Study of Personalized Melphalan Dosing in the Setting of Autologous Transplant

February 19, 2020 updated by: Ashley Rosko, Ohio State University Comprehensive Cancer Center

Randomized Study of Personalized Melphalan Dosing in the Setting of Autologous Transplant

This randomized phase II trial studies the side effects and how well melphalan hydrochloride works in treating patients with multiple myeloma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as melphalan hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

PRIMARY OBJECTIVES:

I. Identify whether targeting approximate (approx.) 3- or 5-days of severe neutropenia after exposure to a personalized melphalan hydrochloride (melphalan) dose results in best clinical outcome.

II. Measure melphalan-related toxicities in both 3-day and 5-day arms. III. Measure response per International Myeloma Working Group (IMWG). IV. Record overall survival (OS) and progression free survival (PFS).

SECONDARY OBJECTIVES:

I. To administer a test dose of melphalan and obtain test dose melphalan pharmacokinetics (PK) data from the first 33 patients.

II. Measure drug-induced deoxyribonucleic acid (DNA) damage in peripheral blood mononuclear cells (PBMCs) treated with melphalan ex vivo post exposure.

III. Measure drug-induced DNA damage in patient myeloma cells treated with melphalan ex vivo.

IV. Assess melphalan-induced DNA damage in treated patients. V. Measure allele and genotype frequencies of variants, as well as gene expression of XRCC1 rs25487 and XRCC3 rs861529.

VI. Additional genetic variants relevant to DNA repair, melphalan transport, and clinical toxicities may be tested as well.

VII. Test cytotoxicity (half maximal inhibitory concentration [IC50]) of patient PBMCs prior to autologous transplant after exposure to melphalan ex vivo.

VIII. Measure p53 and phospho(TP53) in patient PBMCs prior to autologous transplant at baseline and after exposure to melphalan ex vivo.

IX. Incorporate both disease progression and drug-related toxicities into separate models linked to our calculated melphalan area under the curve (AUC) model.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients receive personalized dose of melphalan hydrochloride intravenously (IV) on day -2 for predicted 3-day duration of severe neutropenia and undergo standard of care autologous stem cell transplant on day 0.

ARM II: Patients receive personalized dose of melphalan hydrochloride IV on day -2 for predicted 5-day duration of severe neutropenia and undergo standard of care autologous stem cell transplant on day 0.

After completion of study treatment, patients are followed up for 30 days, at 3 months after transplant, and then every 6-12 months.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

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
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patient must have relapsed or refractory myeloma that fits or did fit IMWG diagnostic criteria for multiple myeloma; patients with AL amyloidosis and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) are excluded; measurable disease is not required
  • Patient undergoing autologous transplant as part of first line therapy
  • All races and ethnic groups are eligible for this study
  • Patients must also have an adequate autologous graft as defined as a cryopreserved peripheral blood stem cell (PBSC) graft containing > 2 x 10^6 CD34+ cells/kg patient weight
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%) is required for eligibility; those patients with lower performance status based solely on bone pain secondary to multiple myeloma are eligible
  • Absolute neutrophil count (ANC) > 1000/uL
  • Platelet count > 50,000
  • Transfusion independent
  • Total bilirubin < 1.5 mg/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x the institutional upper limit of normal
  • Left ventricular ejection fraction >= 40%
  • Carbon monoxide diffusing capability (DLCO) > 50% predicted
  • Forced expiratory volume in 1 second (FEV1) > 50% predicted
  • Forced vital capacity (FVC) > 50% predicted
  • Ability to understand and willingness to sign a written informed consent document
  • Females of childbearing potential (FCBP) must not be pregnant as per institutional standard; if no institutional standard exists, then patients must have a negative serum or urine pregnancy test prior to transplant; a female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Exclusion Criteria:

  • Patients who are receiving any other anti-myeloma investigational agents
  • Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the preceding 6 months, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued
  • Patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, shorten survival to < 1 year, or confound data interpretation
  • Concurrent use of complementary or alternative medicines that in the opinion of the principal investigator would confound the interpretation of toxicities and/or antitumor activity of the study drug

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Arm I (melphalan hydrochloride for 3-day severe neutropenia)
Patients receive personalized dose of melphalan hydrochloride IV on day -2 for for predicted 3-day duration of severe neutropenia and undergo standard of care autologous stem cell transplant on day 0.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Melphalan Hydrochloride
Given personalized dose IV for predicted 3-day duration of severe neutropenia
Other Names:
  • Alkeran
  • Evomela
  • Alkerana
Drug: Melphalan Hydrochloride
Given personalized dose IV for predicted 5-day duration of severe neutropenia
Other Names:
  • Alkeran
  • Evomela
  • Alkerana
Experimental: Arm II (melphalan hydrochloride or 5-day severe neutropenia))
Patients receive personalized dose of melphalan hydrochloride IV on day -2 for predicted 5-day duration of severe neutropenia and undergo standard of care autologous stem cell transplant on day 0.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Melphalan Hydrochloride
Given personalized dose IV for predicted 3-day duration of severe neutropenia
Other Names:
  • Alkeran
  • Evomela
  • Alkerana
Drug: Melphalan Hydrochloride
Given personalized dose IV for predicted 5-day duration of severe neutropenia
Other Names:
  • Alkeran
  • Evomela
  • Alkerana

