucovorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability - Number of patients experiencing adverse events | Safety and tolerability of AZD0156 alone or in combination with either olaparib, cytotoxic chemotherapies, or novel anti-cancer agents as assessed through collection of Adverse Event, Serious Adverse Event, Clinical Chemistry/Haematology/Coagulation/Vital Signs and ECG | Informed consent until end of Safety Follow-up (approximately 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumour activity assessed through tumour measurements | Preliminary assessment of the anti-tumour activity of AZD0156 either as monotherapy alone or in combination with either olaparib, cytotoxic chemotherapies, or novel anti-cancer agents by evaluation of tumour response objective response rate using RECIST version 1.1 | Baseline and then every 6 weeks until Safety follow-up (approximately 6 months) | 
| Changes in expression levels of proteins that may be impacted by ATM protein activity or inhibition | To obtain a preliminary assessment of AZD0156 activity in the tumour by evaluation of pharmacodynamic biomarker changes | From baseline until 21 days of combination therapy (Approximately 11 assessments) | 
| Changes in the number of CTCs (Circulating Tumour Cells) | To obtain a preliminary assessment of AZD0156 activity in the tumour by evaluation of the total amount of circulating tumour cells (CTCs) | From baseline until 21 days of combination therapy (Approx 6 assessments) | 
| Changes in the level of total ctDNA (Circulating tumour DNA) | To obtain a preliminary assessment of AZD0156 activity in the tumour by evaluation of the total amount of ct DNA | From baseline until 21 days of combination therapy (approximately 11 assessments) | 
| Measure maximum plasma concentration (Cmax) | Measurement of Cmax as part of pharmacokinetic assessment | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Measure maximum plasma concentration at steady state (Css max) | Measurement of Css max as part of pharmacokinetic assessment | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Measure time to maximum concentration (tmax) | Measurement of tmax as part of pharmacokinetic assessment | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Measure time to maximum concentration at steady state (tss max) | Measurement of tss max as part of pharmacokinetic assessments | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Measurement of exposure by AUC (Area Under the Curve) calculation | Measurement of AUC as part of pharmacokinetic assessment | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Measure minimum concentration at steady state (Css min) | Measurement of Css min as part of pharmacokinetic assessment | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Measure rate of renal clearance (CLR) | Measurement of renal clearance (CLR) as part of pharmacokinetic assessment | From Baseline until 7 days into treatment period | 
| Measure drug accumulation in the body (RAC) | Measurement of RAC as part of pharmacokinetic assessments | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | 
| Identification of Maximum Tolerated Dose (MTD) | Safety and tolerability of AZD0156 alone or in combination with cytotoxic chemotherapies or novel anti-cancer agents as assessed through collection of Adverse Events | Informed consent untli end of Dose Limiting Toxicity (DLT) period - Approx 1 month | 
| Overall Survival (Part B Only) | Period of time from the start of treatment until end of life from any cause | From start of treatment until the end of Long Term Follow-up (Approx 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, open label study; safety and efficacy of AZD0156; ATM inhibitor