Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (CERTIS1)

• ClinicalTrials.gov Identifier: NCT05417594
• Recruitment Status: Recruiting
• First Posted: June 14, 2022
• Last Update Posted: April 25, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: May 20, 2022
• First Posted Date: June 14, 2022
• Last Update Posted Date: April 25, 2023
• Actual Study Start Date: June 24, 2022
• Estimated Primary Completion Date: September 17, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 9, 2022)

• Incidence of Adverse Events (AEs), and Serious Adverse Events (SAEs) [ Time Frame: From first dose to post-treatment follow-up (approximately three years) ]
  The safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced malignancies will be assessed.
• Changes from baseline in laboratory findings, electrocardiograms (ECGs), and vital signs [ Time Frame: From last assessment prior to first dose to post-treatment follow up visit (approximately three years) ]
  The safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced malignancies will be assessed.
• Change from baseline Eastern Cooperative Oncology Group performance status (ECOG PS) [ Time Frame: From last assessment prior to first dose to post-treatment follow up visit (approximately three years) ]
  The performance status of ECOG will be assessed based on an ECOG grade of 0 to 4 where '0' is a high grade while '4' is a low grade. An ECOG grade of '0' means that the participant is fully active, able to carry on all pre-disease performance without restriction. An ECOG grade of '4' means that the participant is completely disabled, cannot carry on any self-care, and is totally confined to a bed or chair.
• Incidence of Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 0 and Cycle 1 (Day 1 to Day 35) ]
  The safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced malignancies will be assessed at each dose level.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 9, 2022)

• Area Under the Curve (AUC) [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The AUC 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 will be evaluated.
• Maximum plasma concentration (Cmax) [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The Cmax 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 will be evaluated.
• Time to reach maximum plasma concentration (tmax) [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The tmax 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 will be evaluated.
• Minimum plasma concentration at steady state (Cmin,ss) [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The Cmin,ss 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 will be evaluated.
• Half-life (t1/2) [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The t1/2 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 will be evaluated.
• Accumulation ratio [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The accumulation ratio 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 will be evaluated.
• Dose proportionality [ Time Frame: Cycle 0, Cycle 1 Day 1, Cycle 1 Day 16 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The dose proportionality 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 will be evaluated.
• Module 1: Assessment of pH2AX (phospho-histone 2AX) (Ser139) PD biomarker modulations [ Time Frame: Screening, Cycle 0 Day 1, Cycle 1 Day 8, and Cycle 1 day 15 (Cycle 0 = 7 days; Cycle 1 = 28 days) ]
  The PD biomarker modulations of pH2AX (Ser139) at baseline and during treatment or pre-treatment will be assessed in tumour tissue when given orally as monotherapy.
• Module 1: Percentage change in target lesion (TL) size [ Time Frame: From Baseline to every 8 weeks until disease progression (approximately three years) ]
  The percentage change in TL size will be determined for participants with measurable disease at baseline and is derived at each visit.
• Module 1: Objective Response Rate (ORR) [ Time Frame: From Baseline to every 8 weeks until disease progression (approximately three years) ]
  ORR is defined as the percentage of participants who have a confirmed response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) for solid tumours, RECIST v1.1 and/or Prostate Cancer Working Group 3 (PCWG3 [bone]) for prostate cancer, and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for brain metastases.
• Module 1: Duration of Response (DoR) [ Time Frame: First documented response until the date of documented progression or end of study (approximately three years) ]
  The DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, and RANO-BM for brain metastases.
• Module 1: Time To Response (TTR) [ Time Frame: From the first dose until the first documentation of a subsequently confirmed objective response (approximately three years) ]
  TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, and RANO-BM for brain metastases.
• Module 1: Progression Free Survival (PFS)/radiographic Progression-Free Survival (rPFS) [ Time Frame: From the start of first treatment until the date of objective disease progression or death (approximately three years) ]
  PFS and rPFS are defined as the time from start of first treatment until the date of objective disease progression or death regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression according to RECIST v1.1 for solid tumours, RECIST v1.1 and/or PCWG3 for prostate cancer, and RANO-BM for brain metastases.
• Module 1: Cancer Antigen 125 (CA125) response evaluated according to the GCIG criteria [ Time Frame: From Screening until disease progression or death (approximately three years) ]
  CA125 response is defined as at least a 50% reduction in CA125 levels from a pre-treatment sample.
• Module 1: Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result [ Time Frame: From screening until disease progression or death (approximately three years) ]
  PSA50 response is defined as the proportion of participants achieving a ≥ 50% decrease in Prostate Specific Antigen (PSA) from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable participants.
• Module 1: Radiological response evaluated according to RECIST v1.1 + Prostate Cancer Working Group 3 (PCWG3) response evaluation criteria [ Time Frame: Up to the End Of Trial (EOT) [approximately three years] ]
  In participants with prostate cancer, disease progression will be deemed to have occurred if soft tissue disease progression, bone lesion progression, or death are met.
• Module 2: Percentage change in TL size [ Time Frame: From Baseline to every 8 weeks until objective disease progression (approximately three years) ]
  The percentage change in TL size will be determined for participants with measurable disease at baseline and is derived at each visit by the measurability of TL according to Response Assessment in Neuro-Oncology - high-grade glioma (RANO-HGG) or Response Assessment in Neuro-Oncology - low-grade glioma (RANO-LGG).
• Module 2: ORR [ Time Frame: From Baseline to every 8 weeks until objective disease progression (approximately three years) ]
  The ORR is defined as the percentage of participant with high- or low-grade gliomas with at least one visit response of CR or PR according to RANO-HGG or RANO-LGG.
• Module 2: DoR [ Time Frame: First documented response until the date of documented progression or end of study (approximately three years) ]
  The DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression according to RANO-HGG or RANO-LGG.
• Module 2: TTR [ Time Frame: First dose until the first documentation of a subsequently confirmed objective response (approximately three years) ]
  TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response according to RANO-HGG or RANO-LGG.
• Module 2: PFS [ Time Frame: From the start of first treatment until the date of objective disease progression or death (approximately three years) ]
  The PFS is defined as the time from the start of study intervention until the date of objective disease progression or death regardless of whether the participant withdraws from study intervention or receives another anti-cancer therapy prior to progression according to RANO-HGG or RANO-LGG.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies
• Official Title: A Modular Phase I/IIa, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (CERTIS1)
• Brief Summary: This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in combination with anti-cancer agents in patients with advanced cancer that has recurred/progressed.

