A Randomized, MultiCenter, Open-Label, Modified Dose-Ascension, Parallel Study of the Safety, Tolerability, and Efficacy of Oral SCIO-469 in Patients With Myelodysplastic Syndromes
SCIO-469 belongs to a new class of treatment that inhibits p38 MAP kinase. p38 MAPK
activation controls the production of TNF-a, VEGF, and IL-1b. As an inhibitor of p38 MAPK,
SCIO-469 blocks the synthesis of these molecules, as well as TNF-a activity. This
randomized, open-label, modified does-ascension study is designed to assess the safety,
tolerability, and efficacy of oral SCIO-469 in the treatment of patients with MDS. This
patient group was selected because of the inhibitory effect of SCIO-469 on the expression
and activity of cytokines that play a role in the progression of MDS. The treatment arms
will be 30, 60 , 90, or 120 mg tid with 15 subjects per arm (total of 60 subjects) and each
arm may expand to 25 subjects per arm (maximum total of 100 subjects). Initially, subjects
will be randomly assigned to one of the lowest two treatment arms (30 mg tid or 60 mg tid).
When 6 subjects per arm (at least 12 subjects total) have received study drug for at least 4
weeks, predefined criteria will be used to determine whether to open randomization into the
third arm (i.e., 90 mg tid). The criteria will be based on the number of subjects who have
had to suspend study drug due to drug-related toxicity. The 120-mg tid arm will be open for
enrollment after 15 subjects have been enrolled into each of the first three treatment arms;
the decision to open enrollment will be similar to the criteria used to open the third arm.
Subjects will be evaluated at least monthly for safety and some efficacy measurements (AE
reporting, safety labs and vitals). Subjects will receive study drug for 16 weeks. Subjects
who demonstrate hematologic improvement (erythroid, platelet, or neutrophil response by IWG
criteria) at week 16 will be eligible to continue treatment at the same dose of study drug
for up to 36 additional weeks (52 weeks of total drug exposure). Subjects who do not meet
the IWG criteria for hematologic improvement at week 16 but who, in the judgment of the
investigator, experience clinical benefit may also receive up to 36 additional weeks of
treatment. The same judgments for treatment extensions of additional 26 weeks in responding
subjects will be made at 52 weeks and 78 weeks; maximum total drug exposure will be 104
weeks. All subjects will be followed for 4 weeks after the last study drug treatment for
safety assessments or until resolution of Grade 3 or greater treatment-related toxicity as
defined by NCI CTCAE (v. 3.0).
Oral SCIO-469 given for 16 weeks to patients with MDS. Subjects will receive a total daily
dose of SCIO-469 of 90 mg, 180 mg, 270 mg, or 360 mg. The treatment arms will be 30-mg
tablet tid, 60-mg tablet tid, 90-mg tablet tid, or 120 mg (i.e., two 60-mg tablets) tid with
15 subjects per arm (total of 60 subjects). Responding subjects may dose for up to 104
weeks total drug exposure.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Percentage of Participants With Major or Minor Erythroid Response (Hematological Improvement - Erythroid [HI-E])
Improvement in Erythroid (HI-E) lineage will be assessed as per International Working Group (IWG) criteria. HI-E major response is defined as greater than 2.0 gram per deciliter g/dL increase in hemoglobin for red blood cell (RBC) transfusion-dependent participants, transfusion independence. HI-E minor response is defined as 1.0 to 2.0 g/dL increase in hemoglobin for RBC transfusion-dependent participants and 50 percent decrease in transfusion requirements.
Scios, Inc. Clinical Trial
United States: Food and Drug Administration