Combining selumetinib and azacitidine for high-risk chronic blood cancers

Phase I Study of MEK Inhibitor Selumetinib in Combination With Azacitidine in Patients With Higher Risk Chronic Myeloid Neoplasia: MDS, MDS/MPNs, and Myelofibrosis

This study is testing a new combination of two drugs, selumetinib and azacitidine, to see if it can help people with high-risk chronic blood cancers like chronic myeloid leukemia and myelofibrosis.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Chicago (Academic / other)
• Drugs / interventions: ruxolitinib, radiation, selumetinib
• Locations: 1 site (Chicago, Illinois)
• Trial ID: NCT03326310 on ClinicalTrials.gov

What this trial studies

This phase I, open-label, dose-escalation study aims to determine the maximum tolerated dose (MTD) of selumetinib when used alongside azacitidine in patients with high-risk chronic blood cancers, specifically chronic myeloid leukemia and myelofibrosis. Patients will be stratified into two cohorts based on their specific conditions, and the study will follow a 3+3 dose escalation design to assess safety and tolerability. Treatment will begin within 28 days of screening and will continue indefinitely as long as patients benefit from it. The study is expected to last approximately 24 months, with patients monitored for toxicities and disease progression.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with high-risk myelodysplastic syndromes or chronic myeloid leukemia requiring therapy.

Not a fit: Patients with low-risk forms of these conditions or those not requiring therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could provide a new therapeutic option for patients with high-risk chronic blood cancers.

How similar studies have performed: While this approach is novel in combining these specific agents for this patient population, similar studies have shown promise in targeting chronic blood cancers with combination therapies.

Eligibility criteria

Inclusion Criteria:

All of the following criteria must be met:

* Age greater than or equal to 18 years of age
* Histologic confirmation of one of the following:

  a. MDS fulfilling all the criteria below: i. 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 ii. - relapsed/refractory disease iii. Requiring therapy based on the presence of one or more cytopenias (Hb \<10 g/dL and/or red cell transfusion dependence, platelets- \<50,000/μL, or ANC \<1,000/ μL) or excess blasts (≥5% in the peripheral blood or bone marrow).

  b. MDS/MPN as defined by the WHO criteria, including CMML, atypical CML, and MDS/MPN-Unclassifiable fulfilling the criteria listed below i. relapsed/refractory disease ii. Requiring therapy based on the presence of one or more cytopenias (Hb \<10 g/dL and/or red cell transfusion dependence, platelets \<50,000/μL, or ANC \<1,000/ μL), excess blasts (≥5% in the peripheral blood or bone marrow), or palpable splenomegaly iii. or previously untreated subsets (e.g atypical CML, MDS/MPN unclassifiable) requiring therapy as defined above and in whom no approved therapies exist.

  c. Myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis fulfilling the criteria listed below: i. Intermediate-2 or high risk disease according to the Dynamic International Prognostic Scoring System (DIPSS) classification ii. refractory or intolerant to JAK inhibitor therapy, or deemed - ineligible for ruxolitinib therapy due to pre- existing cytopenias (thrombocytopenia \<50,000/uL, anemia hemoglobin \<9g/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/μL, or ANC \<1,000/μL), excess blasts (≥5% in the peripheral blood or bone marrow), or palpable splenomegaly
* No history of prior exposure to a MEK inhibitor
* ECOG performance status of ≤ 2
* Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN or creatinine clearance \>30 mL/min based on the Cockroft-Gault equation: (140 - Age) x (weight in kg) x (0.85 if female) / 72 x serum creatinine
* Adequate liver function, defined as conjugated bilirubin ≤ 2 x ULN as well as 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:

Patients are excluded if any one of the following is present:

* 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 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:

  1. Uncontrolled hypertension (BP \>150/95 mmHg despite medical therapy)
  2. Acute coronary syndrome within 6 months prior to starting treatment
  3. Uncontrolled angina despite medical therapy
  4. Symptomatic heart failure (NYHA class II-IV despite medical therapy)
  5. Baseline LV EF \<50% measured by either echocardiography or MUGA scan
  6. Severe valvular heart disease
  7. Atrial fibrillation with ventricular rate \>100 bpm on EKG at rest.
* Ophthalmologic conditions, including any of the following:

  1. Current or past history of central serous retinopathy
  2. Current or past history of retinal vein occlusion
  3. 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

Where this trial is running

Chicago, Illinois

• The University of Chicago — Chicago, Illinois, United States (Recruiting)

Study contacts

• Principal investigator: Olatoyosi Odenike, MD — University of Chicago
• Study coordinator: Cancer Clinical Trials Office

Conditions Chronic Myeloid Leukemia; Myelofibroses; Myelofibrosis; selumetinib; azacitidine