Ceralasertib Combinations for Cancer
Recruiting in Palo Alto (17 mi)
+22 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: AstraZeneca
Must not be taking: PARP inhibitors
Disqualifiers: Ataxia telangiectasia, Diabetes, others
No Placebo Group
Breakthrough Therapy
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.
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.12345
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.13467
What makes the drug combination of Ceralasertib, AZD5305, Durvalumab, and Olaparib unique for cancer treatment?
Research Team
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.
See 10 more
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.
See 5 more
Treatment Details
Interventions
- AZD5305 (Other)
- Ceralasertib (ATM Kinase Inhibitor)
- Durvalumab (PD-L1 Inhibitor)
- Olaparib (PARP Inhibitor)
Trial OverviewThe 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
14Treatment groups
Experimental Treatment
Group I: Module 5 Part BExperimental Treatment1 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 AExperimental Treatment1 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 Treatment3 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 BExperimental Treatment1 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 AExperimental Treatment1 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 B5Experimental Treatment1 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 B4Experimental Treatment1 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 B3Experimental Treatment1 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 B2Experimental Treatment1 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 B1Experimental Treatment1 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 A2Experimental Treatment1 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 A1Experimental Treatment1 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 BExperimental Treatment1 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 AExperimental Treatment1 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).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Research SitePhiladelphia, PA
Research SiteIrvine, CA
Research SiteBaltimore, MD
Research SiteNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
AstraZeneca
Lead Sponsor
Trials
4491
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]
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 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
Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]
PARP inhibitors in the treatment of ovarian cancer: a review. [2023]
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]
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]
Olaparib shows promise in multiple tumor types. [2014]
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]
Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. [2023]
Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). [2022]
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]