Phase I Study of the Combination of Midostaurin, Bortezomib, and Chemotherapy in Relapsed/Refractory Acute Myeloid Leukemia
I. To determine the maximum tolerated dose (MTD) of bortezomib in combination with
midostaurin and intensive chemotherapy in patients with relapsed/refractory acute myeloid
II. To define the specific toxicities and the dose limiting toxicity (DLT) of midostaurin
and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML.
I. To determine the rate of complete remission (CR) of midostaurin and bortezomib in
combination with intensive chemotherapy. II. To determine the overall response rate (ORR).
III. To characterize the biological activity of midostaurin and bortezomib to potentially
increase endogenous phosphatase activity and therefore inhibit aberrant tyrosine kinases by
assessing FLT3 and KIT tyrosine kinase activity as well as SHP-1(Anti-Src Homology
Phosphatase-1)phosphatase activity. IV. To correlate the biological activity of midostaurin
and bortezomib to potentially increase endogenous phosphatase activity with clinical
response. V. To conduct pharmacokinetic studies of midostaurin and bortezomib together and
in combination with intensive chemotherapy.
VI. To determine the efficacy of midostaurin and bortezomib in combination with intensive
chemotherapy at the maximum tolerated dose in patients with FLT3 or KIT tyrosine kinase
This is a dose escalation study of bortezomib. Patients are assigned to 1 of 2 treatment
groups. GROUP I (Dose levels 1-2): Patients receive oral midostaurin twice daily on days
1-14 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 3
courses in the absence of disease progression or unacceptable toxicity. GROUP II (Dose
levels 3-6): Patients receive mitoxantrone hydrochloride IV over 10 minutes, etoposide IV
over 1 hour, and cytarabine IV over 6 hours on days 1-6. Patients also receive oral
midostaurin twice daily on days 8-21 and bortezomib IV on days 8, 11, 15, and 18. Treatment
continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine maximum tolerated dose (MTD) of bortezomib and midostaurin in combination with MEC salvage chemotherapy
Maximum tolerated dose of bortezomib and midostaurin in combination with MEC(mitoxantrone, etoposide,cytarabine)salvage chemotherapy. Specific toxicities and Dose-limiting toxicity of midostaurin and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML.
up to 28 months
Alison Walker, MD
The Ohio State University James Cancer Hospital
United States: Food and Drug Administration
|The Ohio State University Medical Center||Columbus, Ohio 43210|