Phase I Open-Label Study of Fostamatinib, a SYK Inhibitor, in Patients With Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia Who Have Failed Therapy With Hypomethylating Agents
Phase I Open-Label Study of Fostamatinib, a SYK Inhibitor, in Patients With Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia Who Have Failed Therapy With Hypomethylating Agents
This phase I trial is to find out the best dose, possible benefits and/or side effects of fostamatinib in treating patients with lower-risk myelodysplastic syndromes or chronic myelomonocytic leukemia who have failed therapy with hypomethylating agents. Fostamatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVE:
I. To assess the safety and tolerability of different doses of fostamatinib in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) as the measure of adverse events (AEs), serious AEs (SAEs), and laboratory abnormalities on fostamatinib treatment and frequency of discontinuation or interruptions of fostamatinib due to fostamatinib related AEs.
SECONDARY OBJECTIVES:
I. To assess overall survival (OS), duration of response, relapse-free survival (RFS).
II. To assess overall response (OR) rate to different dose schedules of fostamatinib in patients with MDS and CMML following International Working Group (IWG) 2006 response criteria.
III. Hematological response at the end of 2 cycles for each dose level. IV. Frequency of dose escalation of fostamatinib to a dose greater than 100 mg twice daily (BID).
V. Frequency of platelet transfusion independence. VI. Frequency of red blood cell (RBC) transfusion independence for > 8 weeks. VII. Endpoints related to correlative studies.
OUTLINE: This is a dose-escalation study.
Patients receive fostamatinib orally (PO) BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles (week 24) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 6 months thereafter.
Inclusion Criteria:
Age >= 18 years as MDS is a very rare disease in the pediatric setting
Diagnosis of MDS or CMML according to World Health Organization (WHO) and very low, low or intermediate risk by Revised International Prognostic Scoring System (IPSS-R) (with IPSS-R score of =< 3.5)
Patients need to have not responded to prior therapy with hypomethylating agents (HMAs). These could include azacitidine, decitabine, SGI-110, ASTX727. Patients will need to have received at least 4 cycles of HMA. Patients with relapse or progression after any number of cycles of HMA by IWG 2006 criteria will also be candidates. Patients with MDS with isolated del(5q) must have received prior therapy with lenalidomide
Cytopenias, in the form of anemia and thrombocytopenia, as follows:
Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
Total bilirubin < 2 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 1.5 x ULN
Serum creatinine clearance > 30 mL/min and no end/stage renal disease (using Cockcroft-Gault)
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Hydroxyurea for control of leukocytosis is allowed at any time prior to or during study if considered to be in the best interest of the patient
Both females of childbearing potential and males with female partners of childbearing potential must agree to use contraception during the study period and for at least one month after the last dose
Exclusion Criteria: