Selumetinib + Olaparib for Ovarian and Endometrial Cancer

Recruiting at 302 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: MEK inhibitors, PARP inhibitors, CYP3A inducers, others

Disqualifiers: Uncontrolled illness, Severe liver dysfunction, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 28-day cycles, repeated

165 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for women with ovarian or endometrial cancer that has returned or not responded to previous treatments. It compares the effectiveness of taking two drugs, selumetinib (Koselugo) and olaparib (Lynparza), together versus taking selumetinib alone. The researchers aim to determine if adding olaparib can help shrink tumors and prevent their growth for a longer period. Women with specific genetic mutations in their cancer, who have tried other treatments without success, might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires a washout period for certain medications. If you are taking strong or moderate CYP3A or CYP2C19 inhibitors or inducers, you will need to stop them for a specified time before starting the trial. Check with the trial team to see if your current medications are affected.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining selumetinib and olaparib may help treat ovarian and endometrial cancers with certain mutations. This combination was tested in patients with RAS-mutated cancers and was generally well-tolerated.

Studies on selumetinib alone have found it safe for treating some cancer types, with no new safety issues. The most common side effects are mild and manageable.

The FDA has already approved olaparib for ovarian cancer with specific genetic changes, indicating it is generally safe. Some patients have reported mild side effects.

Overall, both treatments have demonstrated a good safety record in previous studies. Participants in this trial will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine selumetinib and olaparib, targeting specific pathways in cancer cells. Unlike standard chemotherapy for ovarian and endometrial cancer, which often attacks all rapidly dividing cells, selumetinib inhibits the MEK pathway, while olaparib targets the PARP enzyme. This dual approach can potentially enhance effectiveness by disrupting cancer cell survival and repair mechanisms more precisely. Additionally, selumetinib's use as a standalone treatment provides a valuable comparison to understand its individual impact. These strategies represent a promising shift towards more targeted cancer therapies.

What evidence suggests that this trial's treatments could be effective for ovarian and endometrial cancer?

Research has shown that using selumetinib and olaparib together may help treat ovarian and endometrial cancer with RAS mutations. In this trial, one group of participants will receive the combination of selumetinib and olaparib, which has shown promise in earlier studies for patients with these mutations. The drugs work by stopping tumor growth and preventing cancer cells from repairing themselves. Selumetinib blocks enzymes that help tumors grow, while olaparib stops cancer cells from fixing their DNA, potentially leading to cell death. This combination might shrink tumors more and keep them stable longer than using selumetinib alone. Another group of participants will receive selumetinib by itself, which has shown some effectiveness, but adding olaparib could enhance these benefits. ^{1 2 4 5 6}

Who Is on the Research Team?

Shannon Westin, MD

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for women with recurrent or persistent ovarian and endometrial cancers that have RAS pathway mutations. They must have progressed after first-line treatment, not be eligible for further platinum-based therapy (for ovarian cancer), and have measurable disease. Participants need to agree to biopsies, use two forms of birth control if applicable, and meet specific health criteria including organ function tests.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

I had hepatitis C but am cured, or I'm being treated with no detectable virus.

Platelets >= 100,000/mcl (within 14 days prior to registration)

Exclusion Criteria

Patients who have had previous organ transplant, allogenic bone marrow transplant or double umbilical cord blood transplantation

My liver is severely impaired.

I have taken MEK inhibitor medications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive selumetinib and olaparib or selumetinib alone on a 28-day cycle, with tumor biopsies and blood collections

28-day cycles, repeated

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

5 years

Every 3 months for 2 years, then every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Selumetinib Sulfate

Trial Overview The study compares the effectiveness of combining Selumetinib, a cell growth inhibitor, with Olaparib, a DNA repair blocker (PARP inhibitor), versus using Selumetinib alone in treating these cancers. The goal is to see if the combination better shrinks tumors or keeps them stable without progression compared to just one drug.

How Is the Trial Designed?

Group I: Arm I (selumetinib, olaparib) Experimental Treatment 8 Interventions

Patients receive selumetinib PO BID and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tumor biopsy and blood collection during screening and on study, as well as ECHO or MUGA, and CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.

