Ceralasertib Combinations for Cancer

Recruiting at 22 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: PARP inhibitors

Disqualifiers: Ataxia telangiectasia, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

357 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is evaluating whether a drug may help treat cancer.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Ceralasertib Combinations for Cancer?

Research shows that olaparib, a component of the treatment, has been effective in treating ovarian, breast, pancreatic, and prostate cancers, especially in patients with BRCA gene mutations. Additionally, combinations of olaparib with other drugs like cediranib and durvalumab have shown promising response rates in ovarian cancer patients. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination involving Ceralasertib, AZD5305, Saruparib, Durvalumab, and Olaparib for cancer treatment?

Research shows that combining olaparib with other drugs like cediranib or durvalumab can be effective in treating ovarian cancer, especially in patients with certain genetic mutations. Olaparib has also shown promise in treating other cancers like breast, pancreatic, and prostate, particularly in patients with BRCA gene mutations. ^{1 2 3 4 5}

Is the combination of Ceralasertib and other cancer drugs safe for humans?

The combination of durvalumab and olaparib was found to be tolerable with no dose-limiting toxicities, while durvalumab with intermittent cediranib had some serious side effects like high blood pressure and fatigue. In another study, olaparib combined with cediranib or durvalumab showed manageable serious side effects in about 35-37% of patients, which were properly managed. ^{1 3 4 6 7}

Is the combination of Ceralasertib and other drugs generally safe for humans?

The combination of durvalumab and olaparib was found to be tolerable with no dose-limiting toxicities, while durvalumab with intermittent cediranib had some manageable side effects like hypertension and fatigue. In another study, olaparib combined with cediranib or durvalumab showed some treatment-related adverse events, but they were properly managed. ^{1 3 4 6 7}

What makes the drug combination of Ceralasertib, AZD5305, Durvalumab, and Olaparib unique for cancer treatment?

This drug combination is unique because it targets cancer cells with DNA damage response and repair alterations, using a mix of drugs that inhibit specific pathways (like PARP and ATR) and enhance immune response, potentially overcoming resistance seen with other treatments. ^{1 3 4 8 9}

What makes the drug combination of Ceralasertib, AZD5305, Durvalumab, and Olaparib unique for cancer treatment?

This drug combination is unique because it targets cancers with DNA damage response and repair alterations, using a mix of drugs that inhibit specific pathways involved in cancer cell repair and survival. Ceralasertib inhibits ATR, a protein involved in DNA repair, while Olaparib is a PARP inhibitor, and Durvalumab is an immune checkpoint inhibitor, making this combination potentially effective for cancers resistant to standard PARP inhibitor treatments. ^{1 3 4 8 9}

Eligibility Criteria

This trial is for adults with advanced cancers, including specific types of lung, breast, ovarian cancer and other solid tumors. Eligibility varies by module: some require certain genetic mutations or prior treatments. Exclusions include previous ATR inhibitor exposure, contraindications to study drugs like olaparib and durvalumab, diabetes (in Module 4), and bad reactions to ceralasertib.

Inclusion Criteria

My advanced stomach cancer is ATM proficient.

My breast cancer is triple negative and I am seeking second or third line treatment.

My tumor is at least 1 cm big and can be seen on a CT or MRI scan.

Exclusion Criteria

I cannot receive durvalumab due to health reasons.

I have type I or type II diabetes.

I am allergic to PARP inhibitors, including AZD5305.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Dose escalation of ceralasertib in combination with chemotherapy and/or novel anti-cancer agents to determine the maximum tolerated dose and recommended dose.

8 weeks

Cohort Expansion

Cohort expansions in specific patient groups to explore preliminary anti-tumour activity and pharmacokinetics.

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AZD5305
• Ceralasertib
• Durvalumab
• Olaparib

Trial Overview The trial tests ascending doses of ceralasertib alone or in combination with chemotherapy agents like carboplatin or novel anti-cancer agents such as olaparib and durvalumab. It aims to find the optimal dose combinations while monitoring safety closely. Effects on food absorption and ECG parameters are also studied.

Participant Groups

Group I: Module 5 Part B Experimental Treatment 1 Intervention

Module 5 Part B: cohort expansions of ceralasertib in combination with AZD5305 in ovarian patients at dose, frequency and schedule from Module 5 Part A.

Group II: Module 5 Part A Experimental Treatment 1 Intervention

Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D. In case this first dose level is not tolerated, alternative schedules will be evaluated.

Group III: Module 4 (FE/QT) Experimental Treatment 3 Interventions

Ceralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety.

Group IV: Module 3 Part B Experimental Treatment 1 Intervention

Module 3 Part B: cohort expansions of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients at dose, frequency and schedule from Module 3 Part A.

Group V: Module 3 Part A Experimental Treatment 1 Intervention

Module 3 Part A: cohort escalation of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients to define the dose, frequency and schedule of ceralasertib and durvalumab to take into Module 3 Part B. Additionally, Module 3 Part A will include a serial tumour biopsy cohort to evaluate the Proof of Mechanism of ceralasertib in HNSCC and NSCLC patients.

Group VI: Module 2 Part B5 Experimental Treatment 1 Intervention

Patients with BRCA mutant or RAD51C/D mutant (either germline or somatic) or HRD-positive status epithelial ovarian, fallopian tube, or primary peritoneal cancer according to local testing. Patients must be platinum sensitive and previously progressed on a licensed PARPi. The cohort will be split into 2 groups: Cohort 1 - without intervening chemotherapy following progression on a PARPi, Cohort 2 - with intervening chemotherapy following progression on a PARPi. Patients will receive ceralasertib and olaparib, at the RP2D dose, frequency and schedule established from Module 2 Part A2.

