N-Acetylcysteine for Myeloproliferative Disorders

Recruiting at 1 trial location

Overseen By University of California Irvine Medical Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, Irvine

Must not be taking: Interferon-alpha, JAK inhibitors

Disqualifiers: Pregnancy, Breastfeeding, Organ impairment, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests N-acetylcysteine to determine the optimal dose for individuals with myeloproliferative neoplasms (MPN), blood disorders that cause the body to produce too many blood cells. The trial aims to evaluate the effectiveness and safety of different doses. Suitable candidates have specific types of MPN and have not used treatments like interferon-alpha or JAK inhibitors in the past month. Participants may continue current treatments such as aspirin or hydroxyurea. 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 beneficial treatment.

Will I have to stop taking my current medications?

You can continue taking your current medications for myeloproliferative disorders, like aspirin, hydroxyurea, or anagrelide, during the trial. However, you should not have taken interferon-alpha, a JAK inhibitor, or N-Acetylcysteine in the 28 days before joining the study.

Is there any evidence suggesting that N-Acetylcysteine is likely to be safe for humans?

Research has shown that N-acetylcysteine (NAC) is generally safe for people. It often treats certain lung conditions and serves as an antidote for acetaminophen (Tylenol) overdose. Studies have found it well-tolerated, even at doses up to 3000 mg per day. Common side effects include nausea and vomiting. In animal studies, NAC helped prevent blood clots and improved survival in models of certain blood disorders. This suggests that NAC has a promising safety profile. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

N-Acetylcysteine is unique because, unlike many current treatments for myeloproliferative disorders that focus on managing symptoms or slowing disease progression, it works as an antioxidant to potentially reduce oxidative stress, which is thought to contribute to these conditions. This approach targets the underlying cellular environment to possibly improve outcomes. Researchers are excited about N-Acetylcysteine due to its potential to offer a new mechanism of action, providing a complementary option alongside existing therapies like hydroxyurea or interferon, which primarily target blood cell production. This could lead to more comprehensive management of the disease.

What evidence suggests that N-Acetylcysteine might be an effective treatment for myeloproliferative neoplasms?

Research shows that N-acetylcysteine (N-AC) might help treat myeloproliferative neoplasms (MPN), conditions where the body produces too many blood cells. Studies have found that N-AC can lower the risk of blood clots in animal models of MPN, which is crucial since blood clots pose a serious problem for people with MPN. Known as an antioxidant, N-AC helps protect cells from damage. Current research suggests it is generally safe, making it a potential option for MPN treatment. Participants in this trial will receive different doses of N-AC to evaluate its effectiveness and safety at varying levels. ^{1 2 3 6 7}

Who Is on the Research Team?

Angela Fleischman, MD, PhD

Principal Investigator

Chao Family Comprehensive Cancer Center

Are You a Good Fit for This Trial?

Adults diagnosed with essential thrombocythemia, polycythemia vera, or myelofibrosis can join this trial. They must be on stable MPN treatment and not have used interferon-alpha, JAK inhibitors, or N-Acetylcysteine recently. Participants need a certain symptom score and agree to use contraception. Those with severe allergies to N-AC, poor organ function, low blood counts, active infections or pregnancy are excluded.

Inclusion Criteria

I am willing to have my blood drawn and my symptoms checked regularly.

I have been diagnosed with ET, PV, or MF according to the latest criteria.

I have been diagnosed with ET, PV, or MF according to the latest criteria.

Exclusion Criteria

I am not currently taking interferon or a Jak inhibitor.

You have had an allergic reaction to N-AC in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive N-Acetylcysteine at varying doses to determine the optimal biological dose

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• N-Acetylcysteine

Trial Overview The study is testing the best dose of a drug called N-Acetylcysteine for patients with myeloproliferative neoplasms (MPNs). It's in early stages (phase I/II) to see how much should be given safely while participants continue their usual treatments for MPNs.

How Is the Trial Designed?

Group I: Dose Level 3 (DL3) Experimental Treatment 1 Intervention

Patients take N-Acetylcysteince 1800 mg orally twice daily. If DL2 is well tolerated, the next cohort will progress to this dose level.

Group II: Dose Level 2 (DL2) Experimental Treatment 1 Intervention

Patients take N-Acetylcysteince 1200 mg orally twice daily. If DL1 is well tolerated, the next cohort will progress to this dose level.

Group III: Dose Level 1 (DL1) Experimental Treatment 1 Intervention

Patients take N-Acetylcysteince 600 mg orally twice daily. This is the starting dose level for the study.

N-Acetylcysteine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Mucomyst for:

• Mucolytic agent
• Acetaminophen overdose

Approved in European Union as Fluimucil for:

• Mucolytic agent
• Respiratory tract disorders

Approved in Canada as N-Acetylcysteine for:

• Mucolytic agent
• Acetaminophen overdose

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Published Research Related to This Trial

A patient with myelofibrosis that progressed to acute non-lymphocytic leukaemia (ANLL) achieved complete remission twice using low doses of cytosine arabinoside (ARA-C).

