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

This study is currently recruiting participants.
Verified May 2013 by Ohio State University Comprehensive Cancer Center
Sponsor:
Collaborators:
Novartis
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Alison Walker, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01174888
First received: August 2, 2010
Last updated: May 6, 2013
Last verified: May 2013
History of Changes
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia
Acute Myeloid Leukemia With Multilineage Dysplasia Following
Myelodysplastic Syndrome
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
 Drug: midostaurin
Drug: Bortezomib
Drug: mitoxantrone hydrochloride
Drug: etoposide
Drug: cytarabine
 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of the Combination of Midostaurin, Bortezomib, and Chemotherapy in Relapsed/Refractory Acute Myeloid Leukemia

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Ohio State University Comprehensive Cancer Center:

Primary Outcome Measures:
  • Determine maximum tolerated dose (MTD) of bortezomib and midostaurin in combination with MEC salvage chemotherapy [ Time Frame: up to 28 months ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • determine the rate of complete remission (CR) [ Time Frame: up to 28 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    To determine the overall response rate (ORR)

  • Characterize the biological activity of midostaurin and bortezomib [ Time Frame: up to 28 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 21
Study Start Date: August 2010
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GROUP I (Dose levels 1-2):
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.
 Drug: midostaurin
Drug midostaurin, Given orally given twice daily days 1-14
Other Names:
  • N-benzoyl-staurosporine
  • PKC412
Drug: Bortezomib
Bortezomib given IV on days 1, 4, 8, and 11
Other Names:
  • LDP 341
  • MLN341
  • PS-341
  • VELCADE
Experimental: 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 midostaurin PO 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.
 Drug: midostaurin
Drug midostaurin, Given orally given twice daily days 1-14
Other Names:
  • N-benzoyl-staurosporine
  • PKC412
Drug: Bortezomib
Bortezomib given IV on days 1, 4, 8, and 11
Other Names:
  • LDP 341
  • MLN341
  • PS-341
  • VELCADE
Drug: mitoxantrone hydrochloride
Patients receive mitoxantrone hydrochloride IV over 10 minutes
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • dihydroxyanthracenedione
  • mitoxantrone HCl
  • Novantrone
Drug: etoposide
Patients receive etoposide IV over 1 hour
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • epipodophyllotoxin
  • VePesid
  • VP-16
  • VP-16-213
Drug: cytarabine
Patients receive cytarabine IV over 6 hours on days 1-6
Other Names:
  • ARA-C
  • ARA-cell
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01174888

Contacts
Contact: Ohio State University Comprehensive Cancer Center 1-800-293-5066 Jamesline@osumc.edu
Contact: Alison Walker, MD 614-366-3802 Alison.Walker@osumc.edu

Locations
United States, Ohio
The Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Alison Walker, MD     614-366-3802     alison.walker@osumc.edu    
Principal Investigator: Alison Walker, MD            
Sub-Investigator: Leslie Andritsos, MD            
Sub-Investigator: Robert Baiocchi, MD            
Sub-Investigator: Don Benson, MD            
Sub-Investigator: Bill Blum, MD            
Sub-Investigator: John Byrd, MD            
Sub-Investigator: Steven Devine, MD            
Sub-Investigator: Joseph Flynn, DO            
Sub-Investigator: Ramiro Garzon, MD            
Sub-Investigator: Jeffrey Jones, MD            
Sub-Investigator: Rebecca Klisovic, MD            
Sub-Investigator: Guido Marcucci, MD            
Sponsors and Collaborators
Alison Walker
Novartis
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Alison Walker, MD The Ohio State University James Cancer Hospital
  More Information

Additional Information:
Jamesline  This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party: Alison Walker, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01174888     History of Changes
Other Study ID Numbers: OSU-09111, NCI-2010-01335
Study First Received: August 2, 2010
Last Updated: May 6, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Ohio State University Comprehensive Cancer Center:
Acute Myeloid Leukemia
AML

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Etoposide phosphate
4'-N-benzoylstaurosporine
Bortezomib
 Etoposide
Mitoxantrone
Podophyllotoxin
Staurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 13, 2013