Bortezomib, Mitoxantrone, Etoposide, and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia

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Brief Title

Bortezomib, Mitoxantrone, Etoposide, and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia

Official Title

A Phase I Study of Bortezomib in Combination With MEC (Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine) for Relapsed/ Refractory Acute Myelogenous Leukemia (AML)

Brief Summary

      RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes
      needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, 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 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 mitoxantrone, etoposide, and cytarabine in treating patients with
      relapsed or refractory acute myeloid leukemia.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the DLT, MTD, and the recommended Phase 2 dose of bortezomib in combination
      with MEC in patients with relapsed/refractory AML.

      SECONDARY OBJECTIVES:

      I. To describe the non-dose limiting toxicities associated with bortezomib in combination
      with MEC in patients with relapsed/refractory AML.

      II. To describe any preliminary evidence of clinical activity of this combination (CR rate)
      in relapsed/refractory AML.

      III. To determine the median CD74 antigen expression in patients achieving a response versus
      those patients not achieving a response.

      OUTLINE:

      This is a dose-escalation study of bortezomib.

      Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8 and 11; and mitoxantrone IV,
      etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6.
      Treatment continues in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4-5 weeks.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

MTD of bortezomib

Secondary Outcome

 Non-dose limiting toxicities

Condition

Adult Acute Megakaryoblastic Leukemia (M7)

Intervention

bortezomib

Study Arms / Comparison Groups

 Arm I
Description:  Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8 and 11; and mitoxantrone IV, etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6. Treatment continues 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

3

Start Date

July 2010

Completion Date

May 2014

Primary Completion Date

May 2014

Eligibility Criteria

        Inclusion

          -  Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the subject at any time without prejudice to future medical care

          -  Female subject is either post-menopausal or surgically sterilized or willing to use an
             acceptable method of birth control (ie., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study; female subject is not lactating

          -  Male subject agrees to use an acceptable method for contraception for the duration of
             the study

          -  Relapsed or refractory AML (excluding acute promyelocytic leukemia), based on World
             Health Organization Classification; all other subtypes of AML will be eligible;
             refractory disease will be considered failure to respond to 2 cycles of induction
             chemotherapy (7+3 and 5+2); any number of relapses will be eligible

          -  No evidence of leptomeningeal disease; a lumbar puncture does not need to be performed
             unless there is clinical suspicion of leptomeningeal disease

          -  Previous treatment related toxicities must have resolved to Grade 1 (excluding
             alopecia)

          -  Liver enzymes (AST and ALT) can not be greater than 2.5 times the upper limits of
             normal (ULN), and total bilirubin =< 1.5 x ULN within 14 days of enrollment

          -  Renal function: Serum creatinine should be =< 1.5 x ULN within 14 days of enrollment

          -  No serious or poorly controlled medical conditions that could be exacerbated by
             treatment or that would seriously complicate compliance with the protocol

          -  ECOG performance status 0-3

          -  No peripheral neuropathy >= Grade 2 within 14 days of trial enrollment

          -  Echocardiogram or MUGAs scan demonstrating an ejection fraction >= 45%

          -  Patients with secondary AML, and patients with a prior autologous and allogeneic bone
             marrow transplant are eligible

          -  Patients with an allogeneic transplant must meet the following conditions: the
             transplant must have been performed more than 90 days before registration to this
             study, the patient must not have >= Grade 2 acute graft versus host disease (GvHD), or
             either moderate or severe limited chronic GvHD, or extensive chronic GvHD of any
             severity; the patient must be off all immunosuppression for at least 2 weeks

          -  No uncontrolled infections

          -  No history of hypersensitivity to boron or mannitol

          -  No known history of HIV or active hepatitis B or C

          -  No major surgery within 4 weeks prior to trial enrollment

        Exclusion

          -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure, uncontrolled angina, 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

          -  Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment

          -  Female subject is pregnant or breast-feeding; confirmation that the subject is not
             pregnant must be established by a negative serum beta-human chorionic gonadotropin
             (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not
             required for post-menopausal or surgically sterilized women

          -  Patient has received any standard or investigational therapy for their leukemia within
             14 days before enrollment (except for hydrea)

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study

          -  Patients with prior malignancy are eligible; however, the patient must be in remission
             from the prior malignancy and have completed all chemotherapy and radiotherapy at
             least 6 months prior to registration and all treatment-related toxicities must have
             resolved

          -  Leptomeningeal/ central nervous system involvement with AML; a lumbar puncture does
             not need to be performed unless there is clinical suspicion

          -  Patients who have had prior pulmonary radiation

          -  Prohibited Concurrent Therapy: any investigational agent other than VELCADE; G-CSF and
             GM-CSF are not allowed
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Anjali Advani, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01127009

Organization ID

CASE4909

Secondary IDs

NCI-2010-01203

Responsible Party

Sponsor

Study Sponsor

Case Comprehensive Cancer Center


Study Sponsor

Anjali Advani, Principal Investigator, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center


Verification Date

August 2015