Detailed Description

This is a modular phase I/IIa, multi-centre, multi-part, open-label, dose escalation, and dose expansion study.

Approximately 255 participants will be enrolled and assigned to study treatments.

This study consists of individual modules each evaluating safety and tolerability.

• Core protocol which contains information applicable to all modules.

• Module 1 (AZD9574 monotherapy):

  • Part A (dose-escalation cohorts) will include participants with advanced/relapsed ovarian, breast, pancreatic or prostate cancer that are deemed suitable for a Poly ADP-Ribose Polymerase (PARPi) by the Investigator.

  • Part B (dose-expansion cohorts):

    • Cohort B1 will include participants with advanced/relapsed Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer participants with BRCA mutated (BRCA1m, and BRCA2m), PALB2 mutation (PALB2m), RAD51Cm or RAD51Dm, without evidence of brain metastasis at baseline Magnetic Resonance Imaging (MRI) scan.
    • Cohort B2 will include participants with advanced/relapsed HER2-negative breast cancer participants with BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm, who have either untreated or treated brain metastases that are not requiring immediate local therapy.

• Module 2 (AZD9574 in combination with temozolomide (TMZ):

  • Part A (dose-escalation cohorts) will include participants with Isocitrate Dehydrogenase (IDH)-mutant glioma.
  • Dose expansion for Module 2 may be added in the future following a protocol amendment.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Solid Malignancies

Intervention

• Drug: AZD9574
  Participants will receive AZD9574 orally in both the modules.
• Drug: Temozolomide
  Participants will receive temozolomide orally.