Group II: Arm II (selumetinib) Active Control 7 Interventions

Patients receive selumetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients also undergo a tumor biopsy and blood collection during screening and on study, as well as ECHO or MUGA, and CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.

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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

Maintenance treatment with olaparib significantly improves progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer, reducing the risk of disease progression or death by up to 80% compared to placebo, based on data from the SOLO1 trial involving various patient subgroups.

The benefits of olaparib are consistent across different baseline factors, including surgery type, chemotherapy response, and BRCA mutation status, indicating its broad efficacy as a treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial. DiSilvestro, P., Colombo, N., Scambia, G., et al.[2021]

Olaparib significantly improves overall survival in patients with recurrent platinum-sensitive ovarian cancer, with a hazard ratio of 1.24 based on a meta-analysis of 7 randomized controlled trials involving 2406 patients.

However, the treatment is associated with a higher incidence of adverse events, particularly for grades 3 or higher, indicating that while olaparib is effective, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. Chen, Q., Li, X., Zhang, Z., et al.[2022]

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]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

Olaparib (OLA) monotherapy showed a similar overall objective response rate (ORR) compared to chemotherapy (CT) in patients with relapsed ovarian cancer, with ORR of 24.3% for OLA and 28.3% for CT, indicating comparable efficacy.

In patients with platinum-resistant ovarian cancer (PROC) who had received more than four prior lines of treatment, OLA demonstrated a higher ORR of 22.9% compared to 0% for CT, suggesting that OLA may be more effective in heavily pretreated cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. Vanderstichele, A., Loverix, L., Busschaert, P., et al.[2022]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[2022]

In a study of 115 relapsing epithelial ovarian cancer patients with BRCA mutations receiving olaparib, the median progression-free survival (PFS) was 12.7 months and overall survival (OS) was 35.4 months after a median follow-up of 21 months.

Key factors associated with longer PFS and OS included a platinum-free interval of 12 months or more, achieving a complete or partial response to treatment, and normalization of CA-125 levels after the last platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers. Labidi-Galy, SI., de La Motte Rouge, T., Derbel, O., et al.[2022]

In the phase III SOLO1 trial, maintenance treatment with olaparib significantly improved progression-free survival in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, with 260 patients receiving olaparib compared to 131 on placebo.

The most common adverse events associated with olaparib, such as anemia and nausea, occurred early (within 3 months) but were manageable, with only a small number of patients needing to discontinue treatment, indicating a predictable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Colombo, N., Moore, K., Scambia, G., et al.[2022]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4469526/

A phase II evaluation of selumetinib (AZD6244, ARRY ... A Phase II study of low-grade serous ovarian cancer patients reported objective responses in 16% in a tumor associated with limited response to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3627419/

A Phase Ii Trial Of Selumetinib (Azd6244) In Women With ... Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma.

3. nrgoncology.org nrgoncology.org/Home/News/Post/comparing-selumetinib-and-olaparib-to-selumetinib-alone-for-ovarian-and-endometrial-cancers-with-ras-pathway-mutations-eay191-n4-a-combomatch-treatment-trial

Comparing Selumetinib and Olaparib to ... The trial will be comparing the combination of the MEK inhibitor Selumetinib and the PARP inhibitor Olaparib to Selumetinib alone for this patient population.

4. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00986-9/fulltext?rss=yes

Efficacy and safety of selumetinib in adults with ... The observations of reduction in tumour volume by cycle 16, reduction in chronic and spike pain, reduction in analgesia, and decrease in pain ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00551070?term=AZD-6244%20HYDROGEN%20SULFATE&rank=9

Study Details | NCT00551070 | Selumetinib Sulfate in ... This phase II trial studies the side effects and how well selumetinib sulfate works in treating patients with low-grade ovarian cancer that has come back ( ...

6. onclive.com onclive.com/view/selumetinib-nets-eu-approval-for-adult-nf1-associated-plexiform-neurofibromas

Selumetinib Nets EU Approval for Adult NF1-Associated ... No new safety concerns were identified with selumetinib for the treatment of patients with NF1-associated PNs. The most common any-grade ...