Advanced Breast Cancer
Conditions
Brief summary
The primary objective of the study is to measure efficacy of saruparib (AZD5305) plus camizestrant compared with physician's choice CDK4/6i plus ET in patients with BRCA1, BRCA2, or PALB2m, HR-positive, HER2-negative (defined as IHC 0, 1+, 2+/ ISH non-amplified) advanced breast cancer
Detailed description
Approximately 4680 participants will be screened to achieve approximately 788 participants randomised to study intervention. Participants will be randomised in a 2:2:1:2 ratio to one of the following intervention groups: * Arm 1: saruparib (AZD5305) plus camizestrant * Arm 2: Physician's choice CDK4/6i plus physician's choice ET * Arm 3: Physician's choice CDK4/6i plus camizestrant * Arm 4: Saruparib (AZD5305) plus physician's choice ET Treatment continues until BICR-confirmed disease progression, unacceptable toxicity occurs, or the participant withdraws consent.
Interventions
Saruparib (AZD5305) is a potent and selective inhibitor of PARP1, with minimal effect on PARP2.
DRUGCamizestrant
Camizestrant (AZD9833) is an orally bioavailable, next generation SERD with non-clinical and clinical activity in both ESR1 mutant and wild type settings .
DRUGAbemaciclib
CDK4/6 Inhibitor
DRUGRibociclib
CDK4/6 Inhibitor
DRUGPalbociclib
CDK 4/6 Inhibitor
DRUGFulvestrant
Endocrine Therapy
DRUGLetrozole
Endorcine Therapy
DRUGAnastrozole
Endocrine Therapy
DRUGExemestane
Endocrine Therapy
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult females, pre/peri-menopausal and/or post-menopausal, and adult males * Histologically or cytologically documented diagnosis of HR-positive, HER2-negative breast cancer * Advanced breast cancer with either locally advanced disease not amenable to curative treatment or metastatic disease * ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks * FFPE tumour tissue from each participant * Documented germline tumour loss of function mutation in BRCA1, BRCA2, or PALB2 * Adequate organ and marrow function
Exclusion criteria
* Participants with history of MDS/AML or with features suggestive of MDS/AML * Participants with any known predisposition to bleeding * Any history of persisting severe cytopenia * Any evidence of severe or uncontrolled systemic diseases or active uncontrolled infections * Refractory nausea and vomiting, chronic GI disease, inability to swallow the formulated product, or previous significant bowel resection * History of another primary malignancy * Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapy excluding alopecia * Spinal cord compression, brain metastases, carcinomatous meningitis, or leptomeningeal disease * Evidence of active and uncontrolled hepatitis B and/or hepatitis C * Evidence of active and uncontrolled HIV infection * Active tuberculosis infection * Cardiac criteria, including history of arrythmia and cardiovascular disease * Concurrent exogenous reproductive hormone therapy or non-topical hormonal therapy for non-cancer-related conditions * Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study * Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study treatment * Prior treatment with systemic anti-cancer therapy for locoregionally recurrent or metastatic disease is not permitted, apart from treatment with ET for up to 28 days total before randomisation * Prior treatment within 28 days with blood product support or growth factor support * Any systemic concurrent anti-cancer treatment * Concomitant use of the following types of medications or herbal supplements within 21 days or at least 5 half-lives of randomisation: 1. Strong and moderate CYP3A4 inducers/inhibitors 2. Sensitive CYP2B6 substrates 3. Substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index, eg, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin. * Concomitant use of drugs that are known to prolong QT and have a known risk of TdP * Systemic use of atropine * The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (Arm 1 vs arm 2) | Up to approximately 64 months | PFS is defined as time from randomisation until progression per RECIST v1.1 as assessed by BICR, or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | ORR is defined as the proportion of participants who have a complete or partial response, as determined by BICR per RECIST v1.1. |
| Duration of Response (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | DoR is defined as the time from the date of first documented response until date of documented progression per RECIST v1.1 as assessed by BICR, or death due to any cause. |
| Participant-reported tolerability (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | Proportion of all dosed participants reporting different levels of severity of diarrhoea as measured by the diarrhoea single item (EORTC IL237/IL239/IL240) and different levels of severity of abdominal pain as measured by the abdominal pain single item (EORTC IL237/IL239/IL240). |
| Progression-Free Survival (arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | PFS is defined as time from randomisation until progression per RECIST v1.1 as assessed by BICR, or death due to any cause. |
| Overall Survival (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 88 months | OS is defined as the time from randomisation until the date of death due to any cause. |
| Progression Free Survival 2 (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | PFS2 is defined as the time from randomisation to the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death. |
| Time to deterioration in patient-reported global health status/QoL as measured by the global health status/QoL scale within the EORTC quality of life questionnaire (QLQ) (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | This scale includes 2 items asking participants to report overall health and overall quality of life in the past week. Both items are measured on a 6-point verbal rating scale ranging from Very Poor to Excellent. Single item scores are averaged to calculate a subscale score that is transformed to range from 0 to 100, where higher scores indicate better global health status/QoL. |
| Change from baseline in patient-reported global health status/QoL as measured by the global health status/QoL scale within the EORTC quality of life questionnaire (QLQ) (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | This scale includes 2 items asking participants to report overall health and overall quality of life in the past week. Both items are measured on a 6-point verbal rating scale ranging from Very Poor to Excellent. Single item scores are averaged to calculate a subscale score that is transformed to range from 0 to 100, where higher scores indicate better global health status/QoL. |
| Plasma concentrations of saruparib (AZD5305) | Up to approximately 64 months | — |
| Plasma concentrations of camizestrant | Up to approximately 64 months | — |
| Time to chemotherapy (arm 1 vs 2, arm 4 vs 2, arm 1 vs 3, arm 3 vs 2, arm 4 vs 1) | Up to approximately 64 months | Time to chemotherapy is defined as time from randomisation until the start date of the first subsequent chemotherapy treatment after discontinuation of randomised treatment (censoring participants who died prior to initiation of chemotherapy). |
| Samples will be used to develop companion diagnostics by analyzing their performance characteristics and calculate their consistency with clinical trial assays used for enrolment onto the study. | Up to approximately 64 months | Samples will be tested by a CDx to confirm BRCA1/2 and PALB2 gene mutation status |
Countries
Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Chile, China, Czechia, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Japan, Malaysia, Peru, Poland, Portugal, Puerto Rico, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed