NCT03326310

Selumetinib and Azacitidine in 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

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Sponsor: University of Chicago · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when combined with the standard dose of azacitidine. Treatment will begin within 28 days of screening procedures. Treatment will continue indefinitely, provided that the patient continues to derive benefit. A patient will be taken off study for reasons described in detail in section 3.12 including disease progression, unacceptable toxicity, inter-current illness, withdrawal of consent, or at the discretion of the investigator. Patients will be followed for 12 weeks after the last dose of study drug, until any study treatment related toxicities have stabilized, or until death. The total duration of the study is expected to be approximately 24 months.

Detailed description

This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when combined with the standard dose of azacitidine. For the purposes of DLT assessment, subjects will be stratified into 2 cohorts- cohort A will include subjects with MDS and MDS/MPN; cohort B will include subjects with myelofibrosis. Dose escalation will proceed independently in each of these cohorts. Determination of MTD will thus also proceed independently within each cohort. Three dose levels of selumetinib are planned for evaluation. Dose escalation will follow a 3+3 study design. Patients will be enrolled sequentially and stratified according to disease type as outlined above. An increased dose level will only open to accrual once at least 3 patients have been treated at the lower dose, followed for the defined DLT observation period (28 days, see section 2.8 below), and the lower dose level has been deemed safe. The 3+3 dose escalation algorithm will proceed as follows: 1. If 0/3 patients develop a DLT at a dose level, escalate to the next dose level. 2. If 1/3 patients develops a DLT at a dose level, enroll 3 additional patients at that dose level. 1. At that dose level, if 1/6 patients develops a DLT, escalate to the next dose level. 2. If ≥2/6 patients develop a DLT, that dose level will be determined to be too toxic. 3. If 2-3/3 patients develop a DLT at a dose level, that dose level will be determined to be too toxic. 4. Six patients will be treated at the MTD. 1. If the study progresses to dose level 3 with 0/3 patients experiencing a DLT, an additional 3 patients will be enrolled at that dose level to gain additional information regarding toxicity. 2. If a dose level is determined to be too toxic and the next lower dose level only included 3 patients, an additional 3 patients will be treated at the lower dose level to confirm tolerability. 5. If no patients have a DLT reported at dose level 3, that will be defined as the MTD and the dose will not be escalated above that level.

Conditions

• Chronic Myeloid Leukemia
• Myelofibroses

Interventions

Type	Name	Description
DRUG	Azacitidine	Patients will receive azacitidine 75 mg/m2 as a subcutaneous injection on days 1-7. The dose of azacitidine 75 mg/m2 will remain unchanged, unless a dose reduction is required based on toxicities (dose level -1 = selumetinib 50 mg PO twice daily and azacitidine 50 mg/m2). Subjects will continue on this schedule in cycles of 28 days duration in the absence of disease progression
DRUG	Selumetinib	Patients will receive selumetinib administered by mouth on days 8-21. The starting dose cohort (dose level 1) will receive selumetinib 50 mg PO twice daily on days 8-21. Subsequent planned doses include selumetinib 75 mg PO twice daily (dose level 2) and selumetinib 100 mg PO twice daily (dose level 3). Subsequent dose levels will only be given once the prior dose level has shown acceptable safety. Subjects will continue on this schedule in cycles of 28 days duration in the absence of disease progression.

Timeline

• Start date: 2018-09-04
• Primary completion: 2027-09-04
• Completion: 2027-09-04
• First posted: 2017-10-31
• Last updated: 2025-12-29

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study