A Phase I/II, Modular, Open-Label, Multi-Centre Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of AZD9750 as Monotherapy and in Combination With Other Anticancer Agents in Participants With Metastatic Prostate Cancer (ANDROMEDA)
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 300
- Locations
- 27
- Primary Endpoint
- Number of participants with dose-limiting toxicity (DLT), as defined in the protocol (Part A only)
Overview
Brief Summary
ANDROMEDA is a first-in-human, Phase I/II, open-label, multicenter study of AZD9750 in participants with metastatic prostate cancer. The trial evaluates safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary efficacy of AZD9750 as monotherapy and in combination with saruparib.
Detailed Description
This first-in-human (FiH), Phase I/II, open-label, multicenter study will evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9750 as monotherapy and in combination with saruparib in participants with metastatic prostate cancer. Additional combinations with other anticancer agents may be added via protocol amendment as separate modules. The study follows a modular design, allowing initial assessment of safety, tolerability, and preliminary efficacy across multiple treatment arms. Each Module has 2 parts: Part A (monotherapy dose escalation or combination dose finding) and Part B (monotherapy dose optimization and expansion or combination dose expansion). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention occur.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Inclusion Criteria:
- •Participant must be ≥18 years or the legal age at the time of signing the informed consent form.
- •Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate.
- •Documented metastatic disease.
- •Serum testosterone levels ≤ 50 ng/dL.
- •Evidence of disease progression with one of the following:
- •PSA progression defined by a minimum of 3 rising PSA levels with an interval of ≥ 1 week between each determination.
- •Radiographic progression of soft tissue disease by RECIST v1.1 with or without PSA progression.
- •Radiographic progression of bone metastasis with 2 or more documented new bone lesions on a bone scan with or without PSA progression.
- •ECOG performance status score of 0 or
Exclusion Criteria
- •Participants with pathological finding consistent with any presence of small cell carcinoma, predominant neuroendocrine carcinoma, or any predominant histology other than prostate adenocarcinoma.
- •Brain metastases, or spinal cord compression.
- •Any clinically significant cardiac disorders including QT prolongation, abnormal electrocardiogram (ECG).
- •Any clinically significant cardiovascular diseases including symptomatic heart failure, uncontrolled hypertension, acute coronary syndrome, cardiomyopathy, valvular heart disease, atrial fibrillation, stroke.
- •Active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism of AZD9750 and relevant combination IMPs.
- •Participants with any known predisposition to bleeding (eg, active peptic ulceration, recent \[within 6 months\] hemorrhagic stroke, proliferative diabetic retinopathy).
- •Prior treatment with an AR-PROTAC.
- •Other protocol-defined inclusion/exclusion criteria apply.
Arms & Interventions
Module 1 / Part A1
AZD9750 Monotherapy (Dose Escalation) - No randomization
Intervention: AZD9750 (Drug)
Module 1 / Part A2
AZD9750 Monotherapy (Backfills) - No randomization
Intervention: AZD9750 (Drug)
Module 1 / Part B1
AZD9750 Monotherapy (Dose Optimization) - Randomization
Intervention: AZD9750 (Drug)
Module 1 Part B2
AZD9750 Monotherapy (Dose Expansion) - No randomization
Intervention: AZD9750 (Drug)
Module 2/ Part B
AZD9750 + Saruparib (Combination Dose Expansion) - No Randomization
Intervention: AZD5305 (Drug)
Module 2/ Part B
AZD9750 + Saruparib (Combination Dose Expansion) - No Randomization
Intervention: AZD9750 (Drug)
Module 1 / Part B3
AZD9750 Monotherapy (Dose Expansion) - No randomization
Intervention: AZD9750 (Drug)
Module 2 / Part A
AZD9750 + Saruparib (Combination Dose Finding) - No Randomization
Intervention: AZD9750 (Drug)
Module 2 / Part A
AZD9750 + Saruparib (Combination Dose Finding) - No Randomization
Intervention: AZD5305 (Drug)
Outcomes
Primary Outcomes
Number of participants with dose-limiting toxicity (DLT), as defined in the protocol (Part A only)
Time Frame: From first dose of study intervention to 28 days post first dose
To evaluate the safety and tolerability and determine the MTD and/or the RDE(s)/RP2D of AZD9750 as a monotherapy and in combination with other anticancer agents in participants with mCRPC. A DLT is a toxicity defined by the study protocol that occurs from the first dose of study intervention up to the end of the DLT evaluation period that is assessed as clearly unrelated to the primary disease or intercurrent illness.
