Solid Tumours
Conditions
Keywords
Advanced/metastatic homologous recombination repair defective solid tumours, Poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi), Pharmacokinetics, Pharmacodynamics
Brief 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.
Interventions
DRUGAZD4956
AZD4956 will be administered orally.
DRUGSaruparib
Saruparib will be administered orally.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion 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- 1. 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. 2. Histologically or cytologically confirmed advanced ovarian, fallopian tube, or primary peritoneal cancer. 3. Histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic castrate resistant prostate cancer (CRPC). 4. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A and B: Number of participants with adverse events (AEs) and serious adverse events (SAEs) | From Screening (Day -28) to follow-up (up to 3.5 years) | To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s). |
| Part B: Progression free survival (PFS) | Up to 3.5 years | 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. |
| Part A - Number of participants with dose-limiting toxicities (DLTs) | Up to 28 days | To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response (OR) | Up to 3.5 years | OR is defined as if a participant achieves a best overall response (BOR) of confirmed complete response (CR) or partial response (PR), as assessed by the investigator, according to response evaluation criteria in solid tumours (RECIST) v1.1 criterion. |
| Duration of response (DoR) | Up to 3.5 years | DoR is defined as the time from the date of first documented OR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by prostate cancer working group 3 (PCWG3), until the date of documented disease progression or death in the absence of disease progression. |
| Best Overall Response (BOR) | Up to 3.5 years | To assess the preliminary anti-tumour activity of AZD4956 monotherapy and in combination with anti-cancer agent(s). |
| Time to response (TTR) | Up to 3.5 years | TTR is defined as the time from the date of first dose of study intervention until the date of first documented OR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3, which is subsequently confirmed. |
| Disease control (DC) | Up to 3.5 years | DC is defined as if a participant has achieved a best OR of confirmed CR or PR or SD as BOR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3. |
| Clinical benefit rate (CBR) | Up to 3.5 years | CBR is defined as the percentage of advanced cancer participants who achieve CR, PR, or at least 16 weeks/24 weeks of stable disease, assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3, as a result of therapy. |
| Part A: Progression free survival (PFS) | Up to 3.5 years | 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. |
| Percentage change from baseline in tumour size | Up to 3.5 years | The best percentage change from baseline in target lesion (TL) tumour size is the largest decrease (or smallest increase) from baseline for a participant, using RECIST v1.1 assessments. |
| Number of participants with cancer antigen 125 (CA125) response (for ovarian cancer participants) | From baseline up to 3.5 years | CA125 response is defined as if at least a 50% reduction in CA125 levels from a pre-treatment sample. |
| Radiological progression free survival (rPFS) (for prostate cancer participants) | Up to 3.5 years | 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. |
| Change from baseline in prostate specific antigen 50 (PSA50) response rate (for prostate cancer participants) | From baseline up to 3.5 years | PSA50 response is defined as if a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later has been achieved. |
| Change from baseline in PSA90 response rate (for prostate cancer participants) | From baseline up to 3.5 years | PSA90 response is defined as if a ≥ 90% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later has been achieved. |
| Change from baseline in PSA undetectable rate | At 3, 6 and 9 months | Undetectable PSA is defined as a measurement of \< 0.2 ng/mL. |
| Time to PSA50/90 response (for prostate cancer participants) | Up to 3.5 years | Time to PSA50/90 response is defined as the time from the date of first dose of study intervention until the date of first documented PSA response (≥ 50%/90% decrease in PSA from baseline) that is confirmed by a second consecutive PSA assessment at least 3 weeks later. |
| Time to PSA progression (for prostate cancer participants) | Up to 3.5 years | Time to PSA progression is defined as the time from date of first dose of study intervention until the date of first documented PSA progression or the last PSA result in the absence of progression. |
| PSA PFS at 6 months (PSA-6) | At 6 months | PSA progression is defined as an increase in PSA of ≥ 25% from the nadir and an absolute increase of at least 2 ng/mL above nadir beyond 12 weeks. To assess the preliminary anti-tumour activity of AZD4956 monotherapy and in combination with anti-cancer. agent(s) |
| Area under the concentration-time curve (AUC) | From date of first dose of study intervention up to 59 days after first dose | To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
| Maximum concentration (Cmax) | From date of first dose of study intervention up to 59 days after first dose | To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
| Time to maximum concentration (Tmax) | From date of first dose of study intervention up to 59 days after first dose | To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
| Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe(t1-t2)) | From date of first dose of study intervention up to 16 days after first dose | To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
| Renal clearance (CLR) | From date of first dose of study intervention up to 16 days after first dose | To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
| Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae(t1-t2)) | From date of first dose of study intervention up to 16 days after first dose | To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
| Change in amount of KRAB-associated protein-1 phosphorylated on serine 824 [pKAP1 (Ser824)] biomarker in tumour cells at baseline and during treatment | From Baseline up to 3.5 years | To evaluate PD of AZD4956 in tumour cells when given orally as monotherapy and in combination with anti-cancer agent(s). |
Countries
Australia, Japan, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed