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

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Brief Title

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

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 Description

      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 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Determine maximum tolerated dose (MTD) of bortezomib and midostaurin in combination with MEC salvage chemotherapy

Secondary Outcome

 determine the rate of complete remission (CR)

Condition

Acute Myeloid Leukemia

Intervention

midostaurin

Study Arms / Comparison Groups

 GROUP I (Dose levels 1-2):
Description:  Patients receive midostaurin orally (PO) twice daily on days 1-14 and bortezomib intravenously (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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

34

Start Date

August 2010

Completion Date

May 2016

Primary Completion Date

April 2014

Eligibility Criteria

        Inclusion Criteria

          -  Patients age >18 with relapsed or refractory acute myeloid leukemia by WHO criteria
             are eligible for dose levels 1 and 2. Patients age >18 and ≤ 70 with relapsed or
             refractory acute myeloid leukemia by WHO criteria are eligible for dose levels 3
             through 6. Patients with secondary AML are eligible

          -  If the patient has co-morbid medical illness, life expectancy attributed to this must
             be greater than 6 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status <2

          -  Patients must have adequate organ function as defined below:

               -  total bilirubin <2.0mg/dL or ≤1.5 ULN(institutional upper limit of normal)

               -  AST(aspartate aminotransferase)(SGOT)/ALT(Alanine aminotransferase) (SGPT) <2.5 X
                  institutional ULN

               -  creatinine <1.7 mg /dL

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation. If the patient does not agree, the patient is not
             eligible. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately

          -  Ability to understand and willingness to sign the written informed consent document

          -  Patients must have recovered from the toxicity of prior therapy to less than Grade 2

          -  Patients status post prior hematopoietic stem cell transplantation are eligible

        Exclusion criteria

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study. Hydroxyurea may be
             administered until initiation of treatment on the study

          -  Patients receiving any other investigational agents or patients that have received
             other investigational agents within 14 days of enrollment

          -  Patients with active central nervous system disease or with granulocytic sarcoma as
             sole site of disease

          -  Patients with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to midostaurin, bortezomib, mitoxantrone, etoposide
             or cytarabine that are not easily managed. Patient has a hypersensitivity to
             bortezomib, boron, or mannitol.

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements. As infection is a common feature of AML, patients with active infection
             are permitted to enroll provided that the infection is under control. Myocardial
             infarction within 6 months prior to enrollment or has New York Heart Association
             (NYHA) Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension,
             severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities. Prior to study entry, any ECG
             abnormality at screening has to be documented by the investigator as not medically
             relevant.

          -  Ejection fraction <50%

          -  Patients with serious medical or psychiatric illness likely to interfere with
             participation in this clinical study.

          -  Pregnant women or women who are breastfeeding are excluded from this study.

          -  Patients with pre-existing Grade 2 or higher neuropathy or other serious neurologic
             toxicity that would significantly increase risk of complications from bortezomib
             therapy are excluded.

          -  Patients with a known confirmed diagnosis of HIV infection (due to concern for
             increased toxicity with the regimen in combination with HAART) or active viral
             hepatitis.

          -  Patients with any pulmonary infiltrate including those suspected to be of infectious
             origin. In particular, patients with resolution of clinical symptoms of pulmonary
             infection but with residual pulmonary infiltrates on chest x-ray are not eligible
             until pulmonary infiltrates have completely resolved.

          -  Patients who have had any surgical procedure, excluding central venous catheter
             placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1.

          -  Patients with advanced malignant solid tumors are excluded.

          -  Patients with known impairment of gastrointestinal (GI) function or GI disease that
             may significantly alter the absorption of midostaurin.

          -  Patients with prior midostaurin treatment are excluded.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alison Walker, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01174888

Organization ID

OSU-09111

Secondary IDs

NCI-2010-01335

Responsible Party

Sponsor-Investigator

Study Sponsor

Alison Walker

Collaborators

 Novartis

Study Sponsor

Alison Walker, MD, Principal Investigator, The Ohio State University James Cancer Hospital


Verification Date

June 2016