Debio 0123 for Solid Tumors

Recruiting in Palo Alto (17 mi)

+14 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Debiopharm International SA

Must not be taking: Investigational agents

Disqualifiers: Active second malignancies, Brain tumors, Cardiac issues, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests Debio 0123, a new drug, in adults with advanced solid tumors that haven't responded to other treatments. It aims to find the safest dose and see if the drug can shrink tumors.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are using an investigational agent or have had recent chemotherapy, monoclonal antibodies, or radiotherapy, you may need to stop those before starting the study treatment.

What data supports the effectiveness of the drug Debio 0123 for solid tumors?

Research shows that Wee1 inhibitors, like Debio 0123, can make cancer cells more sensitive to chemotherapy, especially in cancers with a specific gene mutation (p53 mutation). This means the drug might help chemotherapy work better in certain types of cancer. ^{1 2 3 4 5}

Is Debio 0123 safe for humans?

Research on a similar drug, MK1775, which also inhibits Wee1, suggests it has a high safety profile in treating sarcomas, both alone and with other cancer drugs. This indicates that Debio 0123 may also be generally safe in humans, but specific safety data for Debio 0123 itself is not provided. ^{3 4 6 7 8}

What makes the drug Debio 0123 unique for treating solid tumors?

Debio 0123 is unique because it targets the WEE1 protein, which is involved in cell cycle regulation, potentially offering a novel approach for treating solid tumors where standard treatments may not exist or be effective. ^{9 10 11 12 13}

Research Team

Eligibility Criteria

Adults with advanced solid tumors that have returned or worsened after treatment, or when no effective standard therapy exists. Participants must be in good physical condition (ECOG PS 0-1), have a life expectancy of at least 3 months, and adequate organ function. They should agree to use contraception and comply with study procedures. Exclusions include active secondary cancers needing treatment within the last 6 months, recent major surgery, brain tumors/metastases requiring recent treatment, current infections needing systemic drugs, pregnancy/breastfeeding, inability to take oral meds.

Inclusion Criteria

Part 1 dose escalation and Part 2 expansion: Life expectancy of at least 3 months, in the best judgment of the Investigator

Part 1 dose escalation only: Measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria

My cancer can be measured using specific criteria.

Exclusion Criteria

Pregnancy or breast-feeding

I don't have severe side effects from past treatments, except for mild anemia, hair loss, or controlled thyroid issues.

I have not had a heart attack, stroke in the last 6 months, severe heart failure, uncontrolled chest pain, fainting without a known cause, dangerous heart rhythms needing treatment, a family history of sudden cardiac death, or heart damage from past chemotherapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive Debio 0123 orally in escalating dose cohorts during each 21-day treatment cycle until progression of disease, unacceptable toxicity, participant's withdrawal, or Investigator's decision

21-day cycles

Expansion

Debio 0123 is administered at the RP2D established in Part 1 to participants with specific types of cancer

21-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Debio 0123 (Other)

Trial Overview The trial is testing Debio 0123 as a solo therapy for solid tumors in two parts: Part 1 finds the safest highest dose; Part 2 uses this dose to assess safety further and see how well it works against specific tumor types. The drug's given repeatedly to adults whose cancer has come back or gotten worse despite previous treatments.

Participant Groups

Group I: Part 2: Expansion Experimental Treatment 1 Intervention

Debio 0123 at the RP2D established in Part 1 participants with uterine serous carcinoma (USC) (arm A), recurrent or progressive, high-grade epithelial ovarian cancer (EOC) with cyclin E1 (arm B), and solid tumor with biomarker-driven selection (arm C).

Group II: Part 1: Dose Escalation Experimental Treatment 1 Intervention

Participants will receive Debio 0123 orally in escalating dose cohorts during each 21-day treatment cycle until progression of disease, unacceptable toxicity, participant's withdrawal, or Investigator's decision, whichever occurs first.

Who Is Running the Clinical Trial?

Debiopharm International SA

Lead Sponsor

Trials

53

Recruited

7,300+

Findings from Research

The study identified a specific mRNA gene signature that indicates the effectiveness of the Wee1 inhibitor MK-1775 in enhancing the anti-tumor effects of DNA damaging agents like gemcitabine, particularly in p53 negative tumors.

This gene signature can serve as a pharmacodynamic biomarker to measure target engagement in clinical trials, showing a dose-dependent response to the Wee1 inhibitor and correlating with the inhibition of CDC2, which is crucial for cell cycle regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor. Mizuarai, S., Yamanaka, K., Itadani, H., et al.[2022]

Silencing WEE1 in breast cancer cell lines MCF7 and MDA-MB-468 led to over a 50% decrease in cell viability and a significant increase in apoptotic cells, indicating its potential as a target for cancer therapy.