Number of participants with Adverse Events and Serious Adverse Events
Time Frame: From first dose of study intervention up to 37 days after the last dose of study treatment
The number of participants with adverse events and with serious adverse events will be assessed.
Number of participants with Adverse Events leading to discontinuation of study intervention
Time Frame: From first dose of study intervention up to 37 days after the last dose of study treatment
The number of participants with clinically significant changes from baseline in vital signs will be assessed.
Clinically significant changes from baseline in vital signs.
Time Frame: From first study dose up to 37 days after the last dose of study treatment
The number of participants with clinically significant changes from baseline in vital signs will be assessed.
Clinically significant changes from baseline in physical examination.
Time Frame: From first dose of study intervention up to 37 days after the last dose of study treatment
The number of participants with clinically significant changes from baseline in physical examination will be assessed.
Clinically significant changes from baseline in ECOG PS.
Time Frame: From first dose of study intervention up to 37 days after the last dose of study treatment
The number of participants with clinically significant changes from baseline in ECOG PS will be assessed.
Clinically significant changes from baseline in ECGs.
Time Frame: From first dose of study intervention up to 37 days after the last dose of study treatment
The number of participants with clinically significant changes from baseline in ECGs will be assessed.
Clinically significant changes from baseline in laboratory parameters.
Time Frame: From first dose of study intervention up to 37 days after the last dose of study treatment
The number of participants with clinically significant changes from baseline in laboratory parameters will be assessed.
Proportion of participants achieving a ≥50% decrease in PSA from baseline (PSA50) (Part B only)
Time Frame: From first dose of study intervention up to 14 days after the last dose of study treatment
To evaluate the preliminary antitumour efficacy of AZD9750 as monotherapy and in combination with other anticancer agents in participants with mCRPC.
Secondary Outcomes
- Proportion of participants achieving a ≥ 50% decrease in PSA from baseline (PSA50) (Part A only)(From first dose of study intervention up to initiation of subsequent anticancer therapy (or radiotherapy on target lesions), PSA progression or 14 days after the last dose of study treatment)
- Proportion of participants achieving a ≥ 90% decrease in PSA from baseline (PSA90)(From first dose of study intervention up to initiation of subsequent anticancer therapy (or radiotherapy on target lesions), PSA progression or 14 days after the last dose of study treatment)
- Objective response rate (ORR)(From randomisation or first dose of study intervention to initiation of subsequent anticancer treatment (or radiotherapy on target lesions) or progression, assessed up to 60 months)
- Duration of response (DoR)(From randomisation or first dose of study intervention to the date of first documented radiological disease progression, assessed up to 60 months)
- Time to response (TTR)(From randomisation or first dose of study intervention to initiation of subsequent anticancer treatment (or radiotherapy on target lesions) or progression, assessed up to 60 months)
- Radiographic progression-free survival (rPFS)(From randomisation or first dose of study intervention to progression, assessed up to 60 months)
- Best percentage change in target lesion size from baseline(From screening (Day -28) to initiation of subsequent anticancer treatment (or radiotherapy on target lesions) or progression, assessed up to 60 months)
- Time to PSA response (TTPSA50, TTPSA90)(From first dose of study intervention up to initiation of subsequent anticancer therapy (or radiotherapy on target lesions), PSA progression or 14 days after the last dose of study treatment)
- Cmax of AZD9750(From date of first dose of study intervention up to 115 days after first dose)
- tmax of AZD9750(From date of first dose of study intervention up to 115 days after first dose)
- AUC of AZD9750(From date of first dose of study intervention up to 115 days after first dose)
- Cmax of saruparib (Module 2 only)(From date of first dose of study intervention up to 57 days after first dose)
- Tmax of saruarib (Module 2 only)(From date of first dose of study intervention up to 57 days after first dose)
- AUC of saruparib (Module 2 only)(From date of first dose of study intervention up to 57 days after first dose)