What side effects are associated with this type of intervention?

Common treatments for prostate cancer, particularly those targeting DNA damage response and cell cycle regulation like ATR kinase inhibitors, often have side effects including hematologic toxicities such as anemia, thrombocytopenia, and neutropenia. Non-hematologic side effects can include nausea, fatigue, and gastrointestinal issues like diarrhea. Androgen receptor signaling inhibitors may cause fluid retention, hypertension, and hypokalemia, while chemotherapy can lead to neutropenia, febrile neutropenia, and peripheral neuropathy. These side effects vary in severity and frequency depending on the specific treatment regimen.

What prior FDA approvals exist?

FDA-approved treatments for prostate cancer that involve mechanisms similar to ATR kinase inhibitors include PARP inhibitors like rucaparib and niraparib. These drugs target DNA damage response pathways, specifically by inhibiting PARP enzymes, which are crucial for repairing single-strand DNA breaks. Rucaparib has shown efficacy in patients with metastatic castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) gene mutations. Niraparib has also demonstrated activity in metastatic CRPC patients with BRCA1 or BRCA2 mutations. These treatments, like ATR inhibitors, aim to exploit the vulnerabilities in cancer cells' DNA repair mechanisms to induce cell death.

What other types of research exist?

Promising alternatives to ATR kinase inhibitor AZD6738 for prostate cancer patients include PARP inhibitors (e.g., olaparib, niraparib) and platinum-based chemotherapy. PARP inhibitors have shown efficacy, particularly in patients with homologous recombination repair (HRR) deficiencies, such as BRCA1/2 mutations. Additionally, combining PARP inhibitors with abiraterone has demonstrated improved progression-free survival in clinical trials. Platinum-based chemotherapy is another reasonable alternative, especially for patients with HRR alterations.

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ATR Kinase Inhibitor

Ceralasertib + Olaparib/Durvalumab for Cancer

Phase 2

Recruiting

Led By Rahul Aggarwal, MD

Research Sponsored by Rahul Aggarwal

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Endometrial Cancer Cohort: Histologically confirmed endometrial cancer with specific genetic alteration requirements and disease measurement criteria

ARID1A Subgroup: Histologically confirmed locally advanced or metastatic solid tumor malignancy with progression on at least one prior systemic therapy, including specific tumor types and requirements for tumor tissue evaluation and disease measurement

Must not have

Contraindications related to medication use, hypersensitivity reactions, chronic active hepatitis B or C, and immunocompromised status

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 3 years

Awards & highlights

Summary

This trial is testing a new drug called ceralasertib to see if it can stop the growth of advanced cancers. It targets patients with various types of advanced solid tumors. The treatment works by blocking enzymes that cancer cells need to grow.

Who is the study for?

This trial is for adults with advanced or metastatic solid tumors, including kidney, pancreatic, endometrial and prostate cancers. Participants must have progressed on prior therapy and have measurable disease. They need adequate organ function, available tumor tissue samples, and must agree to use effective contraception.

What is being tested?

The study tests the effectiveness of Ceralasertib alone or combined with Olaparib or Durvalumab in treating various solid tumors. It aims to see if blocking certain enzymes needed for cell growth can control tumor progression better than current treatments.

What are the potential side effects?

Potential side effects may include fatigue, nausea, skin reactions at the injection site for Durvalumab, anemia from Olaparib, as well as possible liver enzyme changes due to Ceralasertib. The severity of side effects varies among individuals.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My endometrial cancer has been confirmed with specific genetic changes.

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My cancer has spread, worsened after treatment, and requires specific tissue tests.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I don't have allergies to medications, chronic hepatitis B or C, or a weakened immune system.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Composite Prostate Cancer Patient Response Rate (prostate cancer only)

Objective response rate (ORR) (ARID1A cohort)

Objective response rate (ORR) for endometrial cohort

+1 more

Secondary study objectives

Median Overall Survival (Endometrial cohort only)

Median duration of response (DOR) by disease group

Median duration of response (DOR) by treatment regimen

+9 more

Trial Design

3Treatment groups

Experimental Treatment

Group I: Arm III (Ceralasertib, Durvalumab)Experimental Treatment2 Interventions

In combination with durvalumab, ceralasertib will be given at a continuous daily dose of 240 mg BID days 1-7 of a 28-day dosing schedule. Durvalumab will be given at a flat dose of 1500 mg IV on day 8 of a 28-day cycle for participants with histologically confirmed endometrial cancers. Participants treated with the combination of ceralasertib plus durvalumab may continue treatment beyond first radiographic progression until the occurrence of either confirmed radiographic progression or clinical progression, whichever occurs first.

Group II: Arm II (Ceralasertib, Olaparib)Experimental Treatment2 Interventions

In combination with olaparib, ceralasertib will be given at a continuous daily dose of 160 mg daily days 1-7 in each 28-day cycle. Olaparib will be given at a starting dose of 300 mg twice daily days 1-28 of a 28-day cycle for participants who are BAF250a positive. Treatment will continue until disease progression, unacceptable toxicity, or participant withdrawal from study, whichever occurs first.

Group III: Arm I (Ceralasertib Monotherapy)Experimental Treatment1 Intervention

As monotherapy ceralasertib will be given at a starting dose of 160 mg two times per day (BID), on days 1-14 of a 28-day cycle for participants who are BAF250a negative or show an ATM-Mutation by CLIA assay. Treatment will continue until disease progression, unacceptable toxicity, or participant withdrawal from study, whichever occurs first.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ceralasertib

2017

Completed Phase 1

~40

Olaparib

2007

Completed Phase 4

~2190

Durvalumab

2017

Completed Phase 2

~3840

0 / 3Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for prostate cancer include androgen receptor signaling inhibitors like enzalutamide and apalutamide, which block androgen binding and inhibit receptor translocation to the nucleus, thereby reducing cancer cell proliferation. DNA damage response inhibitors, such as the ATR kinase inhibitor AZD6738, disrupt the cell's ability to repair DNA damage, leading to cell cycle arrest and apoptosis. These mechanisms are crucial for prostate cancer patients as they target the cancer cells' survival pathways, potentially improving treatment efficacy and patient outcomes.

ATR and p-ATR are emerging prognostic biomarkers and DNA damage response targets in ovarian cancer.Apalutamide Sensitizes Prostate Cancer to Ionizing Radiation via Inhibition of Non-Homologous End-Joining DNA Repair.Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways.