Onureg for Cancer in Liver Failure

Recruiting at 32 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

32 Participants Needed

Trial Summary

What is the purpose of this trial?

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 tolerability of oral azacitidine in participants with myeloid malignancies.

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 Onureg (Azacitidine) generally safe for use in humans?

Azacitidine, also known as Onureg, has been studied for safety in patients with certain blood disorders. Common side effects include low white blood cell counts and low platelet counts, which can increase the risk of infections and bleeding, but these effects are usually reversible. ^{1 2 3 4 5}

What makes the drug Onureg unique for treating cancer in liver failure?

Onureg (also known as Azacitidine or Vidaza) is unique because it is an oral form of azacitidine, which is typically administered via injection. This makes it more convenient for patients, especially those with liver failure, as it can be taken at home rather than requiring hospital visits for injections. ^{6 7 8 9 10}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

References

1. England 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. [2015]

2. England 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). [2019]

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

Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). [2014]

4. England pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

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

Pharmacokinetic considerations in evaluating the effects of tetrahydrouridine on 5-azacytidine chemotherapy in L1210 leukemic mice. [2013]

6. England 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. [2019]

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

Synthesis and biological activity of 4-beta-Iribofuranosyl-1,3-dihydroxybenzene ("1,3-dideazauridine"). [2019]

8. Greece pubmed.ncbi.nlm.nih.gov

Evaluation of the antitumor activity of 1-(3-C-ethynyl-beta-D-ribofuranosyl) (PJ272), a recent ribonucleoside analogue. [2013]

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

Phase II study of 3-deazauridine in advanced colorectal adenocarcinoma. [2013]

10. England pubmed.ncbi.nlm.nih.gov

9-Deazaadenosine--a new potent antitumor agent. [2021]