Onureg for Cancer in Liver Failure

Not currently recruiting at 33 trial locations

Overseen By BMS Study Connect Contact Center www.BMSStudyConnect.com

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Bristol-Myers Squibb

Disqualifiers: Chemotherapy, Radiotherapy, Inflammatory bowel disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a cancer treatment called Onureg (also known as Azacitidine or Vidaza) to evaluate its effects in people with liver problems. Researchers aim to determine if moderate or severe liver issues influence how the body processes the drug and its safety for these patients. Participants must have specific blood-related cancers, such as myelodysplastic syndrome or acute myeloid leukemia, and stable kidney function without dialysis. The trial includes various groups, including those with normal liver function for comparison. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to early-stage cancer research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had chemotherapy or radiotherapy within 2 weeks or 5 half-lives before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that Onureg has been tested in patients with liver issues. Researchers closely monitored patients with moderate liver problems for any side effects. However, Onureg has not been studied in people with very severe liver damage, so caution is important in these cases.

Research on Vidaza, similar to Onureg, suggests it may harm the liver, especially in patients with severe liver issues. Therefore, doctors need to exercise caution when administering Vidaza to people with liver disease.

This trial tests these treatments to learn more about their safety for people with liver problems. Monitoring for any side effects, especially those affecting the liver, is crucial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Onureg and Vidaza for treating cancer in patients with liver failure because they offer promising new approaches. Onureg is an oral formulation of azacitidine, which allows for easier administration compared to traditional intravenous options. This can be particularly beneficial for patients with liver issues, who may have complications with IV treatments. Vidaza, on the other hand, is known for its ability to modify the expression of genes linked to cancer growth, potentially offering a more targeted approach than conventional chemotherapies. Together, these treatments could provide more effective and manageable options for patients battling cancer with compromised liver function.

What evidence suggests that Onureg might be an effective treatment for myeloid malignancies in patients with liver impairment?

Studies have shown that azacitidine, the active ingredient in both Onureg and Vidaza, can help treat certain blood cancers. In one study with patients who had acute myeloid leukemia, 48% saw their cancer improve after using azacitidine, meaning nearly half experienced positive results. Another study found that 41.4% of patients with other blood disorders, such as MDS (myelodysplastic syndromes) and CMML (chronic myelomonocytic leukemia), had complete or partial improvement. Additionally, 43.8% of patients who needed blood transfusions required them less often after treatment. These findings suggest that azacitidine could benefit people with these conditions. In this trial, researchers will divide participants into different groups to assess the effects of Onureg and Vidaza in patients with liver failure compared to those with normal hepatic function. ^{3 4 6 7 8}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for people with certain blood cancers or inoperable tumors who also have moderate to severe liver problems. They should be expected to live at least 3 more months and not need dialysis. People can't join if they're still dealing with serious side effects from past treatments, have gut diseases that could affect drug absorption, or had chemo/radiotherapy within the last month.

Inclusion Criteria

I have been diagnosed with a specific blood cancer as per WHO 2016.

My liver is not working well.

Life expectancy of ≥ 3 months

Exclusion Criteria

I still have serious side effects from past treatments that haven't improved.

I have a history of serious gut issues that could affect medication absorption or increase my risk of stomach side effects.

I haven't had chemotherapy or radiotherapy in the last 2 weeks or longer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral azacitidine to evaluate its pharmacokinetics and safety in those with varying levels of hepatic function

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Onureg
• Vidaza

Trial Overview The study tests how liver impairment affects Onureg (oral azacitidine) levels in the body and its safety for those with myeloid malignancies. It aims to understand if and how liver function changes the way this cancer medication works.

How Is the Trial Designed?

Group I: Group 3 Experimental Treatment 1 Intervention

Control - participants with normal hepatic function

Group II: Group 2 Experimental Treatment 1 Intervention

Group III: Group 1 Experimental Treatment 1 Intervention

Onureg is already approved in United States, European Union for the following indications:

Approved in United States as Onureg for:

• Acute myeloid leukemia

Approved in European Union as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia
• Chronic myelomonocytic leukemia

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

The new ribonucleoside derivative PJ 272 effectively inhibits the growth of various tumor cell lines, showing an IC50 of less than 25 nM in 7 out of 8 tested lines, indicating strong antiproliferative properties.

In vivo studies demonstrated that PJ 272 significantly increased the survival rate of DBA/2 mice with leukemia when administered at 20 mg/kg every three days, suggesting its potential as an effective treatment for lymphoma and leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the antitumor activity of 1-(3-C-ethynyl-beta-D-ribofuranosyl) (PJ272), a recent ribonucleoside analogue. Holl, V., Jung, P., Weltin, D., et al.[2013]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

The combination of tetrahydrouridine (THU) with 5-azacytidine (5-azaCR) showed minimal increases in therapeutic effects in L1210 leukemia mice, indicating limited efficacy of this combination in enhancing chemotherapy outcomes.

