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Selumetinib and Azacitidine in Treating Patients with Myelodysplastic Syndrome, Myelodysplastic / Myeloproliferative Neoplasm, and Myelofibrosis

Trial Status: Active

This phase I trial studies the best dose and side effects of selumetinib when given together with azacitidine in treating patients with myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, and myelofibrosis. Selumetinib and azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Histologic confirmation of one of the following: * Myelodysplastic syndrome (MDS) fulfilling all the criteria below: ** International Prognostic Scoring System (IPSS) intermediate-2 or high risk MDS; or Revised International Prognostic Scoring System (IPSS-R) intermediate, high, or very high risk MDS ** Relapsed/refractory disease ** Requiring therapy based on the presence of one or more cytopenias (hemoglobin [Hb] < 10 g/dL and/or red cell transfusion dependence, platelets < 50,000/uL, or absolute neutrophil count [ANC] < 1,000/ uL) or excess blasts (>= 5% in the peripheral blood or bone marrow) * Myelodysplastic/myeloproliferative Neoplasm (MDS/MPN) as defined by the World Health Organization (WHO) criteria, including chronic myelomonocytic leukemia (CMML), atypical chronic myelogenous leukemia (CML), and MDS/MPN-unclassifiable fulfilling the criteria listed below ** Relapsed/refractory disease ** Requiring therapy based on the presence of one or more cytopenias (Hb < 10 g/dL and/or red cell transfusion dependence, platelets < 50,000/uL, or ANC < 1,000/ uL), excess blasts (>= 5% in the peripheral blood or bone marrow), or palpable splenomegaly or ** Previously untreated subsets (e.g atypical CML, MDS/MPN unclassifiable) requiring therapy as defined above and in whom no approved therapies exist * Myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis fulfilling the criteria listed below: ** Intermediate-2 or high risk disease according to the Dynamic International Prognostic Scoring System (DIPSS) classification ** Refractory or intolerant to JAK inhibitor therapy, or deemed - ineligible for ruxolitinib therapy due to pre- existing cytopenias (thrombocytopenia < 50,000/uL, anemia hemoglobin < 9 g/dL or red cell transfusion dependence); requiring further therapy based on the presence of one or more cytopenias (Hb < 10 g/dL and/or red cell transfusion dependence, platelets < 50,000/uL, or ANC < 1,000/uL), excess blasts (>= 5% in the peripheral blood or bone marrow), or palpable splenomegaly
  • No history of prior exposure to a MEK inhibitor
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance > 30 mL/min based on the Cockroft-Gault equation
  • Conjugated bilirubin =< 2 x ULN
  • Aspartate transaminase (AST) and alanine aminotransaminase (ALT) =< 3 x ULN
  • Patients must be at least 2 weeks from major surgery, radiation therapy, participation in other investigational trials and must have recovered from clinically significant toxicities of these prior treatments
  • Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
  • Female and male patients must use an effective contraceptive method during the study and for at least 6 months thereafter
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • Receipt of any anti-cancer therapy within 14 days prior to study entry, with the exception of hydroxyurea; if clinically indicated in order to keep white blood cells (WBC) < 30,000/uL, hydroxyurea may be continued through the first cycle
  • Concurrent active malignancy, with the exception of early stage basal cell or squamous cell skin cancer
  • Active cardiac conditions, including any of the following: * Uncontrolled hypertension (blood pressure [BP] > 150/95 mmHg despite medical therapy) * Acute coronary syndrome within 6 months prior to starting treatment * Uncontrolled angina despite medical therapy * Symptomatic heart failure (New York Heart Association [NYHA] class II-IV despite medical therapy) * Baseline left ventricular ejection fraction (LV EF) < 50% measured by either echocardiography or multigated acquisition (MUGA) scan * Severe valvular heart disease * Atrial fibrillation with ventricular rate > 100 beats per minute (bpm) on electrocardiogram (EKG) at rest
  • Ophthalmologic conditions, including any of the following: * Current or past history of central serous retinopathy * Current or past history of retinal vein occlusion * Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
  • Any uncontrolled concurrent illness that, in the judgment of the investigators or treating physician, may put the patient at undo risk including but not limited to active infection, symptomatic cardiac or pulmonary disease, ventricular arrhythmia, or psychiatric illness
  • Pregnant or lactating patients

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Olatoyosi Muinat Odenike
Phone: 773-702-3354

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of selumetinib when combined with azacitidine.

SECONDARY OBJECTIVES:

I. To characterize the tolerability of selumetinib given in combination with azacitidine.

II. To assess the feasibility of prospectively screening patients for RAS pathway activating mutations by next generation sequencing at our center in the context of a clinical trial, by characterizing the time to results and success rate of the assay.

III. To describe preliminary response rates of the combination.

TERTIARY OBJECTIVES:

I. To describe the frequency of RAS pathway activating mutations (including NRAS, KRAS, JAK2, CALR, MPL, FLT3, c-KIT, BRAF, PTPN11, CBL, and NF1) and cooperating mutation CUX1 in patients with higher risk chronic myeloid malignancies.

II. To examine RAS pathway activation at baseline and compare to post-treatment.

III. To observe relationships between the presence of RAS activating mutations, RAS pathway activation, and clinical response.

IV. To collect specimens for banking for use in future research studies with a view towards identifying predictors of response to epigenetic or molecularly targeted therapies.

OUTLINE: This is a dose-escalation study of selumetinib.

Patients receive azacitidine subcutaneously (SC) on day 1-7 and selumetinib orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Olatoyosi Muinat Odenike

  • Primary ID IRB17-0774
  • Secondary IDs NCI-2018-00008
  • Clinicaltrials.gov ID NCT03326310