Study of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced solid malignancies - CERTIS1

Study identifier:D8410C00001

ClinicalTrials.gov identifier:NCT05417594

EudraCT identifier:2021-006227-17

CTIS identifier:N/A

Recruiting

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)

Medical condition

Advanced solid malignancies

Phase

Phase 1/2

Healthy volunteers

Study drug

AZD9574, Temozolomide, [11C]AZ1419 3391

Sex

All

Estimated Enrollment

270

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 24 Jun 2022

Estimated Primary Completion Date: 17 Sept 2024

Estimated Study Completion Date: 12 Jan 2026

Study design

Allocation: Non-randomized
Endpoint Classification: -
Intervention Model: Sequential Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Aug 2023 by AstraZeneca

Collaborators

Inclusion and exclusion 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.
Module 3:
All Panels
- Female participants of childbearing potential:
Must have a negative pregnancy test result at screening and prior to each cycle
If sexually active with a non-sterilised male partner, must use at least one highly effective method of birth control from screening to approximately 6 months after the last dose of study intervention
Must not donate or retrieve ova for their own use from screening to approximately 6 months after the last dose of study intervention.
Panel 1
- Participants must consent to provide mandated blood samples and archival/fresh tumour tissue for confirmatory tests of their cancer using central laboratory.
- Participants must have one of the following:
(a) 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 BRCA1, BRCA2, PALB2, RAD51C, or RAD51D,
(b) 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 BRCA1, BRCA2, PALB2, RAD51C, or RAD51D
(c) Histologically or cytologically confirmed advanced/metastatic castration-resistant prostate cancer (CRPC) and evidence of a predicted loss of function germline or tumour mutation in in 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 in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D .
- Participants must have evaluable disease: at least one measurable and/or non-measurable lesions per RECIST 1.1
- Participants must be refractory to standard therapy or for which no standard therapy exists.
- Any 2 participants in this panel must meet the following CNS criteria:
(a) Participants must have previously treated and progressing or untreated brain metastases confirmed by brain MRI at screening that do not need immediate local therapy.
(b) Participants should have stable neurological function for ≥ 14 days prior to signing the main study ICF.
(c) If receiving steroids, the dose should be stable or decreasing for ≥ 14 days prior to signing the main study ICF.
Panel 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 and at least 1 tumour of > 1cm diameter detected on MRI.
- Formalin-fixed, paraffin-embedded (FFPE) tumour sample from the primary cancer must be available for central testing
- Adequate organ and marrow function (in the absence of transfusions or growth factor
support within 14 days prior to enrolment)
Panel 3
- Participants must consent to provide mandated blood samples and archival/fresh tumour tissue for confirmatory tests of their cancer using central laboratory.
- Participants must have 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 in BRCA1, BRCA2, PALB2, RAD51C or RAD51D .
- Participants must have evaluable disease: at least one measurable and/or non-measurable lesions per RECIST 1.1 .
- Participants must be refractory to standard therapy or for which no standard therapy exists.

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.
Module 3:
All Panels
- Positive Allen’s test
- Participants with a BMI > 30.0 kg/m2 or body weight > 100.0 kg
- Participants who suffer from claustrophobia.
- Participants with implanted metal devices or implants containing metal
- Participants with an INR >1.5
- Participants taking acid-reducing agents.
Panel 1
- Participants that have received > one prior line of therapy in any setting with a PARPi-based regimen .
- Participants with leptomeningeal disease (LMD)
Panel 2
- Participants who have received a PARPi previously.
- Known hypersensitivity to TMZ.
- 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.
Panel 3
- Participants that have received > one prior line of therapy in any setting with a PARPi-based regimen.
- Participants with LMD

This is a modular phase I/IIa, multi-centre, multi-part, open-label, dose escalation, and dose expansion study. Approximately 270 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. • Module 3 (PET Sub-study: AZD9574 monotherapy [Panels 1 and 3), AZD9574 in combination with TMZ (Panel 2). This module is only applicable for Sweden. - Panel 1 (AZD9574 monotherapy) will include up to 8 participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm. - Panel 2 (AZD9574 + TMZ) will include up to 2 participants with IDH-mutant recurrent glioma. - Panel 3 (AZD9574 monotherapy) will include up to 2 participants with breast cancer (without BM).

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Arms	Assigned Interventions
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.	Drug: AZD9574 Participants will receive AZD9574 orally in both the modules.
Experimental: Module 1 Part B: Dose expansion Participants with breast cancer who are PARPi naive at a dose determined in dose-escalation.	Drug: AZD9574 Participants will receive AZD9574 orally in both the modules.
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.	Drug: AZD9574 Participants will receive AZD9574 orally in both the modules. Drug: Temozolomide Participants will receive temozolomide orally.
Experimental: Module 3 Panel 1: AZD9574 monotherapy (Sweden only) Participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.	Drug: [11C]AZ1419 3391 Participants will receive [11C]AZ1419 3391 intravenously.
Experimental: Module 3 Panel 2: AZD9574 + TMZ (Sweden only) Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.	Drug: [11C]AZ1419 3391 Participants will receive [11C]AZ1419 3391 intravenously.
Experimental: Module 3 Panel 3: AZD9574 monotherapy (Sweden only) Participants with breast cancer (without BM).	Drug: [11C]AZ1419 3391 Participants will receive [11C]AZ1419 3391 intravenously.

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]