Adavosertib for Cancer with BRCA Mutations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Aprepitant, Fosaprepitant

Disqualifiers: Hypersensitivity to AZD1775, 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: 24

Duration: 21-day cycles, repeated until disease progression or unacceptable toxicity

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II MATCH treatment trial identifiesay block the protein tyrosine kinase WEE1 the effects of AZD1775 in patients whose cancer has a genetic change called BRCA mutation. AZD1775 may block a protein called WEE1, which may be needed for growth of cancer cells that express BRCA mutations. Researchers hope to learn if AZD1775 will shrink this type of cancer or stop its growth.

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

The trial protocol does not specify if you must stop taking your current medications. However, if you are taking medications that affect CYP3A4, the study investigator will review them, and you may need to stop or adjust them. You cannot take aprepitant or fosaprepitant during the trial.

What data supports the effectiveness of the drug Adavosertib for cancer with BRCA mutations?

Adavosertib has shown promising results in treating various cancers, such as ovarian cancer and solid tumors, by targeting specific genetic mutations. It has been effective in cancers with certain genetic changes, like CCNE1 amplification and mutations in RAS and TP53, which may suggest potential benefits for BRCA-mutated cancers as well. ^{1 2 3 4 5}

Is Adavosertib safe for humans?

Adavosertib has been shown to be safe in patients with advanced solid tumors and CCNE1-amplified solid tumors. It does not cause significant heart rhythm issues, which are a concern with some cancer treatments. ^{1 2 5 6 7}

How is the drug Adavosertib unique for treating cancer with BRCA mutations?

Adavosertib is unique because it is a first-in-class drug that inhibits WEE1 kinase, a protein involved in DNA replication, which may make it effective against cancers with specific genetic mutations like BRCA. This mechanism is different from traditional chemotherapy, which targets rapidly dividing cells more broadly. ^{1 2 3 4 5}

Research Team

Shivaani Kummar

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for cancer patients with a specific genetic change called BRCA mutation. They must have had prior eligibility in the Master MATCH Protocol, normal heart rhythm and function on an ECG, and acceptable blood hemoglobin levels. Those with ovarian or metastatic breast cancer should have tried PARP inhibitors before.

Inclusion Criteria

My heart's electrical system is functioning within a safe range according to my ECG results.

I am taking medication that may affect how my body processes certain drugs.

My tumor has a confirmed BRCA1 or BRCA2 mutation.

Exclusion Criteria

I am not allergic to AZD1775 or similar drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adavosertib (AZD1775) orally once daily on days 1-5 and 8-12 of each 21-day cycle

21-day cycles, repeated until disease progression or unacceptable toxicity

Visits every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 3 years post registration

Every 3 months for < 2 years, then every 6 months for an additional year

Treatment Details

Interventions

• Adavosertib

Trial Overview Researchers are testing AZD1775 to see if it can shrink or stop the growth of cancers that have BRCA mutations. AZD1775 targets a protein called WEE1 which might be essential for these cancer cells' growth.

Participant Groups

Group I: Treatment (adavosertib) Experimental Treatment 1 Intervention

Patients receive adavosertib PO QD on days 1-5 and 8-12 of each cycle. Cycles repeat every 21 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

Adavosertib, when combined with carboplatin, showed a high overall response rate of 66.7% in patients with platinum-resistant ovarian cancer, indicating promising efficacy for this treatment combination.

However, the combination therapy resulted in significant hematologic toxicities, such as neutropenia and anemia, suggesting that while adavosertib is effective, careful monitoring and further optimization of treatment protocols are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study. Moore, KN., Chambers, SK., Hamilton, EP., et al.[2022]

Adavosertib has been found to be safe for use in patients with advanced solid tumors that have CCNE1 amplification.

The treatment shows promising antitumor efficacy, suggesting it could be a potential option for targeting these specific types of tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adavosertib Is Safe and Efficacious in CCNE1-Amplified Solid Tumors. [2023]

Vemurafenib, an oral BRAF kinase inhibitor, has been shown to be a safe and tolerable treatment for patients with metastatic melanoma harboring BRAFV600 mutations, with a median follow-up of 32.2 months in a study involving 3219 patients.

The most common adverse events included arthralgia, alopecia, and hyperkeratosis, and while patients with longer durations of response experienced more severe adverse events, no new safety concerns emerged over the two-year treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, multicentre safety study of vemurafenib in&#160;3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis. Blank, CU., Larkin, J., Arance, AM., et al.[2022]

References

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

Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study. [2022]

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

Adavosertib Is Safe and Efficacious in CCNE1-Amplified Solid Tumors. [2023]

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

Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring. [2022]

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

Uterine Serous Carcinoma Responds to the WEE1 Inhibitor Adavosertib. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study. [2023]

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

Open-label, multicentre safety study of vemurafenib in&#160;3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis. [2022]