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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called Adavosertib for cancer patients with a BRCA mutation. The goal is to determine if Adavosertib can shrink or halt the growth of cancers that depend on a protein called WEE1, which aids the growth of cancer cells with BRCA mutations. Suitable participants have ovarian or HER2-negative metastatic breast cancer and have previously tried a PARP inhibitor. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that adavosertib has undergone testing in various studies to assess its safety for humans. In some studies, it was combined with chemotherapy and found to be generally safe and manageable. However, in studies where patients received a 300 mg dose once daily, tolerance decreased, with some experiencing difficult side effects.

Adavosertib can cause DNA damage as part of its mechanism to fight cancer. This effect is expected and integral to how the treatment targets cancer cells. Despite this, some studies showed limited success in shrinking tumors when used alone.

Adavosertib is currently in a Phase 2 trial, indicating it has passed initial safety tests in humans. Researchers continue to monitor for any serious side effects to ensure its safety for broader use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Adavosertib is unique because it targets a specific weakness in cancer cells with BRCA mutations. Unlike standard chemotherapy treatments, which attack all rapidly dividing cells, adavosertib specifically inhibits a protein called Wee1 kinase. This protein is crucial for cell division, especially in cancer cells with faulty BRCA genes. By blocking Wee1, adavosertib disrupts the cancer cells' ability to repair DNA damage, leading to their destruction while sparing more healthy cells. Researchers are excited about this targeted approach because it promises to be more effective and potentially less toxic than conventional treatments.

What evidence suggests that Adavosertib might be an effective treatment for cancer with BRCA mutations?

Research has shown that adavosertib, also known as AZD1775, might help treat cancers with BRCA mutations. Studies have found that adavosertib can block a protein called WEE1, which cancer cells with these mutations need to grow. In one study, adavosertib combined with carboplatin led to a positive response in 66.7% of patients with resistant ovarian cancer. Other research has demonstrated that it can significantly combat cancer in lab models experiencing high stress on cell replication. This suggests that adavosertib might help shrink tumors or stop them from growing in patients with BRCA-mutated cancer. Participants in this trial will receive adavosertib as the investigational treatment. ^{1 3 6 7 8}

Who Is on the Research Team?

Shivaani Kummar

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10345044/

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].

2. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01606

ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter ... Adavosertib (AZD1775), a Wee1 inhibitor, has shown significant antitumor activity in cancer cell models with high endogenous replication stress, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7887044/

Clinical efficacy and molecular response correlates of the ... Three phase II studies of adavosertib with chemotherapy demonstrated encouraging antitumor efficacy in patients with TP53-mutated or TP53-unselected ovarian ...

4. withpower.com withpower.com/trial/phase-3-multiple-myeloma-2-2017-b1793

Adavosertib for Cancer with BRCA Mutations Adavosertib, when combined with carboplatin, showed a high overall response rate of 66.7% in patients with platinum-resistant ovarian cancer, indicating ...

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

PR072/#1519 Effort: clinical and molecular features ... We report updated progression-free survival (PFS) and clinical/molecular features associated with clinical benefit from adavosertib (A) +/- olaparib (O).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8282703/

Safety, anti-tumor activity, and biomarker analysis in a ... Adavosertib-induced DNA damage resulting from G1/S checkpoint disruption has been demonstrated in vitro and in patient tumors through detection of the DNA ...

7. aacrjournals.org aacrjournals.org/cancerrescommun/article/4/7/1793/746640/A-Phase-II-Trial-of-the-WEE1-Inhibitor-Adavosertib

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2 ... WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite ...

8. link.springer.com link.springer.com/article/10.1007/s10637-023-01371-6

A phase Ib study of adavosertib, a selective Wee1 inhibitor ... Safety data were recorded throughout the study until 30 days after the last adavosertib ... BRCA1/2 mutated and CCNE1 amplified cancers. Eur J ...