Adavosertib + Olaparib for Recurrent Ovarian Cancer

Not currently recruiting at 1 trial location

Overseen By Sara Hull

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: PARP inhibitors

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Uncontrolled brain metastases, Cardiac diseases, Active infections, 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: Unknown

Duration: Up to 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two drug combinations for treating ovarian, primary peritoneal, or fallopian tube cancer that has returned. The study examines the use of adavosertib alone, adavosertib with olaparib, or ceralasertib with olaparib, all targeting tumor growth by blocking vital cell growth enzymes. It suits those with recurrent cancer who have experienced disease progression while on a PARP inhibitor treatment. Participants must have a specific type of cancer and show cancer progression after previous treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires a 'washout' period (time without taking certain medications) for some treatments. You must stop any hormonal therapy directed at the tumor at least one week before joining the study, and other cancer treatments at least three weeks before. Herbal supplements and certain drugs affecting liver enzymes should be stopped two weeks before starting the study.

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

In earlier studies, adavosertib demonstrated some tumor-fighting ability but presented safety issues at higher doses, leading some patients to experience side effects that required dose reduction. However, other research found adavosertib safe when combined with certain chemotherapy treatments.

Studies show that the combination of ceralasertib and olaparib is generally well-tolerated. While some patients needed dose reductions due to side effects, these were manageable.

The combination of adavosertib and olaparib has also been studied, proving safe and tolerable, and helping to determine the highest safe dose for patients with solid tumors. Olaparib alone is already approved for certain cancers, indicating a known safety record for those conditions.

Overall, these treatments have shown some safety concerns, but with careful monitoring and dose adjustments, they are considered manageable in clinical settings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for recurrent ovarian cancer because they combine innovative approaches to target the disease in new ways. Adavosertib is unique because it inhibits a protein involved in cell division, potentially stopping cancer cells from multiplying. Olaparib, a PARP inhibitor, works by preventing cancer cells from repairing their DNA, leading to their destruction. Meanwhile, Ceralasertib enhances the effects of DNA-damaging agents, like olaparib, making it harder for cancer cells to survive. Together, these treatments offer a promising alternative to standard chemotherapy, targeting cancer cells more precisely and potentially leading to better outcomes.

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

Studies have shown that using the drugs ceralasertib and olaparib together can help some patients with recurring ovarian cancer. In this trial, one group of participants will receive the combination of ceralasertib and olaparib. Another group will receive adavosertib alone, which research suggests may benefit patients whose cancer hasn't responded to other treatments. Additionally, a separate group will test the combination of adavosertib and olaparib. Early research indicates that adavosertib can enhance the effects of olaparib, potentially leading to better outcomes. These treatments target enzymes that aid cancer cell growth, which may slow or stop the disease's progression. ^{6 7 8 9 10}

Who Is on the Research Team?

Shannon Westin

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with recurrent ovarian, primary peritoneal, or fallopian tube cancer who've seen their disease progress on PARP inhibitors. They should have a measurable lesion and be in relatively good health (ECOG score 0-1). Women must not be pregnant, breastfeeding, and agree to use contraception. People can't join if they have heart issues like long QT syndrome, uncontrolled brain metastases, severe reactions to study drugs or certain drug interactions.

Inclusion Criteria

Has read and understands the informed consent form (ICF) and has given written informed consent prior to any study procedures.

My ovarian, peritoneal, or fallopian tube cancer has returned and cannot be cured with available treatments.

At least one measurable lesion according to RECIST v1.1.

Exclusion Criteria

I have not had a blood transfusion in the last 4 months.

I do not have a serious infection or condition that would stop me from receiving the study treatment.

I cannot swallow pills or have a stomach condition that affects medication absorption.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive study drugs according to their assigned arm: adavosertib alone, olaparib with adavosertib, or ceralasertib with olaparib. Treatment cycles repeat every 21 days.

Up to 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up for 30 days and periodically afterwards.

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Adavosertib
• Ceralasertib
• Olaparib

Trial Overview The trial tests adavosertib alone or combined with olaparib in patients whose cancer has returned. These drugs may block enzymes that tumor cells need to grow. Participants are chosen for different treatment groups based on specific criteria and will receive the treatments to see which works better.

How Is the Trial Designed?

Group I: Arm III (ceralasertib, olaparib) Experimental Treatment 2 Interventions

Patient receive ceralasertib tablets by PO BID each day on Days 1-14. You will also take olaparib tablets by PO BID each day on Days 1-28.

Group II: Arm II (olaparib, adavosertib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID on days 1-21 and adavosertib PO QD on days 1-3 and 8-10. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm I (adavosertib) Active Control 1 Intervention

Patients receive adavosertib PO QD on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 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]

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]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

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]

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]

Olaparib is an effective first-line maintenance treatment for adults with advanced ovarian cancer who have responded to platinum-based chemotherapy, significantly improving progression-free survival compared to placebo in phase III trials.

When combined with bevacizumab, olaparib further enhances treatment efficacy in patients with homologous recombination deficiency (HRD), but does not show benefits in HRD-negative tumors, indicating its targeted effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: A Review as First-Line Maintenance Therapy in Advanced Ovarian Cancer. Paik, J.[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]

Citations

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Ceralasertib (cerala) + olaparib (ola) in patients (pts) with ... Table shows efficacy in Co1. 24 pts had post-PARPi biopsies evaluable for genomics analysis: 3 (12.5%) had BRCA reversions (rev; 13 pts were ...

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Combination ATR (ceralasertib) and PARP (olaparib) ... Of the 6 confirmed responders, 83% (n=5) had received and progressed on prior olaparib without dose reductions. Of the 6 responders, 4 received prior PARPi for ...

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PR072/#1519 Effort: clinical and molecular features ... There were 35 evaluable patients on each arm. Patients received a median of 4 prior therapies (range 1–11), including olaparib (41%). Median PFS was 5.5 months ...

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EFFORT: EFFicacy Of adavosertib in parp ResisTance: A ... EFFORT: EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with ...

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A Phase Ib Study Assessing the Safety, Tolerability, and ... Phase I studies in patients with advanced solid tumors have demonstrated the safety and tolerability of adavosertib plus chemotherapy [11, 12].

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Phase 2 study of Wee1 inhibitor adavosertib in recurrent ... Overall, UCS carries a poor prognosis with a recurrence rate of 37 % in stage I disease and up to 80 % in stage IV disease, with dismal 5 year overall survival ...

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Adavosertib Shows Early Antitumor Activity Despite Safety ... The data showed that 10 patients achieved responses, including 1 CR, 8 confirmed PRs, and 1 unconfirmed PR, which comprised an ORR of 29.4% (95% ...

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A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2 ... Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) ...