Overview
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 490 participants with advanced cancer that has recurred/progressed.
Description
This is a modular phase I/IIa, multi-centre, multi-part, open-label, dose escalation, and dose expansion study.
Approximately 490 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):
This module will include 220 participants:
- Part A (dose-escalation cohorts) will include 130 participants (including backfills) 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):
This module will include up to 3 expansion cohorts with 30 participants in each:
- 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.
- Up to of 20 participants may be required to get 12 evaluable participants in each cohort for food effect and Acid Reducing Agent (ARA) investigations.
• Module 2 (AZD9574 in combination with temozolomide (TMZ):
- Part A (dose-escalation cohorts) will include 75 participants with Isocitrate Dehydrogenase (IDH)-mutant glioma.
• Module 3 (PET Sub-study: AZD9574 monotherapy [Panels 1 and 3), AZD9574 in combination with TMZ (Panel 2). This module will include 12 participants and 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).
- Module 4 (AZD9574 in combination with Trastuzumab deruxtecan [T-DXd])
This module will include 90 participants (including backfills):
- Part A (dose escalation cohorts) will include participants with advanced, unresectable, or metastatic solid tumours that are HER2-positive.
- Part B (dose expansion cohorts) may be added in the future following a protocol amendment.
- Module 5 (AZD9574 in combination with Datopotamab deruxtecan [Dato-DXd])
This module will include 90 participants (including backfills):
- Part A (dose escalation cohorts) will include participants with advanced, unresectable, or metastatic solid tumours in different types of cancers.
- Part B (dose expansion cohorts) may be added in the future amendment.
Eligibility
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.
- 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 of study treatment.
- If sexually active with a non-sterilised male partner, must use at least one highly effective method of birth control plus a barrier method from screening to approximately 6 months after the last dose of study treatment.
- Female participants 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 treatment.
- 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.
- Female partners of male participants should 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.
- 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.
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.
- Participants must be capable of eating a high fat meal and adhering to fasting
restrictions.
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:
1. Must have a negative pregnancy test result at screening and prior to each cycle
of study treatment.
2. If sexually active with a non-sterilised male partner, must use at least one
highly effective method of birth control plus a barrier method from screening to
approximately 6 months after the last dose of study treatment.
- Female participants 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
treatment.
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:
1. 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,
2. 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
3. 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
4. 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:
1. Participants must have previously treated and progressing or untreated brain
metastases confirmed by brain MRI at screening that do not need immediate local
therapy.
2. Participants should have stable neurological function for ≥ 14 days prior to
signing the main study ICF.
3. 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.
Module 4:
- Participants must have the following HER2 status:
1. Participants with breast cancer must be IHC 3+ or IHC 2+/ISH-positive or IHC
2+/ISH-negative or IHC 1+ as determined by local testing using current American
Society of Clinical Oncology-College of American Pathologists (ASCO-CAP)
guidelines for scoring HER2 + breast cancer.
2. Participants with gastric cancer should be IHC 3+ or IHC 2+/ISH-positive based on
local tissue testing results.
3. Participants with non-breast and non-gastric cancers must have
HER2-overexpression (IHC 3+ or IHC 2+; as determined by local testing using
current ASCO-CAP guidelines for gastric IHC scoring).
4. Participants with NSCLC will also be eligible based on the presence of a
HER2activating mutation.
- Participants must have progressed following at least one prior systemic treatment and
not more than 2 prior lines of cytotoxic therapy for metastatic or advanced disease
and have no satisfactory alternative treatment option.
- Participants should have unresectable, or metastatic disease based on most recent
imaging. The following tumour types are eligible for this study: Breast cancer,
Non-Small Cell Lung Cancer, Colorectal Cancer,Bladder Cancer, Ovarian Cancer, Gastric
Cancer, and Other tumour types ( unresectable or metastatic biliary tract cancer,
cervical cancer, endometrial cancer, and pancreatic adenocarcinoma).
- Adequate organ and marrow function (in the absence of transfusions or growth factor
support) within 14 days prior to the first dose of study intervention.
- Left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram (ECHO) or
multigated acquisition (MUGA) scan within 28 days before start of treatment.
- Participants must have at least one lesion not previously irradiated (or with evidence
of disease progression following radiation).
- 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 6 months after the last dose of study intervention.
- Male participants must refrain from fathering a child or donating sperm during the
study and for approximately 6 months after the last dose of study intervention.
Module 5 :
- Participants should have unresectable, or metastatic disease based on most recent
imaging. The following tumour types are eligible for this study: TNBC, Endometrial
cancer, Ovarian Cancer and CRPC.
