Ivosidenib in Combination with Ruxolitinib for the Treatment of IDH1-Mutated, Ph-negative Advanced-Phase Myeloproliferative Neoplasms

Inclusion Criteria

• Advanced-phase IDH1-mutated Ph-negative MPNs (both untreated and relapsed/refractory) including any of the following: * Polycythemia vera with (PV) ≥ 5% peripheral or bone marrow blasts at time of screening * Essential thrombocythemia (ET) with ≥ 5% peripheral or bone marrow blasts at time of screening * Primary myelofibrosis (PMF) with ≥ 5% peripheral or bone marrow blasts at time of screening * Atypical chronic myeloid leukemia (CML) with ≥ 5% peripheral or bone marrow blasts at time of screening * MPN-not otherwise specified (NOS) with ≥ 5% peripheral or bone marrow blasts at time of screening * Myelodysplastic syndrome (MDS)/MPN overlap syndromes including chronic myelomonocytic leukemia (CMML) with ≥ 5% peripheral or bone marrow blasts at time of screening * Post-PV myelofibrosis with ≥ 5% blasts peripheral or bone marrow blasts at time of screening * Post-ET myelofibrosis with ≥ 5% blasts peripheral or bone marrow blasts at time of screening * Primary and secondary myelofibrosis with inadequate response to JAK inhibitor regardless of blast percentage. Inadequate response to JAK inhibitor will be defined as lack of achieving any clinical improvement criteria within 12 weeks of JAK inhibitor initiation as noted by revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) response criteria for myelofibrosis (MF). For patients on JAK inhibitor for greater than 12 weeks those meeting criteria for relapse or progressive disease by Revised IWG-MRT and ELN response criteria for MF would be eligible. This will be determined by treating physician
• Patients can be on cytoreduction at time of study enrollment with hydroxyurea or steroids. Women of reproductive potential should use effective contraception during treatment with hydroxyurea and for at least 6 months after the last dose of hydroxyurea and males should use effective contraception during treatment and for at least 1 year after the last dose of hydroxyurea. Contraception should also be continued for at least 1 month after the final dose of ivosidenib and ruxolitinib
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of these investigational agents in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Creatinine clearance ≥ 60 mL/min, determined by the Cockroft-Gault formula, OR serum creatinine ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (unless considered due to Gilbert’s syndrome, leukemic involvement, or extravascular hemolysis in the spleen)
• Bilirubin ≤ 1.5 x ULN (unless considered due to Gilbert’s syndrome, leukemic involvement, or extravascular hemolysis in the spleen)
• A platelet count of 50 x 10^9/L should be met for those with chronic-phase myelofibrosis and < 5% blasts peripherally or in bone marrow
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients would need viral load monitoring on a monthly basis during the first 5 cycles and then would be monitoring as recommended by their treating specialist. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Patients would need viral load monitoring on a monthly basis during the first 5 cycles and then would be monitoring as recommended by their treating specialist
• Patients must be at least 4 weeks from major surgery, radiation therapy, or participation in other investigational trials, and must have recovered from clinically significant toxicities related to these prior treatments
• The effects of the investigational agents on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women should also use appropriate contraception for 3 months after completion of administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients cannot be on concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in this protocol. Patients cannot have had prior treatment with ivosidenib
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease or they are not currently requiring treatment for an indolent malignancy. Patients with acute promyelocytic leukemia (APL) and active central nervous system (CNS) disease would also be excluded
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ivosidenib or ruxolitinib
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, venous thromboembolism, stroke, active chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cholangitis, hemochromatosis) or psychiatric illness/social situations that would limit compliance with study requirements
• Subject has corrected QT interval (QTc) interval (i.e., Fridericia’s correction [QTcF]) ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g. family history of long QT interval syndrome) at screening unless due to bundle branch block or pacemaker with approval of the principal investigator
• Pregnant women are excluded from this study because ruxolitinib and ivosidenib carry the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib and ivosidenib, breastfeeding should be discontinued if the mother is treated with any of these agents
• Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
• Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 should have eligibility and alternative medications reviewed by site principal investigator (PI). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product