Oral Tetrahydrouridine-Decitabine in Patients With Advanced Myeloproliferative Neoplasms

This is a phase 2, multicenter trial evaluating the feasibility of administering oral THU-Dec with or without JAK2 inhibitor in patients with advanced MPNs. Eligible subjects will receive oral THU-Dec orally once weekly on a four week (28 day) cycle for a core study period of 6 cycles (24 weeks). The primary endpoint will be assessed after 6 cycles of treatment. Feasibility will be assessed as the treatment completion rate, defined as the proportion of patients who receive ≥75% of planned THU-Decitabine doses for at least 6 cycles or who discontinue treatment to receive allogeneic hematopoietic stem cell transplantation. After 24 weeks, subjects who demonstrate any response as per modified Cheson Criteria or stable disease may continue to receive treatment until loss of response, disease progression, unacceptable toxicity, subject/physician withdrawal, or the study is terminated.

• Oral THU-decitabine (Drug): Combination of Tetrahydrouridine and Decitabine oral treatment. Treatment is ingested weekly without interruption. For convenience of communication and planning, 4 weeks of treatment (28 days) is considered a treatment cycle. The first 2 cycles of therapy (week 1-8 of therapy) is considered an induction phase. After the induction phase (Cycle 3+): Treatment continues weekly.

Primary outcomes

• Treatment Completion Rate [6 Cycles (24 Weeks)]: Proportion of patients who receive ≥75% of planned THU-Dec doses for at least 6 cycles (24 weeks) OR discontinue treatment to receive allogeneic hematopoietic stem cell transplantation

Secondary outcomes

• Overall Survival [48 Months]: The median overall survival of advanced phase MPN patients treated with oral THU-Dec ± JAK2i
• Complete Blast Response [48 Months]: No circulating blasts in peripheral blood and less than 5% in bone marrow.
• Partial Blast Response [48 Months]: A 50% reduction in peripheral blood or bone marrow blasts.
• Chronic Phase BF Blast [6 Cycles (24 Weeks)]: The proportion of treated patients with chronic phase MF and 4%-9% circulating blasts that achieve a response (complete response, partial response, clinical improvement, anemia, spleen, symptom response, cytogenetic or molecular remission).
• MFSAF TSS [48 Months]: Change in MPN-SAF TSS from baseline after 6 and 12 cycles; symptom response will be determined in participants with baseline MPN-SAF TSS ≥ 10. Symptom improvement response is defined as a number of participants with improvement in symptoms response as defined by Myeloproliferative Neoplasms Symptoms Assessment Form (MPN-SAF). The MPN-SAF is a questionnaire that measures certain symptoms and how they improve throughout the study, from baseline. The questionnaire is divided into 4 sections - 1: 16 questions about the most common symptoms in these disease types, rated from 0 (lowest impact) to 10 (biggest impact); 2: Highest grade of fever; 3: Unintentional weight loss; 4. Quality of life, rated from 0 (as good as it can be) to 10 (as bad as it can be). MPN-SAF is an 18-item instrument. Each item score 0-10 averaged, total scale from 0-10, with higher score indicating more symptoms.
• EORTC-QLC-30 [48 Months]: This is a 30-question tool used to assess the overall QoL in cancer participants. It consisted of 15 domains: 1 GHS/QoL scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact). Most items are scored 1 ("not at all") to 4 ("very much") except for the items contributing to the GHS/QoL, which are scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that all transformed scores lie between 0 to 100. For the GHS/QoL and 5 functional scales a high score indicates better global health status/functioning and a negative change from baseline indicated less improvement. For the symptom scales, a high score indicates a higher level of symptoms, and a negative change from baseline indicated an improvement in symptoms.
• PGIC Score [48 Months]: The Patient's Global Impression of Change (PGIC) will be used to assess self-reported relieving effect. It will evaluate pain from no change (score 0-1), minimally improved (score 2-3), much improved (score 4-5), and very much improved (score 6-7). The patients will answer the following question: "Since beginning treatment at this program, how would you describe the change (if any) in activity limitations, symptoms, emotions, and overall quality of life related to your condition?". Full score from 0-7, with higher score indicating more improvement. Change in score at Week 2, Week 10 and Week 14 as compared to Baseline.
• Allogeneic Stem Cell Transplant [48 Months]: Rate of allogeneic stem cell transplant occurrence among those participating in the study.
• Time to Treatment Failure (TTF) [48 Months]: TTF is defined as time from enrollment to discontinuation of treatment for any reason.
• Dose Delays [48 Months]: Frequency of THU-Dec dose delays
• Dose Interruptions [48 Months]: Frequency of THU-Dec dose interruptions
• Rate of Hospitalization [48 Months]: Rate of hospitalizations related to complications of treatment or disease.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adults ≥ 18 years of age
* Diagnosis of one of the following:
* Accelerated-phase (≥ 10% blasts in PB or BM) or blast-phase (≥ 20% blasts in PB or BM) myeloproliferative neoplasm with a history of prior myelofibrosis, polycythemia vera, or essential thrombocythemia; or
* Chronic phase myelofibrosis with 4-9% circulating blasts
* Eastern Cooperative Oncology Group (ECOG) 0-2
* Concurrent use of physician's choice JAK1/2 inhibitors is permitted. Patients must be on stable dose of JAK2i for at least 4 weeks prior to starting the clinical trial.
* Body weight ≥ 41 kg
* Ability to swallow oral medication
* Adequate organ function as demonstrated by all of the following:
* ALT (SGPT) and/or AST (SGOT) < 3x upper limit of normal (ULN), unless, upon judgment of the treating physician, it is believed to be due to MF-related extramedullary hematopoiesis (EMH)
* Direct bilirubin < 2 x ULN; unless it is believed to be due to MF-related EMH or documented/suspected Gilbert's syndrome;
* Creatinine clearance ≥ 40 mL/min
* Women of childbearing potential (WCBP) and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months following completion of therapy. WCBP must also have a negative serum pregnancy test at screening and Cycle 1 Day 1. Should a woman become pregnant or suspect she is pregnant while participating, she should inform her treating physician immediately. Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 6 months after the last dose of study therapy
* Ability to adhere to the study visit schedule and all protocol requirements
* If the patient has co-morbid illness or malignancy, life expectancy attributed to this must be greater than 2 years.

