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
Summary
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.
Arms & interventions
- DrugAZD4956
AZD4956 will be administered orally.
- DrugSaruparib
Saruparib will be administered orally.
Outcome measures
Primary
Parts A and B: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s).
Time frame: From Screening (Day -28) to follow-up (up to 3.5 years)
Part B: Progression free survival (PFS)
PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression.
Time frame: Up to 3.5 years
Part A - Number of participants with dose-limiting toxicities (DLTs)
To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s).
Time frame: Up to 28 days
Secondary
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
Change from baseline in PSA undetectable rate
Time frame: At 3, 6 and 9 months
Time to PSA50/90 response (for prostate cancer participants)
Time frame: Up to 3.5 years
Time to PSA progression (for prostate cancer participants)
Time frame: Up to 3.5 years
PSA PFS at 6 months (PSA-6)
Time frame: At 6 months
Area under the concentration-time curve (AUC)
Time frame: From date of first dose of study intervention up to 59 days after first dose
Maximum concentration (Cmax)
Time frame: From date of first dose of study intervention up to 59 days after first dose
Time to maximum concentration (Tmax)
Time frame: From date of first dose of study intervention up to 59 days after first dose
Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe(t1-t2))
Time frame: From date of first dose of study intervention up to 16 days after first dose
Renal clearance (CLR)
Time frame: From date of first dose of study intervention up to 16 days after first dose
Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae(t1-t2))
Time frame: From date of first dose of study intervention up to 16 days after first dose
Change in amount of KRAB-associated protein-1 phosphorylated on serine 824 [pKAP1 (Ser824)] biomarker in tumour cells at baseline and during treatment
Time frame: From Baseline up to 3.5 years
Eligibility criteria
Study locations (4)
Research Site
New York, New York, 10065
Research Site
Providence, Rhode Island, 02903
Research Site
Houston, Texas, 77030
Research Site
Fairfax, Virginia, 22031