Group VII: Module 2 Part B4 Experimental Treatment 1 Intervention

Module Part B4: Patients with second or third line triple negative breast cancer with no known BRCA mutations. This expansion will be enriched for patients with disease harbouring a HRR-related gene mutation (HRRm) will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Group VIII: Module 2 Part B3 Experimental Treatment 1 Intervention

Module 2 Part B3: Patient with second or third line breast cancer with BRCA mutations (somatic or germline), excluding HER2 positive breast cancer will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Group IX: Module 2 Part B2 Experimental Treatment 1 Intervention

Module 2 part B2: Patients with second line 'ATM proficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Group X: Module 2 Part B1 Experimental Treatment 1 Intervention

Module 2 Part B1: Patients with second line 'ATM deficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Group XI: Module 2 Part A2 Experimental Treatment 1 Intervention

Module 2 Part A2: ascending doses of ceralasertib will be administered in combination with olaparib to patients to define the dose, frequency and schedule of ceralasertib and olaparib to take into Module 2 Part B.

Group XII: Module 2 Part A1 Experimental Treatment 1 Intervention

Module 2 Part A1: ascending doses of ceralasertib will be administered alone to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD) to take into Module 2 Part A2.

Group XIII: Module 1 Part B Experimental Treatment 1 Intervention

Module 1 Part B: patients with advanced lung adenocarcinoma with low expression of ATM will receive ceralasertib and carboplatin, at the dose, frequency and schedule recommended from Module 1 Part A.

Group XIV: Module 1 Part A Experimental Treatment 1 Intervention

Module 1 Part A: ascending doses of ceralasertib in combination with carboplatin AUC5 will be administered to patients to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD).

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

Niraparib has been approved by the FDA for patients with complete or partial response to first-line platinum-based chemotherapy, regardless of their BRCAm or HRD status, expanding treatment options for more patients.

Olaparib, in combination with bevacizumab, has also received FDA approval for patients with epithelial ovarian cancer, indicating that PARP inhibitors are now beneficial not only for BRCAm and HRD-deficient patients but also for those with HRD-proficient tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. Washington, CR., Moore, KN.[2023]

In a phase IIb trial involving 60 women with platinum-resistant recurrent ovarian cancer, the combination of cediranib and olaparib showed a modest objective response rate (ORR) of 15.3%, indicating some clinical activity in this heavily pretreated population.

The treatment was associated with significant safety concerns, as 73.3% of patients experienced grade ≥3 adverse events, highlighting the need for careful monitoring and further research into biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. Lee, JM., Moore, RG., Ghamande, S., et al.[2023]

In a study involving 30 patients with platinum-resistant ovarian cancer and HRR gene mutations, both olaparib-based combinations showed promising efficacy, with objective response rates of 50.0% for olaparib plus cediranib and 42.9% for olaparib plus durvalumab.

Biomarker profiling revealed that specific markers, such as high vascular endothelial growth factor for cediranib and immune markers for durvalumab, could guide treatment decisions, potentially enhancing outcomes for patients based on their individual biomarker status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045. Kim, YN., Joung, JG., Park, E., et al.[2023]

A phase II study of the PARP inhibitor olaparib confirmed its clinical benefits for cancer patients with inherited BRCA1 and BRCA2 mutations, particularly in advanced breast and ovarian cancers.

The study also provided evidence that olaparib is effective against pancreatic and prostate cancers, expanding its potential use in treating various cancer types associated with these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib shows promise in multiple tumor types. [2014]

In a phase I study involving 26 women with recurrent cancers, the combination of the PD-L1 inhibitor durvalumab with olaparib or cediranib was found to be tolerable and showed promising anti-tumor activity, with an 83% disease control rate for the durvalumab plus olaparib group.

The recommended phase II doses were established as durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice daily, or cediranib 20 mg on an intermittent schedule, indicating that these combinations could be viable options for further investigation in treating recurrent women's cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. Lee, JM., Cimino-Mathews, A., Peer, CJ., et al.[2022]

In a phase I study involving 12 patients with advanced solid tumors, the combination of olaparib and bevacizumab was found to be generally well tolerated, with no dose-limiting toxicities reported.

The most common side effects were mild nausea and fatigue, indicating that the treatment has an acceptable safety profile, making it a candidate for further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Dean, E., Middleton, MR., Pwint, T., et al.[2023]

The combination of olaparib and ceralasertib showed preliminary effectiveness in treating patients with ATM-mutated tumors and those with BRCA1/2-mutated high-grade serous ovarian cancer (HGSOC) that were resistant to PARP inhibitors, with a clinical benefit rate of 62.5%.

Among the seven patients with PARP inhibitor-resistant HGSOC, one patient achieved a significant partial response and five maintained stable disease for 16 to 72 weeks, indicating that this combination therapy may provide a new treatment option for difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). Mahdi, H., Hafez, N., Doroshow, D., et al.[2022]

In the EVOLVE study involving 34 heavily pretreated women with high-grade serous ovarian cancer, the combination of cediranib and olaparib showed limited efficacy, with objective responses in only 20% of platinum-resistant patients and 8% in an exploratory cohort.

The study identified key genomic mechanisms of resistance to PARP inhibitors, including BRCA1/2 reversion mutations and ABCB1 upregulation, which were associated with poorer treatment outcomes, highlighting the need for personalized approaches in managing resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. Lheureux, S., Oaknin, A., Garg, S., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

2. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Olaparib shows promise in multiple tumor types. [2014]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). [2022]

9. United States pubmed.ncbi.nlm.nih.gov

EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. [2021]