Adavosertib + Radiation for Esophageal Cancer

Not currently recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Chemotherapy, Radiotherapy, Allergic reactions, others

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

Compensation: Varies

Number of Visits: 16

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and optimal dose of adavosertib, a drug that might stop tumor growth, when combined with radiation therapy for esophageal and gastroesophageal junction cancer that current treatments cannot cure. Researchers hope that adavosertib with radiation will kill more tumor cells than radiation alone. The trial seeks participants with inoperable or metastatic esophageal cancer who can swallow whole capsules. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take medications that strongly affect the enzyme CYP3A4. It's important to discuss your current medications with the trial team to ensure there are no interactions.

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

Research has shown that adavosertib, when combined with radiation therapy, may help fight esophageal and gastroesophageal junction cancers. However, safety data highlight some challenges. In certain studies, patients experienced side effects at higher doses of adavosertib, such as tiredness and low blood cell counts. This indicates that while the drug can be effective, it may not be well-tolerated at higher doses.

Radiation therapy is a more established treatment and is generally considered safe, but it can also cause side effects like skin irritation and fatigue. The goal of combining adavosertib with radiation therapy is to kill more cancer cells, but monitoring for any adverse reactions is important.

This trial is in an early stage, so researchers are still determining the safest dose of adavosertib. Participants in the trial will help gather important safety information. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for esophageal cancer?

Unlike the standard treatments for esophageal cancer, which typically involve chemotherapy and radiation, the combination of adavosertib with radiation therapy targets the cancer in a unique way. Adavosertib is a novel drug that inhibits a protein called Wee1 kinase, which is involved in cell division and DNA repair. By blocking this protein, adavosertib makes cancer cells more sensitive to radiation, potentially enhancing the effectiveness of the treatment and reducing the likelihood of cancer cells repairing themselves. Researchers are excited because this approach could lead to more effective treatments with fewer side effects compared to traditional chemotherapy.

What evidence suggests that adavosertib combined with radiation therapy might be an effective treatment for esophageal cancer?

Research shows that adavosertib can enhance the effects of radiation therapy in treating certain cancers, such as esophageal cancer. In this trial, participants will receive a combination of adavosertib and radiation therapy. Studies have found that this combination can kill more cancer cells than radiation alone. Adavosertib blocks an enzyme called WEE1, which cancer cells need to grow. Radiation therapy is already known to shrink tumors and improve survival in esophageal cancer patients. The combination aims to make cancer cells more sensitive to treatment, increasing the effectiveness of radiation. Overall, this approach could offer a new way to tackle difficult-to-treat esophageal cancers. ^{2 4 6 7 8}

Who Is on the Research Team?

Eric D. Miller

Principal Investigator

Ohio State University Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with inoperable esophageal or gastroesophageal junction cancer, including squamous cell or adenocarcinoma, that is not eligible for definitive chemoradiation. Participants must have proper liver and kidney function, no severe heart conditions, be able to swallow capsules, and have a life expectancy over 3 months. Pregnant women are excluded.

Inclusion Criteria

My recent ECG shows no significant heart issues.

I have another cancer type, but it won't affect this trial's treatment.

My hepatitis B is under control with treatment.

Exclusion Criteria

I don't have long QT syndrome, a history of Torsades de pointes, recent heart attack, or ventricular arrhythmias.

I've had radiation therapy in my chest or belly area that might overlap with new treatment areas.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo radiation therapy once daily 5 days per week for 3 weeks and receive adavosertib orally during weeks 1 and 3

3 weeks

15 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

1 visit at 3 weeks, every 3 months for 2 years, then every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Adavosertib
• Radiation Therapy

Trial Overview The trial tests the safety and optimal dosage of Adavosertib combined with radiation therapy on patients with incurable esophageal or gastroesophageal junction cancers. The goal is to see if this combination is more effective than radiation alone in stopping tumor growth.

How Is the Trial Designed?

Group I: Treatment (radiation therapy, adavosertib) Experimental Treatment 2 Interventions

Patients undergo radiation therapy QD 5 days per week for 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive adavosertib PO QD for 2-5 days (depending on dose level) during weeks 1 and 3 of radiation therapy 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

In a study of 461 patients with stage IV esophageal cancer, those receiving concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control rates (81.6% vs. 64.5% for chemotherapy alone) and better progression-free survival (PFS) of 8.7 months compared to 7.3 months for chemotherapy alone.

Patients treated with CCRT also experienced a higher rate of improvement in dysphagia symptoms (78.5% vs. 61.5%), suggesting that adding radiotherapy may enhance quality of life alongside survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for esophageal squamous cell cancer patients presenting with oligometastases. Chen, Y., Cheng, X., Song, H., et al.[2022]

In a study of 45 patients with esophageal squamous cell carcinoma, simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) demonstrated promising overall survival rates of 42.2% and progression-free survival rates of 40.7% at 3 years, indicating its efficacy as a treatment option.

The treatment was associated with a low toxicity profile, as no patients experienced severe (grade 4-5) side effects, and the most common side effect, radiation esophagitis, was manageable, affecting 64% of patients but only 13% at grade 3 severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study. Yu, WW., Zhu, ZF., Fu, XL., et al.[2021]

Ablative robotic stereotactic body radiosurgery (SBRT) was safely administered to 50 women with recurrent gynecologic cancers, with a 96% target response rate and a 68% clinical benefit observed at 6 months.

The treatment resulted in a median overall survival of 20.2 months, although a significant 62% of patients experienced non-radiosurgical disease relapse, indicating the need for further studies combining SBRT with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Clinical Trial of Robotic Stereotactic Body Radiosurgery for Metastatic Gynecologic Malignancies. Kunos, CA., Brindle, J., Waggoner, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04460937

Testing the Addition of an Anti-cancer Drug, Adavosertib, to ... Giving adavosertib together with radiation therapy kill more tumor cells than radiation therapy alone in treating patients with esophageal and gastroesophageal ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10618648/

Adavosertib Enhances Antitumor Activity of Trastuzumab ... In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10489509/

Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in ... Adavosertib demonstrated promising preliminary antitumor activity, with a response rate of 27% in 30 patients with metastatic malignancies ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1040842825000988

WEE1 inhibition in cancer therapy: Mechanisms, synergies ... WEE1 inhibitors, such as Adavosertib (AZD1775 or MK1775), have shown preclinical efficacy in various cancers, including ovarian, breast, head and neck, ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/27/14/3834/671539/Safety-Antitumor-Activity-and-Biomarker-Analysis

Safety, Antitumor Activity, and Biomarker Analysis in a Phase I ... Results from the twice-daily arm of this study demonstrated adavosertib-mediated Wee1 kinase suppression (pY15-Cdk1/2 reduction) of 80% to 90% accompanied by ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12433026/

a systematic review and meta-analysis - PMC This is the first meta-analysis evaluating the efficacy and safety of ICIs in the adjuvant treatment of esophageal cancer. The findings suggest that ICIs offer ...

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

ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter ... Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this ...

8. onclive.com onclive.com/view/adavosertib-shows-early-antitumor-activity-despite-safety-concerns-in-uterine-serous-carcinoma

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% ...