Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms

Study Overview
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Brief Summary
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This phase II trial evaluates how a curcumin supplement (C3 complex/Bioperine) changes the inflammatory response and symptomatology in patients with clonal cytopenia of undetermined significance (CCUS), low risk myelodysplastic syndrome (LR-MDS), and myeloproliferative neoplasms (MPN). Chronic inflammation drives disease development and contributes to symptoms experienced by patients with CCUS, LR-MDS, and MPN. Curcumin has been shown to have anti-inflammatory and anti-cancer properties and has been studied in various chronic illnesses and hematologic diseases.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the change in inflammatory cytokine levels in study patients treated with curcumin versus placebo over a 12-month follow-up period. II. To compare the change in symptomatology in study patients treated with curcumin versus placebo over a 12-month follow-up period. SECONDARY OBJECTIVES: I. To investigate the effect on variant allele frequency (VAF) of baseline mutations in study patients treated with curcumin versus placebo. II. To investigate the effect on methylation patterns in study patients treated with curcumin versus placebo. III. To evaluate the effect on peripheral blood cells in study patients treated with curcumin versus placebo. IV. To assess the safety of curcumin for patients with CCUS/LR-MDS and symptomatic MPN who do not require disease-modifying therapy. EXPLORATORY OBJECTIVE: I. To investigate the correlation between inflammatory cytokine levels and symptom scores in study patients treated with curcumin versus placebo. OUTLINE: Patients are randomized to 1 of 2 arms. Arm I: Patients receive curcumin/demethoxycurcumin/bisdemethoxycurcumin-containing supplement (C3 complex)/piperine extract (standardized) (Bioperine) orally (PO) twice daily (BID) for 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy at baseline and follow up, and collection of blood samples throughout the trial. Arm II: Patients receive placebo PO BID for 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy at baseline and follow up, and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up annually for up to 10 years.

Official Title
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A Phase 2, Double-blind, Randomized Study to Compare the Effect of Curcumin Versus Placebo on Inflammatory Cytokines, Symptoms and Disease Parameters in Clonal Cytopenia of Undetermined Significance (CCUS), Low-Risk Myelodysplastic Syndrome (LR-MDS), and Myeloproliferative Neoplasms (MPNs)

Conditions
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Polycythemia Vera, Clonal Cytopenia of Undetermined Significance, Essential Thrombocythemia, Myelodysplastic Syndrome, Myelofibrosis

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspiration
* Procedure: Bone Marrow Biopsy
* Dietary Supplement: Curcumin/ Demethoxycurcumin/Bisdemethoxycurcumin-containing Supplement
* Dietary Supplement: Piperine Extract (Standardized)
* Drug: Placebo Administration
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 Eastern Cooperative Oncology Group (ECOG) =< 2 Ability to understand and willingness to sign a written informed consent Diagnosis of polycythemia vera (PV), essential thrombocytosis (ET) or myelofibrosis (MF) per World Health Organization (WHO) 2016 diagnostic criteria Presence of at least one symptom measurable using the MPN-/Symptom Assessment Form (SAF) with a severity greater than 3 MPN patients determined to have stable disease undergoing surveillance and unlikely to require initiation of new cytoreductive therapy (i.e., hydroxyurea, ruxotinib, interferon within the study period); patients on a stable dose of hydroxyurea for at least 6 months who meet the other inclusion/exclusion criteria may be included A diagnosis of CCUS or LR-MDS CCUS defined as persistent cytopenia for > 6 months (hemoglobin [Hgb] < 11.3 g/dL [7 mmol/L] in women and Hgb < 12.9 g/dL [8 mmol/L] in men, platelet < 150 x 10^9/L or neutrophils < 1.8 x 10^9/L), normal cytogenetics, presence of detectable MDS associated mutations and bone marrow morphology non-diagnostic of MDS or any other malignancies LR-MDS as defined by WHO 2016 diagnosis criteria Minimum baseline symptom score of 25 in the fatigue section of the symptom questionnaire Exclusion Criteria: Patients with intake of curcumin as a dietary supplement, including multivitamin and unwillingness to quit more than 24 hours before study start Patients with inability to understand and adhere to information given Patients receiving active treatment for another malignancy except with hormonal therapy for a malignancy considered to be in remission or growth factors (erythropoietin, granulocyte colony-stimulating factor [G-CSF] and luspatercept) Patients with intermediate or high-risk MDS Patients must not be pregnant or nursing Patients must not be on any oral or intravenous steroid or any other anti-inflammatories (ibuprofen > 200mg/week or 400mg/month, naproxen of any dose, > 325mg aspirin daily, any herbal anti-inflammatory concoction of any dose)

