Study of AZD4956 as Monotherapy and in Combination With Anti-Cancer Agents in Participants With Advanced/Metastatic Homologous Recombination Deficient Solid Tumours

Official title

A Modular Open-label, Phase I/IIa Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of Ascending Doses of AZD4956 as Monotherapy, and in Combination With Anti-Cancer Agents in Participants With Advanced/Metastatic Homologous Recombination Repair Defective Solid Tumours

Overview

The purpose of this modular, first trial in human study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of ascending dose levels (DLs) of AZD4956 monotherapy and in combination with other anti-cancer agents in participants with advanced/metastatic solid tumours with homologous recombination repair (HRR) deficiencies.

Detailed description

The study consists of individual modules each evaluating the safety and tolerability of AZD4956 dosed as monotherapy, or with a specific combination partner. There are following 2 modules -

1. Module 1: AZD4956 monotherapy 2. Module 2: AZD4956 in combination with saruparib

Each module may further contain 2 parts-

* Part A (dose escalation/dose finding): To determine the safety, tolerability, PK, PD, and preliminary efficacy of AZD4956 as monotherapy or in combination. * Part B (dose expansion): To further evaluate the safety and preliminary efficacy of AZD4956 in combination with other anti-cancer agents.

Interventions

• Drug AZD4956
  AZD4956 will be administered orally.
• Drug Saruparib
  Saruparib will be administered orally.

Primary outcome measures

• Parts A and B: Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Time frame: From Screening (Day -28) to follow-up (up to 3.5 years)]
• Part B: Progression free survival (PFS) [Time frame: Up to 3.5 years]
• Part A - Number of participants with dose-limiting toxicities (DLTs) [Time frame: Up to 28 days]

Secondary outcome measures (12)

• Objective response (OR) [Time frame: Up to 3.5 years]
• Duration of response (DoR) [Time frame: Up to 3.5 years]
• Best Overall Response (BOR) [Time frame: Up to 3.5 years]
• Time to response (TTR) [Time frame: Up to 3.5 years]
• Disease control (DC) [Time frame: Up to 3.5 years]
• Clinical benefit rate (CBR) [Time frame: Up to 3.5 years]
• Part A: Progression free survival (PFS) [Time frame: Up to 3.5 years]
• Percentage change from baseline in tumour size [Time frame: Up to 3.5 years]
• Number of participants with cancer antigen 125 (CA125) response (for ovarian cancer participants) [Time frame: From baseline up to 3.5 years]
• Radiological progression free survival (rPFS) (for prostate cancer participants) [Time frame: Up to 3.5 years]
• Change from baseline in prostate specific antigen 50 (PSA50) response rate (for prostate cancer participants) [Time frame: From baseline up to 3.5 years]
• Change from baseline in PSA90 response rate (for prostate cancer participants) [Time frame: From baseline up to 3.5 years]

Eligibility criteria

Core Inclusion Criteria:

• Documented locally advanced or metastatic solid tumour malignancy.
• Eastern cooperative oncology group (ECOG) performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to screening and first day of dosing.
• Minimum life expectancy ≥ 12 weeks.
• Adequate organ and marrow function.
• 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 intervention.

Module 1 Inclusion Criteria:

• Demonstrated evidence of disease progression.
• Participants must have advanced or metastatic solid tumours.
• Participants may have received up to one prior line of therapy with a poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi)-based regimen (either as a treatment or as maintenance).

Module 2 Inclusion Criteria:

Part A (AZD4956 in Combination with Saruparib Dose Escalation) and Part A-PD (PD Backfill Cohorts):

• Participants must have one of the following conditions-

• Histologically or cytologically confirmed carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or somatic mutation.
• Histologically or cytologically confirmed advanced ovarian, fallopian tube, or primary peritoneal cancer.
• Histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic castrate resistant prostate cancer (CRPC).
• Histologically or cytologically confirmed advanced/metastatic pancreatic cancer.
• Participants must have evaluable disease.
• Participants in PD backfill cohorts must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).

Part A (PD Backfill Cohorts) - Participants Undergoing Paired Biopsies:

\- Participants must have a tumour suitable for biopsy.

Part A-Non-PD (Non-PD Backfill Cohorts) and Part B (Dose Expansion Cohorts):

• Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic CRPC.
• Participants must have documented metastatic disease by clear evidence of ≥ 1 bone lesion (defined as one lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable or non-measurable).
• Participants must have received the prior approved systemic therapies for metastatic prostate cancer.
• Participants must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).

Core Exclusion Criteria:

• Any significant laboratory finding or any severe and uncontrolled medical condition.
• Participants with any known predisposition to bleeding.
• Spinal cord compression or symptomatic and unstable brain metastases or leptomeningeal disease.
• Allogenic organ transplantation.
• Known to have active infection, including hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Known history of infection with human immunodeficiency virus (HIV).
• Active gastrointestinal disease or other condition that will interfere significantly with the swallowing, absorption, distribution, metabolism or excretion of oral therapy.
• Participants with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
• Participants with a known hypersensitivity to the investigational product(s) or any of the excipients of the product(s).
• Previous dosing with AZD4956.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 6 centers

• Research Site — Barcelona
• Research Site — Barcelona
• Research Site — Barcelona
• Research Site — Logroño
• Research Site — Pozuelo de Alarcón
• Research Site — Seville

United States · 4 centers

• Research Site — New York
• Research Site — Providence
• Research Site — Houston
• Research Site — Fairfax

United Kingdom · 3 centers

• Research Site — Cambridge
• Research Site — London
• Research Site — Sutton

Australia · 2 centers

• Research Site — Melbourne
• Research Site — Westmead

Japan · 2 centers

• Research Site — Chūōku
• Research Site — Kashiwa

South Korea · 2 centers

• Research Site — Seoul
• Research Site — Seoul

Identifiers

NCT: NCT07446855 · D8570C00001 · 2025-524171-22-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