Study Arms

• Experimental: Module 1 Part A: Dose escalation
  Participants with advanced/relapsed ovarian, breast, pancreatic, or prostate cancer who are deemed suitable for a PARPi will receive AZD9574 monotherapy at escalating cohorts.
  Intervention: Drug: AZD9574
• Experimental: Module 1 Part B: Dose expansion
  Participants with breast cancer who are PARPi naive at a dose determined in dose-escalation.
  Intervention: Drug: AZD9574
• Experimental: Module 2 Part A: Dose escalation
  Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.
  Interventions:

  • Drug: AZD9574
  • Drug: Temozolomide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 9, 2022): 195
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 17, 2025
• Estimated Primary Completion Date: September 17, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Eastern Cooperative Oncology Group performance status (ECOG PS) with no deterioration over the previous 2 weeks.
• Progressive cancer at the time of study entry.
• 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.
• Adequate organ and marrow function.

Module 1:

- Female participants of childbearing potential must have a negative pregnancy test result at screening and prior to each cycle administration of AZD9574.

Part A:

• Participants must have one of the following:

  (i) Histologically or cytologically confirmed relapsed advanced ovarian, fallopian tube or primary peritoneal cancer and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C or RAD51D (ii) Histologically or cytologically confirmed HER2-negative carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. (iii) Histologically or cytologically confirmed advanced/metastatic castration-resistant prostate cancer (CRPC) and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D (d) Histologically or cytologically confirmed advanced/metastatic pancreatic cancer and evidence of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.

• Participants must have evaluable disease.
• Patients must be suitable for treatment with a PARPi.

Part B:

• Participants must have metastatic or recurrent locally advanced histologically or cytologically confirmed Human Epidermal growth factor Receptor 2 (HER2)-negative carcinoma of the breast and evidence of a predicted loss of function germline or tumour mutation.
• Participants must have at least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter.
• Participants who have received platinum chemotherapy for advanced breast cancer are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy.
• Participants who have received prior platinum-based chemotherapy as neo-adjuvant/adjuvant treatment are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and first dose of study intervention.

Module 2:

• Participants must be suitable for treatment with TMZ.
• Participants must have IDH1/2-mutant glioma.
• Participants should have progressive disease after prior radiation therapy and one prior line of alkylating chemotherapy for their disease.
• Recurrent disease must be evaluable by MRI.
• Female participants of childbearing potential must have a negative pregnancy test result at screening and prior to each cycle administration of AZD9574 and TMZ.
• Adequate organ and marrow function.

Exclusion Criteria:

• Major surgery within 4 weeks of the first dose of study intervention.
• 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.
• 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.
• Any known history of persisting severe pancytopenia due to any cause.
• 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.
• 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.
• History of severe brain injury or stroke.
• Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
• Uncontrolled intercurrent illness within the last 12 months.
• Any known predisposition to bleeding.
• Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9574.
• Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
• Known contra-indication to gadolinium-enhanced Magnetic Resonance Imaging (MRI) or, if applicable, not able to be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 7 days) prior to the baseline MRI.
• Any concurrent anti-cancer therapy or concurrent use of prohibited medications.

Module 1:

Part A:

• Participants that have received > one prior line of therapy in any setting with a PARPi-based regimen.
• Participants with an INR >1.5 unless the patient is receiving non-vitamin K antagonist oral anticoagulants.
• Participants with LMD unless the LMD is of low volume or is previously irradiated and the participant is asymptomatic from the LMD.

Part B:

• Participants with an International Normalised Ratio (INR) >1.5 unless the patient is receiving non-vitamin K antagonist oral anticoagulants.
• Participants with LMD are excluded unless the LMD is of low volume or is previously irradiated and the participant is asymptomatic from the LMD.

Module 2:

• Participants who have received a PARPi previously.
• Known hypersensitivity to TMZ or dacarbazine or known history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD9574.
• Participants who have received > 1 prior line of alkylating chemotherapy regimen.
• Participants who had previously experienced Grade 4 haematological toxicities or Grade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia with clinically significant bleeding during prior alkylating chemotherapy.
• Participants who have received bevacizumab within the last 6 months.
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Australia, Germany, Korea, Republic of, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT05417594
• Other Study ID Numbers: D8410C00001; 2021-006227-17 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: April 2023