Olaparib + Cediranib/Ceralasertib for Advanced Breast Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Banu Arun

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Untreated brain metastases, Active infection, Uncontrolled hypertension, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well olaparib with cediranib or AZD6738 works in treating patients with germline BRCA mutated breast cancer that has spread to other places in the body (advanced or metastatic). Olaparib, cediranib, and AZD6738 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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

The trial requires you to stop taking any strong inhibitors or inducers of CYP3A4, with a washout period of 2 weeks for inhibitors and 4 weeks for inducers. You must also stop using natural herbal products or complementary alternative medications 7 days before starting the study drugs. Dihydropyridine calcium-channel blockers are allowed for managing hypertension. If you are on other medications, it's best to discuss with the trial team to see if they are permitted.

What data supports the idea that Olaparib + Cediranib/Ceralasertib for Advanced Breast Cancer is an effective drug?

The available research shows that Olaparib alone has been effective in treating certain types of advanced breast cancer, particularly in patients with specific genetic mutations (BRCA mutations). In the OlympiAD trial, Olaparib was shown to significantly extend the time patients lived without their cancer getting worse compared to standard chemotherapy. While there is no direct data on the combination of Olaparib with Cediranib or Ceralasertib for breast cancer, Olaparib has shown promise on its own. Additionally, the combination of Cediranib and Olaparib has been effective in treating ovarian cancer, suggesting potential benefits for breast cancer as well. ^{1 2 3 4 5}

What safety data is available for the combination of Olaparib and Cediranib/Ceralasertib in cancer treatment?

The combination of Olaparib and Cediranib has been studied in various trials, primarily in ovarian cancer. In a Phase II trial, the combination increased progression-free survival in recurrent platinum-sensitive ovarian cancer compared to Olaparib alone. The CONCERTO trial evaluated the safety and tolerability of Cediranib plus Olaparib in platinum-resistant ovarian cancer. A Phase I trial investigated the toxicities and recommended dosing of Olaparib and Cediranib in recurrent ovarian and triple-negative breast cancer. These studies provide insights into the safety profile of the combination, although specific safety data for breast cancer is limited. ^{1 2 5 6 7}

Is the drug Olaparib a promising treatment for advanced breast cancer?

Yes, Olaparib is a promising drug for advanced breast cancer. It has been shown to help patients live longer without the cancer getting worse compared to standard chemotherapy. It is especially beneficial for patients with specific genetic mutations (BRCA1/2) and those with triple-negative breast cancer. Olaparib also improves the quality of life for patients. ^{1 2 3 4 6}

Eligibility Criteria

This trial is for women with advanced or metastatic breast cancer that has a BRCA mutation. They must have previously responded to PARP inhibitor treatment for at least 4 months, have good organ function, and controlled blood pressure. Pregnant or breastfeeding women can't join, nor those who've had certain treatments recently or have conditions affecting drug absorption.

Inclusion Criteria

I have taken a pregnancy test that was negative before starting the study treatment.

I am not pregnant and use effective birth control or cannot become pregnant.

My kidney function is good, based on tests.

Exclusion Criteria

I haven't had symptoms of bowel blockage in the last 3 months.

I do not have any bleeding disorders.

I have had a bone marrow or double cord blood transplant.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive olaparib with either cediranib or ceralasertib in 28-day cycles

28 days per cycle, repeated until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 days post treatment

Treatment Details

Interventions

• Cediranib (Tyrosine Kinase Inhibitor)
• Ceralasertib (ATR Kinase Inhibitor)
• Olaparib (PARP Inhibitor)

Trial Overview The study tests how well olaparib works with either cediranib or AZD6738 in treating BRCA mutated breast cancer that's spread. It aims to see if these combinations can block enzymes needed for tumor growth more effectively than current treatments.

Participant Groups

Group I: Arm II (olaparib plus ceralasertib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID on days 1-28 and ceralasertib PO QD on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (olaparib plus cediranib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID and cediranib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Olaparib is already approved in European Union, United States for the following indications:

🇪🇺 Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

🇺🇸 Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

M D Anderson Cancer Center Houston, TX

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center Lead Sponsor

National Cancer Institute (NCI) Collaborator

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] Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone.

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022] Olaparib (Lynparza) is now approved for the adjuvant treatment of adult patients who have, or are suspected to have, the germline variation of BRCA-mutated human epidermal growth factor receptor 2-negative high-risk early breast cancer and who were previously treated with neoadjuvant or adjuvant chemotherapy.

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

Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial. [2023] In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N = 302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300 mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favored olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) vs TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib vs decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD.

4. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. [2019] Mutations in BRCA1 and BRCA2 genes account for around 2-3% of breast cancer events and more than 10% of triple negative breast cancers. Olaparib (Lynparza®), an orally administered PARP inhibitor, demonstrated clinical benefit in a phase III trial for mutated BRCA-positive HER2 negative metastatic breast cancer. Areas covered: This review gives an overview of available preclinical and clinical data regarding olaparib, including its chemistry, mechanism of action, pharmacokinetics and pharmacodynamics, and evidence supporting antitumor efficacy and safety profile in breast cancer patients. Expert commentary: Olaparib improves progression-free survival in germline BRCA mutated HER2 negative metastatic breast cancer patients as compared to standard chemotherapy, with a manageable toxicity profile. Efficacy is of clinical relevance especially in the context of triple negative breast cancer. However, several aspects, such as sequencing or combination of these agents with other anticancer agents and identification of appropriate biomarkers, still need to be clearly defined.

5. 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] The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer.

6. England pubmed.ncbi.nlm.nih.gov

Olaparib for advanced breast cancer. [2021] Olaparib, an oral PARP-inhibitor, has shown clinical benefit for HER2-negative advanced breast cancer patients carrying a germinal BRCA1/2 mutation. In a randomized Phase III trial, olaparib significantly prolonged progression-free survival as compared with chemotherapy of physician choice. Moreover, in the same trial, a prespecified subgroup analysis reported an overall survival benefit for patients not previously pretreated with chemotherapy for metastatic disease. This review focuses on available preclinical, pharmacokinetic and pharmacodynamic data regarding olaparib and clinical evidence of its antitumor efficacy (both as monotherapy and in combination) and tolerability in breast cancer patients. Open questions, such as use of appropriate biomarkers for patient selection and combination/sequencing with other anticancer drugs, are also addressed.

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

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. [2021] Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648).