A Pilot Study of Momelotinib in Combination With Hypomethylating Agent for Chronic Phase Myelodysplastic Syndromes/Myeloproliferative Overlap Neoplasms and Chronic Neutrophilic Leukemia (M-HArbOr)
This research is being done to evaluate effectiveness, safety, and tolerability of a study drug called momelotinib in participants with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), MDS/MPN-not otherwise specified (MDS/MPN-NOS), MDS/MPN with neutrophilia (MDS/MPN-N), also called as atypical chronic myeloid leukemia, or chronic neutrophilic leukemia. Momelotinib will be added to standard treatment which usually includes a hypomethylating agent like azacitidine. Treatment options for this diagnosis remain limited and investigators need better treatments to help control the disease, improve symptoms, and potentially help more patients become eligible for transplant. Participants for this study will be asked to take some screening tests which will include routine physical examination, blood tests, and imaging scans to determine eligibility for the study. Those who continue to qualify for this study will begin treatment and may be asked to remain on the study drug for up to 24 months, depending upon how they are responding to treatment. After the study drug is completed, patients will have one additional clinic visit to evaluate overall health and response to study drug. The study drug treatment on this study will include taking momelotinib by mouth in combination with azacitidine, which is given by injection for all patients for the first 5 days of each 28-day cycle. The most common side effect that may be related to participation in this study can include (i) infections which can present as fever, chills, cough, breathing problems, diarrhea, vomiting, pain or burning with urination; or (ii) low blood platelet count which can result in bruising or bleeding for longer than usual if the participant hurts themself.
• Patients of age 18 or older
• Has a diagnosis of MDS/MPN or CNL by WHO or ICC diagnostic criteria:
‣ Chronic myelomonocytic leukemia
⁃ MDS/MPN with neutrophilia, previously known as atypical chronic myeloid leukemia
⁃ Chronic neutrophilic leukemia
⁃ MDS/MPN -not otherwise specified
• Chronic phase disease with \<10% blasts in peripheral blood and marrow within 1 month from planned start of treatment
• Eastern Cooperative Oncology Group (ECOG) Performance Score44 of 0-2
• Patients can be treatment naïve or could have undergone prior treatments for MDS/MPN as below:
‣ Prior treatment with non-JAK inhibitors or hypomethylating agents are allowed (e.g., hydroxyurea, immunomodulatory agents, steroids). Hydroxyurea can be continued until or even beyond initiation of treatment for 2 months if needed for cytoreduction
⁃ If non-MMB JAK inhibitors were used for treatment and stopped due to side effects (e.g., anemia from ruxolitinib, gastrointestinal toxicity from fedratinib, etcetera), these patients will be allowed to enroll on this study as long as JAK inhibitor was stopped at least 2 weeks prior to anticipated start date of treatment
⁃ If prior hypomethylating agent was used and stopped longer than 3 months prior to anticipated start date of treatment due to side effects, these patients will be eligible. However, if hypomethylating agents were stopped due to lack of clinical benefit, these patients will not be deemed eligible
⁃ Prior treatment with erythropoietic stimulating agents is allowed if last treatment was more than 4 weeks prior to anticipated start date of treatment
⁃ Splenic radiation should have been performed more than 2 months before anticipated start date of treatment
⁃ Any prior or ongoing investigation therapy or agents should be stopped longer than 4 weeks of anticipated start date of treatment
• Blood counts with platelets ≥25,000/microL, ANC ≥0.75 x 10\^9/L (without transfusion or growth factor support)
• Baseline splenomegaly with ≥5 cm below costal margin or ≥450 cm3 on imaging (ultrasound, CT or MRI)
• Adequate organ function with creatinine clearance measured by Cockcroft-Gault calculation ≥30 mL/min, total bilirubin ≤1.5×ULN (isolated bilirubin \>1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%), INR ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants, albumin ≥2.5 g/dL.
• Willing and able to sign the informed consent form
• Life expectancy \> 24 weeks
• Willing and able to complete patient-reported outcome assessments using an ePRO device according to protocol
• Patients of child-bearing potential, or those with partners of child-bearing potential or pregnant or lactating partners, who are willing to follow highly effective contraceptive requirements. Females of reproductive potential should use effective contraception during study treatment and for 6 months following the last dose for HMA-MMB and 1 week following the last dose for MMB monotherapy. Males with female partners of reproductive potential should use effective contraception during study treatment and for 3 months following the last dose for HMA-MMB and 1 week following the last dose for MMB monotherapy. Patients should not breastfeed during treatment and for 1 week after the last dose.
• Patients of child-bearing potential with a negative highly sensitive serum pregnancy test within 24 hours before the first dose of momelotinib.