This phase II trial studies how well ceralasertib, am Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, works alone or in combination with olaparib or durvalumab in treating participants with renal cell carcinoma (RCC), urothelial carcinoma, all pancreatic cancers, endometrial cancer, and other solid tumors excluding clear cell ovarian cancer that have spread to nearby tissue or lymph nodes or other parts of the body. ATR kinase inhibitor AZD6738 and olaparib or durvalumab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not known if giving ATR kinase inhibitor AZD6738 with or without olaparib or durvalumab may work better in treating participants with solid tumors.
PRIMARY OBJECTIVES: I. To assess objective response rate (ORR) of ceralasertib monotherapy and ceralasertib + olaparib by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria (ARID1A Cohort). II. To assess the composite response rate (objective response and/or PSA50 response) of ceralasertib monotherapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) (N = 5-10) harboring pathogenic ATM mutations and/or loss of ATM expression by Immunohistochemistry (IHC) (ATM Cohort). III. To assess objective response rate of ceralasertib monotherapy in patients with other advanced solid tumor malignancies harboring pathogenic ATM mutations and/or loss of ATM expression by IHC (ATM Cohort). IV. To assess the objective response rate (ORR) of ceralasertib in combination with durvalumab by RECIST 1.1 criteria (Endometrial Cohort) SECONDARY OBJECTIVES: I. To determine the median duration of response (DOR) in each study arm and cohort. II. To determine the median progression-free survival and progression-free survival rate at 6 and 12 months in each study arm and cohort. III. To determine the median overall survival (Endometrial cohort only). IV. To further characterize the safety and tolerability profile of ceralasertib alone and in combination with olaparib and durvalumab, respectively. V. To determine the percent change from baseline in the sum of the longest diameter of target lesions. VI. Prostate cancer patients only: To determine the PSA50 response rate and radiographic progression-free survival by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. OUTLINE: Participants will be assigned to receive one of 3 treatment regimens (ceralasertib monotherapy, ceralasertib plus olaparib combination therapy, or ceralasertib plus durvalumab combination therapy) based on the immunohistochemistry (IHC) and or Chemiluminescent immunoassay (CLIA) and disease type. ARID1A Subgroup: Participants with renal cell carcinoma with predominant clear cell histology, urothelia, all pancreatic cancers, endometrial and ovarian, and other solid tumors (excluding clear cell ovarian cancer and endometrial cancer) will receive either ceralasertib monotherapy if the IHC results for BAF250a is positive or ceralasertib plus olaparib combination therapy IHC results for BAF250a expression is negative. ATM-Loss Subgroup: Participants with metastatic castrate resistant prostate cancer (mCRPC), or other solid tumors with evidence of ATM loss by either pathogenic ATM mutation in CLIA-approved assay and/or loss of ATM expression by IHC will receive ceralasertib monotherapy. Endometrial Cancer Cohort: Participants with the presence of pathogenic ARID1A alteration on CLIA-approved next-generation sequencing panel without evidence of microsatellite instability and/or presence of intact mismatch repair proteins by immunohistochemistry will receive ceralasterib + durvalumab. Participants may continue treatment until disease progression by RECIST 1.1/PCWG3 (when applicable) criteria, unacceptable toxicity, or participant withdrawal from study, whichever occurs first. Participants may be treated beyond disease progression with prior evidence of clinical benefit and only upon approval of Principal Investigator. Participants will be followed for up to 30 days following last dose of protocol therapy, and up to 3 years for the endometrial cohort.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
89
City of Hope Comprehensive Cancer Center
Duarte, California, United States
RECRUITINGUniversity of California, San Francisco
San Francisco, California, United States
RECRUITINGUniversity of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
RECRUITINGObjective response rate (ORR) (ARID1A cohort)
On overall response will be reported as a percentage of participants with a complete response (CR) or partial response (PR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time frame: Up to 3 years
Composite Prostate Cancer Patient Response Rate (prostate cancer only)
In prostate cancer patients only: To determine the 50% decline in prostate-specific antigen (PSA50) response rate Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or objective response by RECIST 1.1
Time frame: Up to 3 years
Objective response rate (ORR) for other solid tumors
ORR for participants with other solid tumors will be measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Will be based on one-sided exact binomial test comparison of the observed ORR in evaluable patients to the null-hypothesized value of 5%, using the 5% significance level.