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Complete response proportion
Time Frame: At 90 days
Complete response will be defined as complete response + stringent complete response according to the International Myeloma Working Group Uniform response criterion. Will be calculated with an exact 95% confidence interval, both within arms and across arms.
At 90 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of melphalan hydrochloride-related toxicities
Time Frame: Up to 3.5 years
Will assess melphalan-related toxicities (possibly, probably, or definitely related to high dose melphalan) including the incidence of grade 3/4 mucositis, grade 3/4 bacteremia, length of inpatient stay, duration of severe neutropenia (absolute neutrophil count < 500), duration of severe thrombocytopenia (Platelet < 20K), and proportion with tachyarrhythmias (e.g. atrial fibrillation with rapid ventricular rate).
Up to 3.5 years
Minimal residual disease negative proportions
Time Frame: Pre-transplant
Will be assessed by standard next generation sequencing.
Pre-transplant
Minimal residual disease negative proportions
Time Frame: up to 1 year
Will be assessed by standard next generation sequencing.
up to 1 year
Overall survival
Time Frame: time from randomization to death, assessed up to 3.5 years
Will be assessed.
time from randomization to death, assessed up to 3.5 years
Progression free survival
Time Frame: Time from transplant to death, clinical relapse, progressive disease, and death in all treated patients, assessed up to 3.5 years
Will be assessed.
Time from transplant to death, clinical relapse, progressive disease, and death in all treated patients, assessed up to 3.5 years
Time to biochemical relapse
Time Frame: Time from start of melphalan hydrochloride until the earliest of the following time points: progressive disease, clinical relapse, or relapse from complete response, assessed up to 3.5 years
Will be assessed.
Time from start of melphalan hydrochloride until the earliest of the following time points: progressive disease, clinical relapse, or relapse from complete response, assessed up to 3.5 years
Time to progression
Time Frame: Time from start of melphalan hydrochloride until the criteria for disease progression are met, assessed up to 3.5 years
Will be assessed.
Time from start of melphalan hydrochloride until the criteria for disease progression are met, assessed up to 3.5 years

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Deoxyribonucleic acid (DNA) damage repair
Time Frame: Up to 3.5 years
Will compare DNA damage repair efficiency in patients that have minimal response to induction and high dose melphalan hydrochloride (partial response or less) compared to those that are sequencing minimal residual disease negative.
Up to 3.5 years
Half maximal inhibitory concentration (IC50)
Time Frame: Up to 3.5 years
Will create a multivariate linear regression model that includes each patient?s IC50, DNA repair gene single nucleotide polymorphism (SNP) presence or absence, and revised Multiple Myeloma International Staging System with progression free survival as the outcome.
Up to 3.5 years
Melphalan hydrochloride pharmacokinetics (PK) parameters
Time Frame: Within 2 hours prior to start of melphalan hydrochloride infusion and at 5, 30, 45, and 60 minutes, and 3 and 6 hours
Will compare the prediction accuracy of melphalan hydrochloride pharmacokinetics using the test dose versus the current PK model. Test the use of aspects of test dose PK as a covariate in the current high dose melphalan hydrochloride prediction model.
Within 2 hours prior to start of melphalan hydrochloride infusion and at 5, 30, 45, and 60 minutes, and 3 and 6 hours
p53 messenger ribonucleic acid
Time Frame: Up to 3.5 years
Will correlate with progression free survival.
Up to 3.5 years
Phosphorylated TP53
Time Frame: Up to 3.5 years
Will correlate with progression free survival.
Up to 3.5 years
PK/pharmacodynamics (PD) model
Time Frame: Up to 3.5 years
Will determine the parameter accuracy and precision of the newly integrated PK/PD model for absolute neutrophil count, mucositis, tachyarrhythmias, and disease progression.
Up to 3.5 years
XRCC1 rs25487 and XRCC3 rs861529 variant alleles
Time Frame: Up to 3.5 years
Will use Cox survival analysis, measure progression free survival of patients with XRCC1 rs25487 and XRCC3 rs861529 variant alleles compared to wild type.
Up to 3.5 years

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Ohio State University Comprehensive Cancer Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Cancer Institute (NCI)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ashley Rosko, MD, Ohio State University Comprehensive Cancer Center

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.

Helpful Links

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 (Anticipated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2018

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 31, 2021

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 3, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 31, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
November 1, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 21, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 19, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • OSU-17082
  • P30CA016058 (U.S. NIH Grant/Contract)
  • NCI-2017-01702 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

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.

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