Low Dose Melphalan and Bortezomib for AML and High-Risk MDS

October 22, 2018 updated by: Marc Gautier, Dartmouth-Hitchcock Medical Center

A Pilot Study of Low Dose Melphalan and Bortezomib for Treatment of Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndromes

The purpose of this study is to determine the response rate of the combination of bortezomib and melphalan in patients with Acute Myelogenous Leukemia (AML) or high-risk Myelodysplastic Syndromes (MDS).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In patients who develop acute myelogenous leukemia (AML) or a high-risk myelodysplastic syndrome (MDS), the current standard treatment involves multidrug induction chemotherapy utilizing an anthracycline or anthraquinone with cytarabine. While chemotherapy has proven effective at inducing remission in up to 90% of patients, elderly patients fair far worse. In patients over the age of sixty, the disease is not only less responsive to therapy, but an increased number of comorbid conditions makes induction therapy a more dangerous endeavor. Because of this, many patients are not offered standard induction chemotherapy and there is a dearth of viable alternatives for treatment of these otherwise fatal diseases.

Low dose melphalan has previously been shown to be an effective palliative treatment for patients diagnosed with AML and high-risk MDS. It was found to have an overall response rate of 40% in AML patients (30% complete remission and 10% partial remission) and a 57% overall response in high-risk MDS patients (33% complete remission, 5% partial remission, and 19% minor responses). This therapy, while not curative, is one of the few options for patients unable to tolerate more intensive treatment regimens, but desiring a potentially effective palliative regimen.

Bortezomib (VELCADE®) is an intravenously administered reversible, selective inhibitor of the 26S proteosome. Although all of the mechanisms by which this novel drug acts as an antineoplastic agent are not fully understood, in vivo and in vitro studies indicate they ultimately result in the inhibition of the gene expression necessary for cell growth and survival pathways, apoptotic pathways, and cellular adhesion, migration, and angiogenesis mechanisms.

Preclinical and clinical evaluation of the combination of melphalan and bortezomib has demonstrated impressive synergy in refractory multiple myeloma cell lines and patients with myeloma. This study aims to determine if these findings hold true in AML and MDS patients.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Jacksonville, Florida, United States, 32256
        • Integrated Community Oncology Network
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03756
        • Dartmouth-Hitchcock Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Pathologic diagnosis of AML or high-risk MDS Patients with chronic myelomonocytic leukemia or a refractory cytopenia with multilineage dysplasia are eligible if that have one of the following criteria:

    • >4 units of red blood cells transfused during the previous 3 months
    • platelet count <50,000/uL
    • absolute neutrophil count <1000/uL and a recent infection requiring antibiotics
  • Patients may either be considered to be poor candidates for standard induction chemotherapy based on reasonable medical evidence or have declined such therapy, but still desire palliative treatment beyond that of best supportive care
  • Primary refractory disease or have disease that has relapsed after prior cytoxic therapy
  • Karnofsky performance status of >50%
  • Patients may receive prior growth factor therapy
  • Patients who received prior therapies (ex. melphalan, 5-azacitidine, low-dose cytarabine) to control their MDS or AML prior to registration (Stratum 2), but are clearly nonresponders are eligible for enrollment if expected toxicity of the prior therapy has resolved
  • Voluntary written informed consent
  • If female, the 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
  • If male, the subject agrees to use an acceptable method for contraception for the duration of the study

  • Patients that have been previously treated will be eligible for study if:

    1. the previous therapy was ineffective and
    2. all expected toxicity of the previous treatment has resolved

    3. In general the following guidelines regarding the elapsed time from previous treatment to eligibility should be followed

      1. High intensity cytotoxic treatment (7&3 induction, High Dose Ara-C): 4 weeks
      2. Hematopoeitic growth factors: no delay required
      3. Low intensity treatment (such as oral melphalan or hydrea, low dose cytarabine or 5-azacitidine) No delay required if expected toxicity has resolved and regimen ineffective

Exclusion Criteria:

  • AML FAB M3
  • No concomitant malignancy other than a curatively treated carcinoma in situ of cervix or basal or squamous cell carcinoma of the skin
  • Active, uncontrolled infections
  • Chronic liver disease not due to AML, or bilirubin >2.0mg/dL
  • End stage kidney disease on dialysis
  • Active CNS disease. A lumbar puncture prior to treatment is not required and should not be performed in the absence of significant CNS symptoms or signs
  • Patient has sensory peripheral neuropathy > grade 2 or painful peripheral neuropathy > grade 1 (see appendix A for NCI sensory neuropathy toxicity criteria) within 14 days before enrollment
  • Hypersensitivity to bortezomib, boron or mannitol
  • Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Study treatment
All patients will receive the following regimen: 1) Melphalan 2 mg orally, once daily. 2) Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11.
Drug: Melphalan
Melphalan: 2mg orally, once daily
Other Names:
  • Velcade
Drug: Bortezomib
Bortezomib: 1.0mg/M2 IV on days 1, 4, 8, 11
Drug: Melphalan and bortezomib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Rate of the Combination of Bortezomib and Melphalan in Patients With AML and High-risk MDS.
Time Frame: Post Cycle 1 through 28 days post-treatment
Determine disease response to treatment using Cheson 2000 report of an international working group to standardize response criteria for myelodysplastic syndromes.
Post Cycle 1 through 28 days post-treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determine Safety Profile of the Combination of Bortezomib and Melphalan.
Time Frame: Start of treatment through 28 days post-treatment
The safety profile is based on the number of adverse events experienced by participants as reported in the Adverse Events results section for this protocol.
Start of treatment through 28 days post-treatment
Number of Participants With Correlation Between in Vitro and in Vivo Activity of the Combination of Bortezomib and Melphalan.
Time Frame: Pre-treatment and at complete response
Leukemic cells will be collected to test the presence of the study drugs using a cell viability assay in vitro and in vivo.
Pre-treatment and at complete response

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dartmouth-Hitchcock Medical Center

Collaborators

Millennium Pharmaceuticals, Inc.

Investigators

  • Principal Investigator: Marc Gautier, MD, Dartmouth-Hitchcock Medical Center
  • Principal Investigator: Jeffrey Bubis, DO, Integrated Community Oncology Network

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2004

Primary Completion (ACTUAL)

December 1, 2008

Study Completion (ACTUAL)

December 1, 2008

Study Registration Dates

First Submitted

October 6, 2008

First Submitted That Met QC Criteria

November 10, 2008

First Posted (ESTIMATE)

November 11, 2008

Study Record Updates

Last Update Posted (ACTUAL)

October 24, 2018

Last Update Submitted That Met QC Criteria

October 22, 2018

Last Verified

October 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D0337

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Myelodysplastic Syndromes

Clinical Trials on Melphalan

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Venezuela

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe