Debio 0123 for Solid Tumors

Not currently recruiting at 18 trial locations

Overseen By Debiopharm International S.A

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Debiopharm International SA

Must not be taking: Investigational agents

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

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called Debio 0123 for individuals with advanced solid tumors that have returned or worsened after other treatments. The study consists of two parts: the first aims to determine the optimal dose of Debio 0123, while the second assesses the treatment's safety and effectiveness against tumors. It suits those with specific cancers, such as ovarian or uterine cancer, who have not benefited from standard treatments. Participants should have a measurable tumor and be willing to undergo a biopsy for the study. As a Phase 1 trial, this research focuses on understanding how Debio 0123 works in people, offering participants the chance to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that Debio 0123 is likely to be safe for humans?

Research has shown that Debio 0123 is being tested for safety and effectiveness in treating advanced solid tumors. In earlier studies, patients received increasing doses of Debio 0123 to determine the highest tolerable amount without serious side effects. So far, the treatment has been generally well-tolerated, with most participants not experiencing severe reactions.

Some patients have experienced mild to moderate side effects, which are common in early testing. These side effects might include tiredness or nausea, but they are usually manageable. It is important to note that this treatment remains in the early stages of research. While initial results are promising, further studies are needed to fully understand its safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for solid tumors, like chemotherapy and radiation, target rapidly dividing cells but often lack precision, affecting healthy cells and causing significant side effects. Debio 0123 is unique because it targets tumors based on specific biomarkers, potentially offering a more personalized and precise treatment option. This approach not only aims to minimize damage to healthy cells but also enhances the effectiveness against the tumor. Researchers are excited about Debio 0123 because it represents a shift towards more tailored cancer therapies, which could lead to better outcomes and fewer side effects for patients.

What evidence suggests that Debio 0123 might be an effective treatment for solid tumors?

Research has shown that Debio 0123 targets a protein called WEE1, which aids cancer cells in repairing their DNA. By blocking WEE1, Debio 0123 prevents these cells from fixing their DNA during division. This can weaken the cancer cells, making them more likely to die. Studies have found that blocking WEE1 can reduce tumor growth, especially in cancers with certain mutations. In this trial, participants will receive Debio 0123 in different treatment arms, including a dose escalation phase and an expansion phase. Early results from studies testing various doses are promising for treating advanced solid tumors, suggesting Debio 0123 might help slow or stop the growth of some cancers. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Debio 0123

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

MK1775, a Wee1 inhibitor, shows promising therapeutic efficacy in treating sarcomas by inducing apoptotic cell death and enhancing the effects of gemcitabine, a commonly used chemotherapy drug, in various sarcoma cell lines and patient-derived samples.

The study demonstrated that MK1775 has a high safety profile and effectively induces significant cell death in a mouse model of osteosarcoma, suggesting its potential as a new treatment option for both adult and pediatric sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas. Kreahling, JM., Foroutan, P., Reed, D., et al.[2022]

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]

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]

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]

Patient-derived organoids from ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), were successfully established, showing a moderate derivation efficiency of 36% for HGSOC patients and 44% overall, which allows for better modeling of the disease.

These organoids not only mimic the tumor's characteristics and genetic profile but also demonstrate specific sensitivities to chemotherapy drugs, making them valuable tools for studying ovarian cancer biology and for personalized drug testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing Organoids from Ovarian Cancer as Experimental and Preclinical Models. Maenhoudt, N., Defraye, C., Boretto, M., et al.[2021]

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]

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]

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]

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]

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]

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]

In a study involving 28 samples of pancreatic ductal carcinoma, both fresh and cryopreserved tissues showed comparable success rates for xenografting into nude mice, with 15 tumors successfully growing from the samples.

The ability to successfully xenograft cryopreserved tissues allows for better sharing of tumor samples between research institutions, facilitating the development of in vivo cancer models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful xenografting of cryopreserved primary pancreatic cancers. Sorio, C., Bonora, A., Orlandini, S., et al.[2019]

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]

Citations

1. debiopharm.com debiopharm.com/drug-development/press-releases/debiopharm-launches-expansion-of-wee1-inhibitor-monotherapy-research-in-gynecological-cancers-and-other-biomarker-driven-solid-tumors

Debiopharm Launches Expansion of WEE1 Inhibitor ... Debiopharm aims to further characterize the safety, tolerability, and preliminary anti-tumor activity of its potent WEE1 inhibitor Debio 0123 as a monotherapy.

2. debiopharm.com debiopharm.com/wp-content/uploads/2024/06/28063_ASCO-phase-1-Debio-0123-in-solid-tumors-poster.pdf

results of a phase 1, dose-finding study of debio 0123 as ... WEE1 inhibition reduces the phosphorylation (P) of CDC2, allowing cancer cells to proceed through the cell cycle without DNA damage repair, leading to mitotic ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05109975

NCT05109975 | A Study to Evaluate Safety and ... A Study to Evaluate Safety and Preliminary Anti-tumor Activity of Debio 0123 as Monotherapy in Adult Participants With Advanced Solid Tumors · Study Overview.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11195673/

Targeting WEE1 Kinase in Gynecological Malignancies WEE1i has been shown to inhibit tumor activity and enhance the sensitivity of chemotherapy or radiotherapy in preclinical models, particularly in p53-mutated ...

5. researchgate.net researchgate.net/publication/392303570_Debio_0123_a_highly_selective_WEE1_inhibitor_in_adult_patients_with_advanced_solid_tumors_A_phase_1_dose_escalation_and_expansion_monotherapy_study

Debio 0123, a highly selective WEE1 inhibitor in adult ... This Phase 1 study (NCT05109975) is evaluating Debio 0123 monotherapy in patients with advanced solid tumors who have recurred or progressed following prior ...

6. synapse.patsnap.com synapse.patsnap.com/blog/debiopharm-expands-wee1-inhibitor-monotherapy-study-in-gynecological-and-biomarker-selected-solid-tumors

Debiopharm Expands WEE1 Inhibitor Monotherapy Study in ... Debiopharm, has initiated a Phase 1 study expansion to evaluate the safety, tolerability, and potential anti-tumor effects of Debio 0123, a potent WEE1 ...