6-FLUORO-5-[4-[(5-FLUORO-2-METHYL-3-OXO-4H-QUINOXALIN-6-YL)METHYL]PIPERAZIN-1-YL]-N-METHYLPYRIDINE-2-CARBOXAMIDE for Advanced solid malignancies|Ovarian cancer|Breast cancer|Pancreatic cancer|Prostate cancer|IDH-mutant glioma|Non-small cell lung cancer|Endometrial cancer|HER2-positive metastatic solid tumours

Inclusion criteria

• {"criterion_text":"- Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses.\n- Male participants must refrain from fathering a child or donating sperm from the start of study intervention and for approximately 3 months after the last dose of study intervention\n- Adequate organ and marrow function as defined by the protocol\n- Participants should be capable of self-administering oral formulations\n- Provision of archival formalin-fixed and paraffin-embedded (FFPE) tumour specimen is mandatory, where available, except if stated that it is optional in a specific module. An archival tissue specimen is preferred but a new tissue sample may be used\n- Age ≥ 18 years at the time of screening.\n- Eastern Cooperative Oncology Group performance status (ECOG PS: 0-2) with no deterioration over the previous 2 weeks.\n- Life expectancy ≥ 12 weeks.\n- Progressive cancer at the time of study entry.\n- 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\n- Female subjects must not breastfeed and must not donate or retrieve ova for their own use, from screening to approximately 6 months after the last dose of study intervention.\n- 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\n- Female partners of male participants must also use at least one highly effective method of contraception from screening to approximately 3 months after the last dose of study intervention of the male participant"}

Exclusion criteria

• {"criterion_text":"- 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 before enrollment for biological products\n- Any concurrent anti-cancer therapy or concurrent use of prohibited medications\n- Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements\n- Major surgery within 4 weeks of the first dose of study intervention\n- Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study intervention or interpretation of participant safety or study results\n- Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study\n- Involvement in the planning and/or conduct of the study\n- Previous study intervention assignment in the present study Other module specific criteria may apply.\n- 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\n- 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\n- Any known history of persisting (> 2 weeks) severe pancytopenia due to any cause\n- 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.\n- 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\n- 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\n- History of severe brain injury or stroke\n- 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\n- Any live virus or bacterial cancer vaccine within 4 weeks of the first dose of study intervention\n- Any known predisposition to bleeding\n- 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\n- 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\n- Patients with myelodysplastic syndrome/acute myeloid leukaemia\n- 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).\n- Known allergy or hypersensitivity to IP(s) or any of the excipients of the IP(s)\n- Known contra-indication to gadolinium-enhanced MRI imaging or, if applicable, not able to be maintained on a stable or decreasing dose of corticosteroid regimen prior to the baseline MRI."}