The treatment with low-dose ARA-C was effective and did not result in serious toxicity, suggesting it could be a safe therapeutic option for patients with myeloproliferative disorders transitioning to ANLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose cytosine arabinoside therapy in a patient with myelofibrosis during transformation to acute non-lymphocytic leukemia. Jensen, MK., Johansen, P., Ahlbom, G.[2019]

The discovery of the JAK2V617F mutation has led to significant advancements in the treatment of myeloproliferative neoplasms (MPN), particularly with the development of JAK inhibitors like Ruxolitinib, which has shown effectiveness in reducing spleen size and improving quality of life in patients with myelofibrosis (MF).

In addition to JAK inhibitors, other innovative treatments such as immunomodulatory drugs (like pomalidomide), kinase inhibitors, and HDAC inhibitors are being explored in clinical trials, suggesting a promising future for combination therapies in MPN management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Novel therapeutic options in the treatment of BCR/ABL-negative myeloproliferative neoplasms]. Döhner, K., Stegelmann, F., Schlenk, RF., et al.[2021]

Reactive oxygen species (ROS) play a significant role in the progression of myeloproliferative neoplasms (MPNs) by promoting inflammation and genomic instability, suggesting that targeting ROS could be a promising therapeutic strategy.

N-acetyl-cysteine (NAC) has shown potent efficacy in reducing ROS levels and may benefit MPN patients, alongside other agents like interferon-alpha2, statins, and JAK inhibitors, potentially leading to improved treatment outcomes and reduced inflammation-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Reactive Oxygen Species in Myelofibrosis and Related Neoplasms. Bjørn, ME., Hasselbalch, HC.[2018]

N4-Palmitoyl-1-beta-D-arabinofuranosylcytosine (PLAC) showed some efficacy in treating acute leukemia and myelodysplastic syndromes, with 2 out of 20 patients with acute myelogenous leukemia achieving complete remission and 1 patient with acute lymphoblastic leukemia achieving partial remission after 25-66 days of treatment.

Despite some gastrointestinal side effects and myelosuppression, PLAC's oral administration offers a less intensive treatment option for patients with MDSs and MPDs, making it suitable for older patients who may not tolerate aggressive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of leukemia and myelodysplastic syndromes with orally administered N4-palmitoyl-1-beta-D-arabinofuranosylcytosine. Ohno, R., Hirano, M., Yamagata, K., et al.[2019]

N-Acetylcysteine is effective as a mucolytic agent for chronic bronchitis and as an antidote for paracetamol poisoning, with peak plasma concentrations achieved within 1 to 2 hours after oral doses of 200 to 400 mg.

While it has significant therapeutic benefits, common side effects include nausea, vomiting, and diarrhea, and it may interact with other drugs, particularly paracetamol and certain anticancer agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of N-acetylcysteine. Holdiness, MR.[2022]

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) accounts for 25-34% of AML cases and is associated with poor outcomes, including low remission rates and a median overall survival of only 9-12 months, highlighting the urgent need for more effective treatments.

Liposomal daunorubicin-cytarabine (CPX-351) is the only therapy specifically approved for AML-MRC, showing promise for newly diagnosed patients, while hypomethylating agents like azacitidine are commonly used for those who cannot tolerate CPX-351, indicating a need for further research on combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances. Koenig, KL., Sahasrabudhe, KD., Sigmund, AM., et al.[2021]

N-acetylcysteine (NAC) significantly extended the lifespan of JAK2V617F knockin mice, a model for polycythemia vera, without affecting blood counts or spleen size, suggesting its potential safety as a treatment.

NAC demonstrated antithrombotic effects by reducing thrombus formation and platelet activation, comparable to aspirin, indicating its promise as a therapeutic option to lower thrombotic risk in patients with myeloproliferative neoplasms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm. Craver, BM., Ramanathan, G., Hoang, S., et al.[2021]

Histone deacetylase inhibitors (HDACi) show promise as a new treatment option for myeloproliferative neoplasms (MPNs) by potentially overcoming resistance to existing therapies like tyrosine kinase inhibitors and JAK2 inhibitors.

Preliminary studies suggest that combining HDACi with these existing treatments may enhance their effectiveness by promoting cell death in MPN cells, indicating a novel approach to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deactylase inhibition in myeloproliferative neoplasms. Mithraprabhu, S., Grigoriadis, G., Khong, T., et al.[2023]

N4-Palmitoyl-1-beta-D-arabinofuranosylcytosine (PL-AC) showed efficacy in treating various forms of leukemia and myelodysplastic syndromes, with 11 out of 76 patients with acute myeloid leukemia achieving complete remission after a median of 26 days on doses ranging from 100-900 mg/day.

