Advanced Solid Tumours
Conditions
Keywords
Phase I, open label study; safety and efficacy of AZD0156; ATM inhibitor
Brief summary
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
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
Interventions
DRUGAZD0156
All patients will receive AZD0156 as a monotherapy or in combination to assess safety and tolerability.
DRUGOlaparib
Module 1 combination with olaparib
DRUGirinotecan
Module 2 combination with irinotecan/FOLFIRI
DRUGFluorouracil
Module 2 combination with irinotecan/FOLFIRI
DRUGFolinic Acid
Module 2 combination with irinotecan/FOLFIRI
Sponsors
Syneos Health
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability - Number of patients experiencing adverse events | Informed consent until end of Safety Follow-up (approximately 6 months) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-tumour activity assessed through tumour measurements | Baseline and then every 6 weeks until Safety follow-up (approximately 6 months) | 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 |
| Changes in expression levels of proteins that may be impacted by ATM protein activity or inhibition | From baseline until 21 days of combination therapy (Approximately 11 assessments) | To obtain a preliminary assessment of AZD0156 activity in the tumour by evaluation of pharmacodynamic biomarker changes |
| Changes in the number of CTCs (Circulating Tumour Cells) | From baseline until 21 days of combination therapy (Approx 6 assessments) | To obtain a preliminary assessment of AZD0156 activity in the tumour by evaluation of the total amount of circulating tumour cells (CTCs) |
| Changes in the level of total ctDNA (Circulating tumour DNA) | From baseline until 21 days of combination therapy (approximately 11 assessments) | To obtain a preliminary assessment of AZD0156 activity in the tumour by evaluation of the total amount of ct DNA |
| Measure maximum plasma concentration (Cmax) | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of Cmax as part of pharmacokinetic assessment |
| Measure maximum plasma concentration at steady state (Css max) | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of Css max as part of pharmacokinetic assessment |
| Measurement of exposure by AUC (Area Under the Curve) calculation | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of AUC as part of pharmacokinetic assessment |
| Measure time to maximum concentration at steady state (tss max) | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of tss max as part of pharmacokinetic assessments |
| Measure minimum concentration at steady state (Css min) | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of Css min as part of pharmacokinetic assessment |
| Measure rate of renal clearance (CLR) | From Baseline until 7 days into treatment period | Measurement of renal clearance (CLR) as part of pharmacokinetic assessment |
| Measure drug accumulation in the body (RAC) | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of RAC as part of pharmacokinetic assessments |
| Identification of Maximum Tolerated Dose (MTD) | Informed consent untli end of Dose Limiting Toxicity (DLT) period - Approx 1 month | Safety and tolerability of AZD0156 alone or in combination with cytotoxic chemotherapies or novel anti-cancer agents as assessed through collection of Adverse Events |
| Overall Survival (Part B Only) | From start of treatment until the end of Long Term Follow-up (Approx 12 months) | Period of time from the start of treatment until end of life from any cause |
| Measure time to maximum concentration (tmax) | From Baseline until 31 days into combination treatment (maximum of 52 timepoints) | Measurement of tmax as part of pharmacokinetic assessment |
Countries
South Korea, Spain, United Kingdom, United States
Outcome results
None listed