Sequential Olaparib + Adavosertib for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: PARP inhibitors

Must not be taking: CYP3A inducers/inhibitors

Disqualifiers: MDS/AML, Cardiac diseases, others

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

Compensation: Varies

Number of Visits: 58

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and side effects of two drugs, olaparib (Lynparza) and adavosertib, for treating advanced solid tumors. Olaparib prevents cancer cells from repairing themselves, while adavosertib inhibits enzymes that promote cancer cell growth. Together, they might shrink tumors or halt their growth with fewer side effects. This trial targets individuals whose cancer has spread and who have specific genetic changes affecting DNA repair. Those who have previously received PARP inhibitors and experienced disease progression may be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does require a washout period (time without taking certain medications) for certain drugs. Specifically, you must stop using strong or moderate CYP3A inhibitors and inducers for 2 to 5 weeks before starting the study treatment.

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

Research shows that using olaparib and adavosertib together might help treat cancer. However, some safety concerns require attention. Studies have found that while this combination can be effective against certain tumors, it may also cause side effects like tiredness, nausea, and changes in blood cell counts.

In earlier research, patients who took both drugs experienced some side effects, but these were generally manageable. Taking the drugs sequentially, rather than simultaneously, might help reduce side effects while still effectively fighting cancer.

Since this trial is in the early stages, the researchers are still learning about the full safety profile. The current phase focuses on finding the best dose of adavosertib to use with olaparib, so safety information is still being collected. Always consult a healthcare provider to understand what this might mean for you. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Olaparib and Adavosertib because it targets cancer cells in a novel way. Most cancer therapies focus on directly killing cancer cells or inhibiting their growth. However, Olaparib is a PARP inhibitor, which prevents cancer cells from repairing their DNA, while Adavosertib is a WEE1 inhibitor that disrupts the cell cycle, making it harder for cancer cells to survive. This combination has the potential to be more effective by tackling cancer cells on multiple fronts, potentially offering a new hope for patients with treatment-resistant cancers.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research has shown that combining adavosertib with olaparib may help treat certain advanced cancers. In this trial, participants will receive both drugs in a sequential treatment regimen. Studies suggest that adavosertib can enhance the effects of drugs like olaparib, increasing their effectiveness against cancer cells. This combination has proven effective for patients with ovarian cancer that did not respond to other treatments. By blocking certain enzymes and preventing cancer cells from repairing themselves, this treatment may shrink or stabilize tumors. This approach offers hope for managing cancers that have spread and are difficult to treat. ^{1 3 6 7 8}

Who Is on the Research Team?

Timothy Yap

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that have spread and are not treatable by surgery or other standard treatments. Participants must have specific genetic mutations, including BRCA1/2, and their cancer must have progressed after previous PARP inhibitor treatment. They should be in good physical condition (ECOG score 0-1), able to undergo a biopsy, and willing to use effective contraception.

Inclusion Criteria

I am fully active or can carry out light work.

My liver and kidney function tests are within acceptable ranges.

I have a genetic mutation in BRCA1 or BRCA2.

Exclusion Criteria

I have or had myelodysplastic syndrome or acute myeloid leukemia.

I am not taking strong or moderate drugs that affect liver enzymes.

You are pregnant or currently nursing a baby.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib and adavosertib in a sequential dosing schedule. Olaparib is administered orally twice daily on days 1-5 and 15-19, and adavosertib is administered orally once daily on days 8-12 and 22-26 of each 28-day cycle.

2 years

Cycles repeat every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 30 days and then every 3-6 months for up to 2 years.

2 years

Follow-up at 30 days, then every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Adavosertib
• Olaparib

Trial Overview The STAR study is testing the sequential use of two anti-cancer drugs: Olaparib followed by Adavosertib in patients with advanced solid tumors resistant to PARP inhibitors. The goal is to find the safest doses with the least side effects while trying to shrink or stabilize the cancer.

How Is the Trial Designed?

Group I: Treatment (olaparib, adavosertib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID on days 1-5 and 15-19 of each cycle and adavosertib PO QD on days 8-12 and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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, a PARP inhibitor, has shown significant clinical benefits in improving progression-free survival for patients with BRCA1 or BRCA2 mutated HER2 negative metastatic breast cancer compared to standard chemotherapy.

The drug has a manageable safety profile, making it a promising treatment option, particularly for triple negative breast cancer, although further research is needed to optimize its use with other therapies and identify suitable biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. Griguolo, G., Dieci, MV., Guarneri, V., et al.[2019]

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 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]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[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]

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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Adavosertib in Combination with Olaparib in Patients with ... Preclinical data demonstrate that adavosertib has the potential to both enhance the antitumor effect of PARP inhibitors such as olaparib as well ...

2. jons-online.com jons-online.com/articles/effort-study-of-adavosertib-with-or-without-olaparib-in-women-with-parp-resistant-ovarian-cancer

EFFORT Study of Adavosertib with or without Olaparib in ... These data suggest that adavosertib with or without olaparib demonstrates efficacy in patients with PARP inhibitor–resistant ovarian cancer. Adverse events ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1048891X24114053

PR072/#1519 Effort: clinical and molecular features ... Efficacy of adavosertib +/- olaparib was retained across multiple clinical cohorts of PARPi-resistant OC, including BRCAwt and platinum-resistant disease.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03579316

Study Details | NCT03579316 | Adavosertib With or Without ... Adavosertib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

5. asco.org asco.org/abstracts-presentations/ABSTRACT344345

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 ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39487373/

Adavosertib in Combination with Olaparib in Patients with ... Limited antitumor activity was observed with adavosertib plus olaparib combination therapy.

7. theoncologynurse.com theoncologynurse.com/december-2021-year-in-review-ovarian-cancer/effort-study-of-adavosertib-with-or-without-olaparib-in-women-with-parp-resistant-ovarian-cancer

EFFORT Study of Adavosertib with or without Olaparib in ... These data suggest that adavosertib with or without olaparib demonstrates efficacy in patients with PARP inhibitor–resistant ovarian cancer. Adverse events ...

8. ecancer.org ecancer.org/en/news/22346-anti-cancer-drugs-olaparib-and-adavosertib-work-best-when-given-sequentially-in-patients-with-advanced-tumours-driven-by-dna-damage-response-mutations-results-from-phase-ib-star-clinical-trial

Anti-cancer drugs, olaparib and adavosertib, work best ... Anti-cancer drugs, olaparib and adavosertib, work best when given sequentially in patients with advanced tumours driven by DNA damage response mutations.