- Participants must have progressed following at least one prior systemic treatment for
metastatic or advanced disease and have no satisfactory alternative treatment option.
- Participants must have at least one lesion, not previously irradiated that can be
accurately measured at baseline as ≥ 10 mm in the longest diameter.
- Non-sterilised male participants who are sexually active with a female partner of
childbearing potential must use a condom with spermicide from screening to at least 4
months after the last dose of study.
- Male participants must refrain from fathering a child or donating sperm during the
study and for at least 4 months after the last dose of study intervention.
- Adequate organ and marrow function (in the absence of transfusions or growth factor
support) within 14 days prior to the first dose of study intervention.
Module 4 & 5:
- Female participants of childbearing potential:
1. Must have a negative pregnancy test result at screening and prior to each cycle
of study intervention.
2. If sexually active with a non-sterilised male partner, must use at least one
highly effective method of birth control in combination with one effective method
(male condom plus spermicide) from screening until at least 7 months after the
last dose of study intervention
- Female participants must not breastfeed and must not donate or retrieve ova for any
use from screening to at least 7 months after the last dose of study intervention.
- Participants must provide an existing FFPE tumour sample for retrospective,
tissue-based IHC testing in a central laboratory to determine HER2 expression and
other correlatives.
- ECOG performance status of 0 or 1.
- Participants recruited specifically for PD evaluation must have at least 1 tumour
suitable for paired biopsies and be willing to consent to pre-treatment and
on-treatment biopsies.
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 leptomeningeal disease (LMD) unless the LMD is of low volume or is
previously treated and the participant is asymptomatic or minimal symptoms.
- Participants with insulin-dependent diabetes.
- Participants currently on ARA treatment.
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
Module 4:
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of T-DXd and within 4 weeks for continuous corticosteroids at a dose of
approximately > 10 mg prednisone/day or equivalent.
- Participants should not have received more than 2 prior lines of systemic cytotoxic
therapy.
- Prior treatment with HER2 directed TOPO1i ADCs and prior AZD9574 is not permitted.
- Participants must not enter the study if they received chloroquine/hydroxychloroquine
< 14 days prior to the first dose.
- Presence of unresolved toxicities from previous anti-cancer therapy, defined as
toxicities not yet resolved to Grade ≤ 1 or baseline.
- Participants with a known history of prior platelet transfusion(s) or febrile
neutropenia in the advanced disease treatment setting.
- Participants with medical history of myocardial infarction. Participants with troponin
levels above ULN at screening and without any myocardial related symptoms.
- History of (non-infectious) ILD/pneumonitis that required steroids, has current
ILD/pneumonitis, or suspected ILD/pneumonitis.
- Additional lung-related exclusion criteria: (a) Lung-specific intercurrent clinically
significant illnesses (b) Any autoimmune, connective tissue or inflammatory disorders
(c) Prior pneumonectomy.
- Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal
shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy.
- Participants with a known hypersensitivity to T-DXd, any the excipients or other mAbs.
- History of another primary malignancy.
- Participants with an uncontrolled infection requiring IV antibiotics, antivirals, or
antifungals.
- Active primary immunodeficiency, known uncontrolled active HIV infection or active
hepatitis B or hepatitis C infection.
Module 5:
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of Dato-DXd and within 4 weeks for continuous corticosteroids at a dose of
approximately > 10 mg prednisone/day or equivalent.
- Corticosteroid mouthwash formulations are permitted to prevent and manage certain AEs.
- Prior anti-cancer treatments:
(d) Participants should not have received more than 2 prior lines of systemic
cytotoxic therapy (e) Prior treatment with PARPi is permitted (f) Prior TOPO1
inhibitor therapy is NOT permitted (g) Prior treatment with TROP2-directed ADCs is NOT
permitted. (h) Prior radiation therapy requires the washout periods.
- Participants must not enter the study if they received chloroquine /
hydroxychloroquine < 14 days prior to the first dose.
- History of another primary malignancy.
- Participant has history of non-infectious ILD/pneumonitis including radiation
pneumonitis that required steroids, has current or suspected ILD/pneumonitis.
- Clinically severe pulmonary function compromise.
- Clinically significant corneal disease.
- History of severe hypersensitivity reactions to Dato-DXd, or any of the excipients of
the product.
- History of severe hypersensitivity reactions to other monoclonal antibodies.
- Participant is pregnant or breastfeeding or planning to become pregnant.