Open Actively Recruiting

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

About

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 270 patients with advanced cancer that has recurred/progressed.

Primary Purpose

Treatment

Study Type

Interventional

Phase

Phase I/II

Eligibility

Gender

All

Healthy Volunteers

Minimum Age

18 Years

Maximum Age

130 Years

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:
  - 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,
  - 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
  - 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
  - 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:
  - Participants must have previously treated and progressing or untreated brain metastases confirmed by brain MRI at screening that do not need immediate local therapy.
  - Participants should have stable neurological function for ≥ 14 days prior to signing the main study ICF.
  - 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