Primary endpoints

• {"endpoint_text":"- Incidence of AEs/SAEs; DLTs; MTD; Changes from baseline in laboratory findings, ECOG PS, ECGs and vital signs.","definition_or_measurement_approach":"Assessment by incidence recording of AEs/SAEs, identification of DLTs, determination of MTD, and changes from baseline in laboratory findings, ECOG PS, ECGs and vital signs as recorded per protocol assessments."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Measurement of plasma AZD9574 concentrations and derivation of PK parameters (AUC, Cmax, Tmax, Cmin, t1/2, accumulation ratio, dose proportionality) from plasma sampling."}
• {"endpoint_text":"- Module 1: Assessment of pH2AX PD biomarker modulations at baseline and during treatment or pre-treatment in PD biomarkers","definition_or_measurement_approach":"Pharmacodynamic assessment of pH2AX biomarker modulation in tumour tissue at baseline and during treatment (or pre-treatment) from available samples."}
• {"endpoint_text":"- Module 1: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) − Percentage change in target lesion size − ORR, DoR, TTR, PFS/rPFS. For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria.","definition_or_measurement_approach":"Radiological assessment per RECIST v1.1 (and CA125 GCIG criteria for ovarian cancer) to derive percent change in target lesion size, ORR, DoR, TTR, PFS/rPFS."}
• {"endpoint_text":"- Module 1: 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","definition_or_measurement_approach":"PSA50 determined by serial PSA measurements confirmed by repeat assessment ≥3 weeks later; radiological response per RECIST v1.1 and PCWG3 for bone disease."}
• {"endpoint_text":"- Module 1: PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without a high fat meal.","definition_or_measurement_approach":"PK sampling to estimate AUC, Cmax, Tmax and ratios comparing fed vs fasted states."}
• {"endpoint_text":"- Module 1: PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without famotidine.","definition_or_measurement_approach":"PK sampling to estimate PK parameters with and without famotidine co-administration."}
• {"endpoint_text":"- Module 2: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • ORR, DoR, TTR, PFS","definition_or_measurement_approach":"Radiological response per RANO-HGG or RANO-LGG criteria to derive percent change in target lesions, ORR, DoR, TTR, PFS."}
• {"endpoint_text":"- Module 3: Plasma concentrations of AZD9574 and plasma PK parameters including but not limited to • Area under the curve (AUC) after a single dose and after multiple doses • Maximum plasma concentration (Cmax) after a single dose and after multiple doses • Time to reach maximum plasma concentration (tmax) • Minimum plasma concentration at steady state (Cmin,ss) • Half-life (t1/2) • Accumulation ratio","definition_or_measurement_approach":"Plasma PK sampling and derivation of standard PK parameters for AZD9574."}
• {"endpoint_text":"- Module 3: Difference in radioligand binding to PARP1 from baseline to study intervention administration (occupancy [%])","definition_or_measurement_approach":"PET radioligand binding assessment to quantify PARP1 occupancy (%) change from baseline."}
• {"endpoint_text":"- Module 3: Radiological response evaluated according to RECIST v1.1 − Percentage change in target lesion size − ORR, DoR, TTR, PFS/rPFS • For ovarian cancer participants: CA125 response evaluated according to the GCIG criteria","definition_or_measurement_approach":"Radiological response per RECIST v1.1 and CA125 GCIG criteria as applicable to derive response metrics."}
• {"endpoint_text":"- Module 3: For prostate cancer participants: − 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 (soft tissue) + PCWG3 (bone) response evaluation criteria","definition_or_measurement_approach":"PSA-based response confirmed by repeat PSA; radiological response per RECIST v1.1 and PCWG3."}
• {"endpoint_text":"- Module 3: Radiological response evaluated according to RANO-HGG or RANO-LGG • Percentage change in target lesions size • ORR, DoR, TTR, PFS","definition_or_measurement_approach":"Radiological response per RANO criteria to derive response outcomes."}
• {"endpoint_text":"- Module 4: Measurement of plasma concentrations AZD9574 and serum concentrations of T-DXd after administration of a single dose and multiple doses; and derivation of the following PK parameters including, but not limited to (as data allow): • AUC • Cmax • Tmax","definition_or_measurement_approach":"Plasma/serum PK sampling for AZD9574 and T-DXd; derivation of AUC, Cmax, Tmax."}
• {"endpoint_text":"- Module 4: Assessment of modulation from baseline (Visit 1) or pre-treatment in PD biomarkers from (optional) tumour samples; including, but not limited to assessment of pH2AX (Ser139)","definition_or_measurement_approach":"PD biomarker assessment in tumour samples (optional), including pH2AX (Ser139) modulation from baseline."}
• {"endpoint_text":"- Module 4: Presence of ADAs for T-DXd","definition_or_measurement_approach":"Assessment of anti-drug antibodies (ADAs) for T-DXd in serum."}
• {"endpoint_text":"- Module 4: Incidence of: • ILD/pneumonitis • LVEF • ≥ Grade 3 Neutropenia (Part B only)","definition_or_measurement_approach":"Incidence rates of ILD/pneumonitis, changes in LVEF, and grade ≥3 neutropenia (Part B) as recorded per safety assessments."}
• {"endpoint_text":"- Module 4: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) percentage change in target lesion size • ORR, DoR, PFS, TTR • Where appropriate, tumour marker response data will be summarized depending on the cancer type, eg, CA125 for ovarian cancer • PFS6 (Part B only)","definition_or_measurement_approach":"Radiological response per RECIST v1.1 and tumor marker summaries by cancer type; PFS6 for Part B."}
• {"endpoint_text":"- Module 5: Measurement of plasma concentrations of AZD9574 and Dato-DXd after a single dose and multiple doses; and derivation of the following PK parameters, including, but not limited to (as data allow): − AUC − Cmax − Tmax","definition_or_measurement_approach":"Plasma PK sampling for AZD9574 and Dato-DXd; derivation of PK parameters."}
• {"endpoint_text":"- Module 5: Assessment of modulation from baseline (Visit 1) or pre-treatment in PD biomarkers from (optional) tumour samples; includes, but is not limited to assessment of pH2AX (Ser139)","definition_or_measurement_approach":"PD biomarker assessment in tumour samples (optional), including pH2AX (Ser139) modulation."}
• {"endpoint_text":"- Module 5: Presence of ADAs for Dato-DXd","definition_or_measurement_approach":"Assessment of anti-drug antibodies (ADAs) for Dato-DXd in serum."}
• {"endpoint_text":"- Module 5: Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1) − percentage change in target lesion size − ORR, DoR, PFS, TTR • Where appropriate, tumour marker response data will be summarized depending on the cancer type, eg, CA125 for ovarian cancer.","definition_or_measurement_approach":"Radiological response per RECIST v1.1 and tumour marker response summaries as applicable."}
• {"endpoint_text":"- Module 5 : • For participants with prostate cancer: − ORR and rPFS according to RECIST v1.1 (soft tissue) + PCWG3 (bone) response evaluation criteria − Proportion of patients achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response)","definition_or_measurement_approach":"Radiological response per RECIST v1.1 and PCWG3; PSA50 measured and confirmed by repeat PSA."}
• {"endpoint_text":"- Module 5: Incidence of: • Interstitial Lung Disease/Pneumonitis • Infusion-related Reactions • Oral Mucositis/Stomatitis • Mucosal Inflammation Other than Oral Mucositis/Stomatitis • Ocular Surface Events","definition_or_measurement_approach":"Incidence rates for specified adverse events collected via safety monitoring and assessments."}

Sweden

Latest Decision Or Authorization Date

24-06-2024

Number Of Sites

2

Number Of Participants

26

Spain

Latest Decision Or Authorization Date

25-06-2024

Number Of Sites

6

Number Of Participants

150

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Clinical trial management/support (sponsorDuties codes provided in CTIS record); contact Clinicaltrial.Enquiries@parexel.com

Third parties

• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"Sponsor duties codes: [1,10,11,12,2,6,7,8,9]; contact Clinicaltrial.Enquiries@parexel.com","organisation_type":"Pharmaceutical company"}