Despite some major side effects like gastrointestinal toxicities and myelosuppression, PL-AC may be a valuable treatment option for older patients with acute leukemia and myelodysplastic syndromes, as it can be administered orally and does not always require hospitalization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A phase II study of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (PL-AC) in patients with acute leukemia and myelodysplastic syndromes. Cooperative Study Group for PL-AC]. Kimura, K.[2013]

A systematic review of 3 randomized controlled trials and 5 observational studies involving a total of 21,141 patients evaluated the effects of N-acetylcysteine (NAC) on COVID-19 pneumonia, but the evidence for its efficacy was very low due to serious imprecision and indirectness.

While NAC showed no significant impact on in-hospital mortality or the need for ICU admission in RCTs, some observational studies suggested potential benefits, indicating that further research is needed to confirm its safety and effectiveness in treating COVID-19 pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis. Paraskevas, T., Kantanis, A., Karalis, I., et al.[2023]

N-acetylcysteine (NAC) can significantly reduce the production of inflammatory markers like TNF-alpha and TGF-beta1 in alveolar macrophages from patients with idiopathic pulmonary fibrosis (IPF), suggesting its potential as an anti-inflammatory treatment.

In a study involving 16 IPF patients, NAC demonstrated a dose-dependent effect, with the highest concentration (10 mM) leading to substantial suppression of both spontaneous and LPS-stimulated inflammatory responses, indicating its possible role in slowing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine inhibits TNF-alpha, sTNFR, and TGF-beta1 release by alveolar macrophages in idiopathic pulmonary fibrosis in vitro. Cu, A., Ye, Q., Sarria, R., et al.[2016]

In a phase 2 clinical trial involving patients with high-risk myelofibrosis who had previously failed JAK inhibitor therapy, the SMAC mimetic LCL161 showed a 30% objective response rate, indicating potential efficacy in this difficult-to-treat population.

The treatment was generally well-tolerated, with the most common side effects being mild nausea and fatigue, and it provided clinical improvements in anemia for some patients, suggesting it could be a valuable option for those with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis. Pemmaraju, N., Carter, BZ., Bose, P., et al.[2021]

Inhibition of histone deacetylases (HDACs) shows potential as a therapeutic strategy for acute myelogenous leukaemia (AML), with some patients achieving complete haematological remission, although this is rare (< 5%).

Common side effects from HDAC inhibitors like butyrate derivatives, valproic acid, and depsipeptide include neurological toxicity and gastrointestinal issues, indicating that while there may be some antileukaemic effects, the overall clinical benefit is limited and further research on combination therapies is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML. Bruserud, Ø., Stapnes, C., Tronstad, KJ., et al.[2019]

A review of 41 studies found that N-Acetylcysteine (NAC) can be safely used at doses higher than the standard 600 mg/day, with some studies administering up to 3000 mg/day for chronic respiratory diseases.

The safety profile of NAC at higher doses was comparable to standard doses, with gastrointestinal symptoms occurring at similar rates as in control groups, suggesting that increasing the dose may not significantly raise the risk of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of N-Acetylcysteine at High Doses in Chronic Respiratory Diseases: A Review. Calverley, P., Rogliani, P., Papi, A.[2023]

In a study involving 12 hemodialysis patients, intravenous administration of 2 g of N-acetylcysteine (NAC) over 3 hours was found to be safe, with no observed side effects during the six dialysis sessions.

NAC reached a steady state concentration after the fourth infusion, indicating effective pharmacokinetics in dialysis patients, with a significant dialytic clearance of 5.52 l/h.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. Soldini, D., Zwahlen, H., Gabutti, L., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6988398/

N-acetylcysteine inhibits thrombosis in a murine model of ... These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2 V617F mice and provide a pre-clinical rationale for investigating NAC as a ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05123365

An Optimal Dose Finding Study of N-Acetylcysteine in ... This is a phase I/II open-label clinical trial determining the optimal biological dose (OBD) of N-acetylcysteine in subjects with myeloproliferative neoplasms.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123130400

An Optimal Dose Finding Study of N-Acetylcysteine in ... We have found that N-acetylcysteine (N-AC), an anti-oxidant with an established safety profile, protects animal MPN models from thrombosis and extends survival.

4. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/311097

An Optimal Dose Finding Study of N-Acetylcysteine in ... This is a phase I/II study evaluating the optimal dose of N-acetylcysteine (N-AC) in patients with myeloproliferative neoplasms (MPN).

5. clinicaltrial.be clinicaltrial.be/en/details/1092?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

An Optimal Dose Finding Study of N-Acetylcysteine in Pati... This is a phase I/II open-label clinical trial determining the optimal biological dose (OBD) of N-acetylcysteine in subjects with ...

6. go.drugbank.com go.drugbank.com/drugs/DB06151

Acetylcysteine: Uses, Interactions, Mechanism of Action Acetylcysteine is a medication that can be used as a mucolytic in patients with certain lung conditions and as an antidote for acetaminophen overdose.

7. withpower.com withpower.com/trial/phase-2-polycythemia-10-2021-31c39

N-Acetylcysteine for Myeloproliferative Disorders N-Acetylcysteine (NAC) is generally considered safe for humans, even at higher doses up to 3000 mg/day, with common side effects like nausea, vomiting, and ...