Exclusion Criteria:

* Concurrent treatment with venetoclax
* Treatment with any MF-directed drug treatments (including investigational therapies; excluding hydroxyurea and JAK inhibitor) within 2 weeks or 5.5 half-lives, whichever is shorter, of Cycle 1 Day 1
* Prior treatment with more than 2 cycles of prior IV or subcutaneous (SC) hypomethylating agent
* Patients willing and able to undergo allogeneic stem cell transplant immediately without need for cytoreduction
* Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates, including, but not limited to:
* Ongoing or active infection
* Uncontrolled concurrent other malignancy
* Congestive heart failure of New York Heart Association (NYHA) class III/IV. Patients with compensated heart failure are permitted.
* Unstable angina pectoris
* New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are permitted
* Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD score ≥21)
* Psychiatric illness/social situations that would limit compliance with study requirements.
* Any other prior or ongoing condition, in the opinion of the investigator, that could adversely affect the safety of the patient or impair the assessment of study results.
* Hematopoietic cell transplant (HCT) within 100 days of the first dose of study therapy, receipt of immunosuppressive therapy post-HCT at screening, use of calcineurin inhibitors within 4 weeks prior to first dose of study therapy, or clinically significant GVHD
* Note: The use of topical steroids or < 20mg oral prednisone for ongoing skin GVHD is permitted
* Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of oral THU-Dec, including any unresolved nausea, vomiting, or diarrhea > NCI CTCAE grade 2
* Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject
* History of major surgery within 28 days prior to Cycle 1 Day 1 or any planned surgical procedures 10.
* Organ transplant recipients other than bone marrow transplant
* Women who are pregnant or lactating\\
* Concurrent enrollment in another interventional trial

• John Mascarenhas, MD, Study director, Icahn School of Medicine at Mount Sinai
• Marina Kremyanskaya, MD, PhD, Study chair, Icahn School of Medicine at Mount Sinai
• Shivani V Handa, MD, Study chair, Ohio State University

NIH grants: P01CA108671