Module 1: advanced/relapsed ovarian, breast, pancreatic or prostate cancer where patients loss of function or predicted loss of function mutation in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D Mdoule 2: IDH-mutant glioma Module 3: advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm, IDH-mutant recurrent glioma, breast cancer (without BM) MedDRA version: 20.0 Level: PT Classification code 10033128 Term: Ovarian canc
Conditions
Interventions
Product Name: AZD9574
Product Code: AZD9574
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Not yet available
Current Sponsor code: AZD9574
Other descriptive name: AZD9574
Concentration u
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1 Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses. 2 Age = 18 years at the time of screening. 3 Eastern Cooperative Oncology Group performance status (ECOG PS: 0-2) with no deterioration over the previous 2 weeks. 4 Life expectancy = 12 weeks. 5 Progressive cancer at the time of study entry. 6 Patients must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria. 7 Patients must have evaluable disease as defined in module-specific criteria for Part A and Part B 8 Adequate organ and marrow function as defined by the protocol 9 Female subjects of childbearing potential: Must have negative pregnancy test result at screening and prior to each cycle administration of study treatment and must use at least one highly effective method of birth control. 10 Female subjects must not breastfeed and must not donate or retrieve ova for their own use, from screening to approximately 1 months after the last dose of study intervention. 11 Non-sterilised male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to approximately 3 months after the last dose of study intervention Other module specific criteria may apply Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 163 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 107
Exclusion criteria
Exclusion criteria: 1 Treatment with any of the following: (a) Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 3 weeks (whichever is shorter) of the first dose of study intervention (b) Any other anti-cancer treatment within 5 half-lives or 3 weeks for cytotoxic and non-cytotoxic treatment or 4 weeks for biological products 2 Major surgery within 4 weeks of the first dose of study intervention 3 Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study intervention 4 With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study intervention 5 Any known history of persisting (> 2 weeks) severe pancytopenia due to any cause 6 Spinal cord compression unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study intervention 7 History of uncontrolled seizures or with need for concurrent administration of more than 2 antiepileptic drugs, or history of epileptic disorder or any seizure history unrelated to tumour 8 History of severe brain injury or stroke 9 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required 10 Uncontrolled intercurrent illness within the last 12 months, including but not limited to, active interstitial lung disease, serious chronic GI conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent. 11 Any known predisposition to bleeding 12 Any of the following cardiac criteria: (a) Mean resting corrected QT interval (QTcF) >450 milliseconds (b) Any factors that increase the risk of QT prolongation or risk of arrhythmic events (c) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG and clinically significant sinus node dysfunction not treated with pacemaker 13 Other cardiovascular diseases as defined by any of the following: (a) Symptomatic heart failure (b) Uncontrolled hypertension (c) Hypertensive heart disease with significant left ventricular hypertrophy (d) Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention or coronary artery bypass grafting or cardiac valve replacement/repairment within 6 months (e) Cardiomyopathy of any aetiology (f) Presence of clinically significant valvular heart disease (g) History of atrial or ventricular arrhythmia requiring treatment (h) Transient ischaemic attack, or stroke within 6 months prior to screening (i) Patients with symptomatic hypotension at screening 14 Patients with myelodysplastic syndrome/acute myeloid leukaemia 15 Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the investigational product(s) (IP). 16 Known allergy or hypersensitivi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced malignancies;Secondary Objective: To characterise the PK of AZD9574, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents. Module 1: - To evaluate PD of AZD9574 in tumour tissue when given orally as monotherapy - To assess the preliminary antitumour activity of AZD9574 as monotherapy Module 2: -To assess the preliminary anti-tumour activity of AZD9574 in combination with temozolomide Module 3: - To determine PARP1 occupancy in brain by AZD9574 at examined doses and plasma concentration - Evaluate safety of radioligand [11C]AZ14193391;Primary end point(s): Incidence of AEs/SAEs DLTs MTD Changes from baseline in laboratory findings, physical examination, ECOG PS, ECGs and vital signs.;Timepoint(s) of evaluation of this end point: First dose of study drug administration | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Plasma concentrations of AZD9574 and plasma PK parameters including but not limited to • Area under the curve after a single dose and after multiple doses • Maximum plasma concentration after a single dose and after multiple doses • Time to reach maximum plasma concentration • Minimum plasma concentration at steady state • Half-life • Accumulation ratio • Dose proportionality Module 1: Assessment of pH2AX PD biomarker modulations at baseline and during treatment or pre treatment in PD biomarkers. Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) • Percentage change in target lesion size • Overall response rate, Duration of response, Time to response, Progression-free survival/Radiographic progression-free survival, Overall Survival For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria For prostate cancer participants: • Proportion of participants achieving a = 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response) • Radiological response evaluated according to RECIST v1.1 + PCWG3 response evaluation criteria Module 2: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • Overall response rate, Duration of response, Time to response, Progression-free survival Module 3: • Difference in radioligand binding to PARP1 from baseline to study intervention administration (occupancy [%]) • Incidence of AEs/SAEs ;Timepoint(s) of evaluation of this end point: First dose of study drug administration. | — |
Countries
Australia, Korea, Republic of, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Study Information Center
AstraZeneca
Outcome results
None listed