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (C3 Complex/Bioperine)<br>Patients receive C3 complex/Bioperine PO BID for 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy at baseline and follow up, and collection of blood samples throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Dietary Supplement: Curcumin/ Demethoxycurcumin/Bisdemethoxycurcumin-containing Supplement<br>* Given PO<br>* Other names: Curcumin C3 Complex;Dietary Supplement: Piperine Extract (Standardized)<br>* Given PO<br>* Other names: Standardized Piperine Extract;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO BID for 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy at baseline and follow up, and collection of blood samples throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Drug: Placebo Administration<br>* Given PO<br>* Other names: Sugar pills;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in peripheral blood levels of inflammatory cytokines | Interleukin (IL) 1beta, IL-6, IL-18, transforming growth factor-beta, and tumor necrosis factor-alpha will be assessed. Mean inflammatory cytokine changes in the treatment group will be compared to that of the control group. A two-sided two-sample unequal-variance t-test will be applied to compare the difference of the mean of changes at 12-months from the baseline measurement between the two arms, respectively. P-values from the test and the 95% confidence interval of the estimated difference will be reported for each of the inflammatory cytokines. | At baseline, 3 months, and 12 months | 
| Mean change in symptom scores for clonal cytopenia of undetermined significance and low risk myelodysplastic syndrome patients | Symptoms scores will be assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version 3 (EORTC-QLQ-C30 version 3).This is a validated tool for assessing health-related quality of life in cancer patients. The questionnaire is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. Scores range from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems.(no symptom) to 10 (worst possible symptom). | At baseline, 3 months, 12 months | 
| Mean change in symptom scores for myeloproliferative neoplasm (MPN) patients | MPN-related symptoms will be assessed using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Possible scores range from 0 (no symptom) to 10 (worst possible symptom). | At baseline, 3 months, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the variant allele frequency of mutated clones | Both parametric methods i.e., the two-sample t-test and the non-parametric Wilcoxon rank sum test (with no assumption on the distribution of the data) will be applied. | After 12 months of treatment | 
| Change in the deoxyribonucleic acid methylation pattern | Both parametric methods i.e., the two-sample t-test and the non-parametric Wilcoxon rank sum test (with no assumption on the distribution of the data) will be applied. | After 12 months of treatment | 
| Change in peripheral blood cell counts | Peripheral blood cell counts will include absolute neutrophil count, hemoglobin, and platelets. Change in peripheral blood cell counts will be compared to pretreatment. Both parametric methods i.e., the two-sample t-test and the non-parametric Wilcoxon rank sum test (with no assumption on the distribution of the data) will be applied. | After 12 months of treatment | 
| Safety of curcumin in patients with CCUS/LR-MDS and symptomatic MPN | Will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. | Every 2 weeks for the first month of treatment, every month for the following 2 months, then every 3 months for a total of 12 months. | 
| Change in the rate of transfusion requirement measured | Will be measured by the number of units required per 8-week period. Both parametric methods i.e., the two-sample t-test and the non-parametric Wilcoxon rank sum test (with no assumption on the distribution of the data) will be applied. | Up to 10 years |