An Optimal Dose Finding Study of N-Acetylcysteine in Patients With Myeloproliferative Neoplasms

Study Overview
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Brief Summary
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This is a phase I/II study evaluating the optimal dose of N-acetylcysteine (N-AC) in patients with myeloproliferative neoplasms (MPN).

Detailed Description
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This is a phase I/II open-label clinical trial determining the optimal biological dose (OBD) of N-acetylcysteine in subjects with myeloproliferative neoplasms. These are subjects who have a diagnosis of essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF).

Official Title
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An Optimal Dose Finding Study of N-Acetylcysteine in Patients With Myeloproliferative Neoplasms

Conditions
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MPN, Myeloproliferative Neoplasm, Essential Thrombocythemia, Polycythemia Vera, Myelofibrosis

Intervention / Treatment
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* Drug: N-Acetylcysteine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Have a diagnosis of essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) according to the 2016 WHO criteria Has not taken interferon-alpha or a JAK inhibitor (such as ruxolitinib or fedratinib) for treatment of MPN in the past 28 days before enrollment. May continue on current MPN treatment, including aspirin, hydroxyurea, or anagrelide. Therapeutic phlebotomies should continue per the patient's usual regimen. Has not taken N-Acetylcysteine (N-AC) or preparations containing N-AC in the past 28 days before enrollment. Baseline MPN-TSS score of ≥ 10 at the time of enrollment. Peripheral blast count <10% during Screening. Free of other active or metastatic malignancies other than localized skin cancer. Amenable to blood draws and symptom assessments. Agree to the use of contraceptives. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential, should both use an effective contraception method during the study and continue to use contraception for 60 days after the last dose of study drug. Exclusion Criteria: Eastern Cooperative Oncology Group (ECOG) questionnaire score of ≥3 Currently pregnant or planning on being pregnant within the study period. Currently breastfeeding. Known uncontrolled active viral or bacterial infection. Significant impairment of major organ function defined as Serum creatinine clearance less than 50 ml/min (calculated with Cockroft-Gault formula). Bilirubin more than 1.5 mg/dl except for Gilbert's disease. ALT or AST more than 2X upper normal limit or has radiologic evidence of liver cirrhosis. Platelets < 100 × 10^9/L Hgb < 10 g/dL ANC < 0.75 × 10^9/L Known history of allergic reaction to N-AC.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 (DL1)<br>Patients take N-Acetylcysteince 600 mg orally twice daily. This is the starting dose level for the study. | Drug: N-Acetylcysteine<br>* Given PO<br>* Other names: N-AC;|
| Experimental: Dose Level 2 (DL2)<br>Patients take N-Acetylcysteince 1200 mg orally twice daily. If DL1 is well tolerated, the next cohort will progress to this dose level. | Drug: N-Acetylcysteine<br>* Given PO<br>* Other names: N-AC;|
| Experimental: Dose Level 3 (DL3)<br>Patients take N-Acetylcysteince 1800 mg orally twice daily. If DL2 is well tolerated, the next cohort will progress to this dose level. | Drug: N-Acetylcysteine<br>* Given PO<br>* Other names: N-AC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal Biological Dose (OBD) of N-Acetylcysteine | Determination of the optimal biological dose (OBD) will be utilized to evaluate the safety and tolerability of N-AC as a treatment for patients with MPN. Optimal biological dose is defined as the therapeutic dose that possesses the highest efficacy probability while inducing acceptable toxicity | From the start date of treatment until 7 days after completion of treatment or removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, up to 8 weeks. | 
| Proportion of subjects who achieve 30% reduction of MPN-SAF Total symptom score (MPN-TSS) | MPN-SAF Total symptom score (MPN-TSS) is a validated tool to objectively measure the burden of symptoms associated with MPN. Baseline TSS will be defined as the average of the daily TSS of 7 consecutive days immediately prior to beginning N-AC. The end of study MPN-TSS will be defined as the average of the daily TSS of 7 consecutive days during week 8. | 7 days prior to beginning treatment until end of treatment, average of 9 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPN, Myeloproliferative Neoplasm, Essential Thrombocytemia, Polycythemia Vera, Myelofibrosis