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

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of adavosertib when given together with olaparib in treating patients with solid tumors that have spread to other places in the body (advanced) with selected mutations. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Giving olaparib and adavosertib one after the other may shrink or stabilize advanced solid tumors as successfully as using them together, with fewer side effects.

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.

What data supports the effectiveness of the drug combination of Olaparib and Adavosertib for cancer?

Olaparib, a part of the treatment, has shown effectiveness in treating certain types of ovarian and breast cancers, especially in patients with specific genetic mutations. It is used as a maintenance therapy to prolong the time before the cancer progresses in patients with ovarian cancer who have responded to chemotherapy. ^{1 2 3 4 5}

Is the combination of Olaparib and Adavosertib generally safe for humans?

Olaparib (also known as Lynparza) has been studied for safety in various cancers, including breast and ovarian cancer. It is generally considered safe, but like all medications, it can have side effects, which should be discussed with a healthcare provider. ^{2 3 5 6 7}

How is the drug combination of Olaparib and Adavosertib unique for cancer treatment?

The combination of Olaparib and Adavosertib is unique because it involves using two drugs that target different aspects of cancer cell survival: Olaparib inhibits a protein that helps repair DNA damage in cancer cells, while Adavosertib targets a protein involved in cell division, potentially making the treatment more effective than using either drug alone. ^{2 3 6 8 9}

Research Team

Timothy Yap

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

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

My liver and kidney function tests are within acceptable ranges.

I am fully active or can carry out light work.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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, 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]

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]

References

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

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. [2022]

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. [2020]

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

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. [2022]

6. England 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. [2022]

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

Olaparib shows promise in multiple tumor types. [2014]

8. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. [2015]

9. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. [2019]