Time frame: Up to 3 years
Objective response rate (ORR) for endometrial cohort
ORR for participants with endometrial cancers will be measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Will be based on one-sided exact binomial test comparison of the observed ORR in evaluable patients to the null-hypothesized value of 5%, using the 5% significance level.
Time frame: Up to 3 years
Median duration of response (DOR) by treatment regimen
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The median duration of response will be summarized by treatment regimen using Kaplan-Meier estimates with associated 95% confidence limits.
Time frame: Up to 3 years
Median duration of response (DOR) by disease group
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The median duration of response will be summarized by disease group using Kaplan-Meier estimates with associated 95% confidence limits.
Time frame: Up to 3 years
Median progression-free survival (PFS) at 6 months by treatment regimen
Progression-free survival (PFS) is defined as the duration of time from start of treatment up until 6 months or at time of progression. For prostate cancer patients, PCWG3 criteria will be used to define radiographic progression-free survival. The median duration of response will be summarized by treatment regimen using Kaplan-Meier estimates with associated 95% confidence limits.
Time frame: 6 months
Median progression-free survival (PFS) at 12 months by treatment regimen
Progression-free survival (PFS) is defined as the duration of time from start of treatment up until 12 months or at time of progression. For prostate cancer patients, PCWG3 criteria will be used to define radiographic progression-free survival. The median duration of response will be summarized by treatment regimen using Kaplan-Meier estimates with associated 95% confidence limits.
Time frame: 12 months
Median progression-free survival (PFS) at 6 months by disease group
Progression-free survival (PFS) is defined as the duration of time from start of treatment up until 6 months or at time of progression. For prostate cancer patients, PCWG3 criteria will be used to define radiographic progression-free survival. The median duration of response will be summarized by disease group using Kaplan-Meier estimates with associated 95% confidence limits.
Time frame: 6 months
Median progression-free survival (PFS) at 12 months by disease group
Progression-free survival (PFS) is defined as the duration of time from start of treatment up until 12 months or at time of progression. For prostate cancer patients, PCWG3 criteria will be used to define radiographic progression-free survival. The median duration of response will be summarized by disease group using Kaplan-Meier estimates with associated 95% confidence limits.
Time frame: 12 months
Progression-free survival (PFS) rate over time
Progression-free survival (PFS) is defined as the duration of time from start of treatment up until time of progression. For prostate cancer patients, PCWG3 criteria will be used to define radiographic progression-free survival. The PFS rate will be summarized as a proportion with an exact binomial 95% confidence interval.
Time frame: Up to 3 years
Proportion of participants reporting treatment-related adverse events (AEs)
Safety analyses will be reported as a proportion of participants having received at least one dose of study drug and classified per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: Up to 3 years
Prostate Cancer Patient Progression Free Survival (prostate cancer patients only)
Progression-free survival (PFS) is defined as the duration of time from start of treatment up until time of progression. For prostate cancer patients, PCWG3 criteria will be used to define radiographic progression-free survival. The PFS rate will be summarized as a proportion with an exact binomial 95% confidence interval.
Time frame: Up to 3 years
Percentage of participants with a PSA50 response (prostate cancer patients only)
The 50% decline in prostate-specific antigen (PSA50) response rate from nadir as defined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for prostate cancer patients will be reported
Time frame: Up to 3 years
Median Overall Survival (Endometrial cohort only)
Summarized using Kaplan-Meier estimates with associated 95% confidence limits for participants with endometrial cancers only
Time frame: Up to 3 years
Overall percent change in tumor size
The overall percent change in tumor size from baseline measurements will be reported with 95% confidence intervals.
Time frame: Up to 3 years
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