THU significantly increased the excretion of 5-azaCR and altered its urinary metabolites, but high doses of THU with 5-azaCR also raised toxicity levels, particularly when plasma concentrations of 5-azaCR exceeded 61 micrograms/ml.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic considerations in evaluating the effects of tetrahydrouridine on 5-azacytidine chemotherapy in L1210 leukemic mice. Kelly, CJ., Gaudio, L., Yesair, DW., et al.[2013]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

In a phase II study involving 15 patients with advanced colorectal adenocarcinoma, 3-deazauridine (DAUR) showed no responses, indicating poor efficacy for this treatment in previously treated patients.

The treatment was associated with mild side effects such as nausea, vomiting, and diarrhea, but only minimal myelosuppression was observed, suggesting a relatively safe profile despite lack of effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of 3-deazauridine in advanced colorectal adenocarcinoma. Bruno, S., Creaven, PJ., Ledesma, E., et al.[2013]

In a study involving 14 patients with metastatic renal adenocarcinoma, the new drug 1,2,4-triglycidylurazol (TGU) did not result in any objective tumor regression, despite its promising preclinical activity.

The treatment was associated with significant side effects, including severe and prolonged thrombocytopenia (low platelet count) and nausea, indicating that while TGU was chosen for its potential benefits, its safety profile raised concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary resistance of renal adenocarcinoma to 1,2,4-triglycidylurazol (TGU, NSC 332488), a new triexpoxide cytostatic agent--a phase II study of the EORTC early clinical trials group. Bruntsch, U., Dodion, P., Ten Bokkel Huinink, WW., et al.[2019]

9-Deazaadenosine (9-DAA) effectively inhibits the growth of various human solid tumor cell lines, with IC50 values ranging from 1.1 to 8.5 X 10(-8)M, and shows significant tumor reduction in pancreatic carcinoma in immunosuppressed mice.

In vivo studies demonstrated that 9-DAA reduced pancreatic tumor weights by about 50% at a dosage of 0.4 mg/kg/day, and the use of a nucleoside transport inhibitor enhanced its antitumor effects while protecting normal tissues from toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

9-Deazaadenosine--a new potent antitumor agent. Chu, MY., Zuckerman, LB., Sato, S., et al.[2021]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

The newly synthesized compound 4-(beta-D-ribofuranosyl)-1,3-dihydroxybenzene showed significant antitumor activity, inhibiting leukemia L1210 cells by 50% at a concentration of 7 x 10(-6) M and mammary carcinoma TA3 cells at 5 x 10(-5) M.

In comparison, the original compound dideazauridine was less effective against the cancer cells but demonstrated notable antiviral activity against herpes simplex virus type I in vitro.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and biological activity of 4-beta-Iribofuranosyl-1,3-dihydroxybenzene ("1,3-dideazauridine"). Sharma, RA., Bobek, M., Bloch, A.[2019]

In a Phase I trial involving 27 adult patients with refractory cancer, 1-beta-D-arabinofuranosyl-5-azacytosine (ara-AC) showed dose-limiting toxicities, primarily reversible granulocytopenia and thrombocytopenia, with significant side effects observed at a dose rate of 1.96 mg/m2/h.

Despite the toxicity, minor clinical responses were noted in several patients, leading to a recommended dose of 2.0 mg/m2/h for future Phase II studies, indicating potential efficacy in treating certain types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). Surbone, A., Ford, H., Kelley, JA., et al.[2014]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK548363/

Azacitidine - LiverTox - NCBI Bookshelf - NIH (Among 302 Austrian patients with acute myeloid leukemia treated with azacitidine the overall response rate was 48% and serious adverse events ...

2. withpower.com withpower.com/trial/phase-1-liver-failure-10-2022-86dfb

Onureg for Cancer in Liver Failure · Info for Participants Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05209295?term=AREA%5BBasicSearch%5D(AREA%5BExpandedAccessNCTId%5DNCT03723135)&rank=1

A Study to Evaluate CC-486/Onureg in Participants With ... The purpose of this study is to evaluate the effect of moderate or severe liver impairment on the drug levels of oral azacitidine and the safety and ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2152265023021973

Real-world Effectiveness of Azacitidine in Treatment-Naive ... Median follow-up was 12.9 months; median overall survival was 17.9 months (95% CI, 15.5-21.7). •. This study highlights an important unmet need for new ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/050974s034lbl.pdf

VIDAZA (azacitidine - accessdata.fda.gov Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and. Reference ID: 4987350. This label ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/214120s000lbl.pdf

ONUREG (azacitidine) tablets, for oral use - accessdata.fda.gov Hepatic Impairment. ONUREG has not been studied in patients with pre-existing severe hepatic impairment (total bilirubin > 3 × ULN). A ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/onureg-epar-product-information_en.pdf

Onureg, INN-azacitidine - European Medicines Agency Patients with moderate (BIL > 1.5 to 3 × ULN) and severe hepatic impairment (BIL > 3 × ULN) should be monitored more frequently for adverse ...

8. bms.com bms.com/assets/bms/ca/documents/productmonograph/ONUREG_EN_PM.pdf

product monograph including patient medication information hepatic impairment (total bilirubin > 1.5 to 3 × ULN). No dose adjustment of ONUREG® is recommended for patients with mild hepatic impairment.