WEE1 inhibition resulted in the upregulation of the pro-apoptotic marker p53 and downregulation of the anti-apoptotic factor Bcl-2, suggesting that targeting WEE1 can enhance apoptosis and reduce tumor growth in breast cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumour suppressive effects of WEE1 gene silencing in breast cancer cells. Ghiasi, N., Habibagahi, M., Rosli, R., et al.[2019]

WEE1 inhibitors can be safely combined with chemotherapy and radiotherapy, but their clinical use has been limited due to a higher incidence of severe side effects (grade 3 toxicities) when added to standard treatments.

The effectiveness of WEE1 inhibitors in enhancing chemotherapy response has been modest, particularly in trials using TP53 mutations as a biomarker, prompting ongoing research into their combination with novel agents like ATR and PARP inhibitors to improve anti-tumor efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WEE1 Inhibitor: Clinical Development. Kong, A., Mehanna, H.[2022]

MK-1775, a Wee1 inhibitor, significantly enhances the effectiveness of gemcitabine (GEM) in treating p53-deficient pancreatic cancer xenografts, leading to a 4.01-fold increase in tumor regression compared to GEM alone.

The combination therapy of MK-1775 and GEM not only promotes tumor cell death by overcoming checkpoint arrest but also results in longer-lasting effects compared to GEM treatment alone, although neither treatment was effective in p53 wild-type tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Rajeshkumar, NV., De Oliveira, E., Ottenhof, N., et al.[2022]

Wee1 inhibition using the drug MK1775 enhances the effectiveness of the chemotherapy drug cytarabine in treating acute myelogenous leukemia (AML) cells, regardless of whether the p53 gene is functional or dysfunctional.

In mouse models, the combination of MK1775 and cytarabine was well tolerated and improved survival rates, supporting further clinical testing of this combination for leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Van Linden, AA., Baturin, D., Ford, JB., et al.[2021]

WEE1 inhibitors, particularly adavosertib, show promising efficacy in treating gynecological cancers, with objective response rates ranging from 23% to 43% and median progression-free survival between 3.0 to 9.9 months across various trials.

The treatment is associated with common adverse effects such as bone marrow suppression and gastrointestinal issues, and biomarkers like TP53 and CCNE1 alterations may help identify patients who are more likely to respond to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review. Schutte, T., Embaby, A., Steeghs, N., et al.[2023]

The small molecule inhibitor MK1775 effectively induces cell death in various sarcoma cell lines and patient-derived tumor explants by promoting premature mitotic entry, demonstrating its potential as a single-agent treatment for sarcomas.

MK1775's cytotoxic effects are consistent across sarcoma cells with different p53 mutations, indicating that its mechanism of action is independent of p53 status, which is significant for treating diverse sarcoma types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Kreahling, JM., Gemmer, JY., Reed, D., et al.[2021]

A new cancer model using human cerebral organoids allows for direct observation of glioma tumor initiation and invasion, demonstrating that transformed cells can rapidly destroy surrounding structures.

The study shows that tumor cells derived from these organoids exhibit characteristics of aggressive human glioblastoma, suggesting that this model can effectively mimic key aspects of cancer malignancy for research and testing purposes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glioblastoma Model Using Human Cerebral Organoids. Ogawa, J., Pao, GM., Shokhirev, MN., et al.[2021]

Using patient-derived tumor organoids (PDTOs) from 194 specimens of 126 sarcoma patients, researchers were able to identify effective treatment options for 59% of the cases, highlighting the potential of PDTOs in personalizing therapy for rare sarcoma subtypes.

The study demonstrated that drug sensitivity in PDTOs correlated with various clinical factors, such as tumor subtype and patient treatment history, suggesting that organoid drug screening can guide treatment decisions and improve patient outcomes in sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The landscape of drug sensitivity and resistance in sarcoma. Al Shihabi, A., Tebon, PJ., Nguyen, HTL., et al.[2023]

The SPOT platform allows for the creation of standardized, 3D bioengineered microtissues from patient-derived organoids, which can be used for high-throughput drug screening in a 96- or 384-well format.

Using SPOT, researchers successfully tested the response of pancreatic cancer organoids to chemotherapy, highlighting its potential to improve drug sensitivity assessments and enhance the drug discovery process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An off-the-shelf multi-well scaffold-supported platform for tumour organoid-based tissues. Li, NT., Wu, NC., Cao, R., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor. [2022]

2. Thailand pubmed.ncbi.nlm.nih.gov

Tumour suppressive effects of WEE1 gene silencing in breast cancer cells. [2019]

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

WEE1 Inhibitor: Clinical Development. [2022]

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

MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. [2022]

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

Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review. [2023]

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

Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas. [2022]

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

MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. [2021]

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

Glioblastoma Model Using Human Cerebral Organoids. [2021]

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

The landscape of drug sensitivity and resistance in sarcoma. [2023]

11. Netherlands pubmed.ncbi.nlm.nih.gov

An off-the-shelf multi-well scaffold-supported platform for tumour organoid-based tissues. [2022]

12. Germany pubmed.ncbi.nlm.nih.gov

Successful xenografting of cryopreserved primary pancreatic cancers. [2019]

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

Developing Organoids from Ovarian Cancer as Experimental and Preclinical Models. [2021]