Clinical Trial: Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase I Study of the Combination of Midostaurin, Bortezomib, and Chemotherapy in Relapsed/Refractory Acute Myeloid Leukemia

Brief Summary:

RATIONALE: Bortezomib and midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and midostaurin together with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with midostaurin with or without combination chemotherapy in treating patients with relapsed or refractory acute myeloid leukemia.


Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of bortezomib in combination with midostaurin and intensive chemotherapy in patients with relapsed/refractory acute myeloid leukemia (AML).

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.

SECONDARY OBJECTIVES:

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 mutations.

OUTLINE:

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 ev
Sponsor: Alison Walker

Current Primary Outcome: Determine maximum tolerated dose (MTD) of bortezomib and midostaurin in combination with MEC salvage chemotherapy [ Time Frame: up to 28 months ]

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.


Original Primary Outcome: Determine MTD of bortezomib and midostaurin in combination with MEC salvage chemotherapy [ Time Frame: 24 months ]

Maximum tolerated dose of bortezomib and midostaurin in combination with MEC salvage chemotherapy Specific toxicities and Dose-limiting toxicity of midostaurin and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML


Current Secondary Outcome:

  • determine the rate of complete remission (CR) [ Time Frame: up to 28 months ]
    To determine the rate of complete remission (CR) of midostaurin and bortezomib in combination with intensive chemotherapy.
  • Determine the overall response rate (ORR) [ Time Frame: up to 28 months ]
    To determine the overall response rate (ORR)
  • Characterize the biological activity of midostaurin and bortezomib [ Time Frame: up to 28 months ]
    Characterize the biological activity of midostaurin and bortezomib to potentially increase endogenous phosphatase activity and therefore inhibit aberrant tyrosine kinases by assessing FLT3(fetal liver kinase-2)and KIT tyrosine kinase activity as well as SHP-1 phosphatase activity.
  • Correlate the biological activity of midostaurin and bortezomib [ Time Frame: up to 28 months ]
    To correlate the biological activity of midostaurin and bortezomib to potentially increase endogenous phosphatase activity with clinical response.
  • Conduct pharmacokinetic studies of midostaurin and bortezomib [ Time Frame: up to 28 months ]
    To conduct pharmacokinetic studies of midostaurin and bortezomib together and in combination with intensive chemotherapy.
  • Determine the efficacy of midostaurin and bortezomib [ Time Frame: up to 28 months ]
    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 mutations.


Original Secondary Outcome:

Information By: Ohio State University Comprehensive Cancer Center

Dates:
Date Received: August 2, 2010
Date Started: August 2010
Date Completion:
Last Updated: July 4, 2016
Last Verified: June 2016