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Study of Personalized Melphalan Dosing in the Setting of Autologous Transplant

Primary Purpose

Hematopoietic Cell Transplantation Recipient, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

Status

Withdrawn

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Laboratory Biomarker Analysis

Melphalan Hydrochloride

Pharmacological Study

About this trial

This is an interventional treatment trial for Hematopoietic Cell Transplantation Recipient

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm I (melphalan hydrochloride for 3-day severe neutropenia)

Arm II (melphalan hydrochloride or 5-day severe neutropenia))

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Complete response proportion

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.

Secondary Outcome Measures

Incidence of melphalan hydrochloride-related toxicities

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).

Minimal residual disease negative proportions

Will be assessed by standard next generation sequencing.

Minimal residual disease negative proportions

Will be assessed by standard next generation sequencing.

Overall survival

Will be assessed.

Progression free survival

Will be assessed.

Time to biochemical relapse

Will be assessed.

Time to progression

Will be assessed.

Full Information

NCT ID

NCT03328936

First Posted

October 3, 2017

Last Updated

February 19, 2020

Sponsor

Ohio State University Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT03328936

Brief Title

Study of Personalized Melphalan Dosing in the Setting of Autologous Transplant

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2020

Overall Recruitment Status

Withdrawn

Why Stopped

Sponsor decision

Study Start Date

September 1, 2018 (Anticipated)

Primary Completion Date

March 31, 2021 (Anticipated)

Study Completion Date

March 31, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Ohio State University Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematopoietic Cell Transplantation Recipient, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm I (melphalan hydrochloride for 3-day severe neutropenia)

Arm Type

Experimental

Arm Description

Arm Title

Arm II (melphalan hydrochloride or 5-day severe neutropenia))

Arm Type

Experimental

Arm Description

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.

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Drug

Intervention Name(s)

Melphalan Hydrochloride

Other Intervention Name(s)

Alkeran, Alkerana, Evomela

Intervention Description

Given personalized dose IV for predicted 3-day duration of severe neutropenia

Intervention Type

Drug

Intervention Name(s)

Melphalan Hydrochloride

Other Intervention Name(s)

Alkeran, Alkerana, Evomela

Intervention Description

Given personalized dose IV for predicted 5-day duration of severe neutropenia

Intervention Type

Other

Intervention Name(s)

Pharmacological Study

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Complete response proportion

Description

Time Frame

At 90 days

Secondary Outcome Measure Information:

Title

Incidence of melphalan hydrochloride-related toxicities

Description

Time Frame

Up to 3.5 years

Title

Minimal residual disease negative proportions

Description

Will be assessed by standard next generation sequencing.

Time Frame

Pre-transplant

Title

Minimal residual disease negative proportions

Description

Will be assessed by standard next generation sequencing.

Time Frame

up to 1 year

Title

Overall survival

Description

Will be assessed.

Time Frame

time from randomization to death, assessed up to 3.5 years

Title

Progression free survival

Description

Will be assessed.

Time Frame

Time from transplant to death, clinical relapse, progressive disease, and death in all treated patients, assessed up to 3.5 years

Title

Time to biochemical relapse

Description

Will be assessed.

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

Title

Time to progression

Description

Will be assessed.

Time Frame

Time from start of melphalan hydrochloride until the criteria for disease progression are met, assessed up to 3.5 years

Other Pre-specified Outcome Measures:

Title

Deoxyribonucleic acid (DNA) damage repair

Description

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.

Time Frame

Up to 3.5 years

Title

Half maximal inhibitory concentration (IC50)

Description

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.

Time Frame

Up to 3.5 years

Title

Melphalan hydrochloride pharmacokinetics (PK) parameters

Description

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.

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

Title

p53 messenger ribonucleic acid

Description

Will correlate with progression free survival.

Time Frame

Up to 3.5 years

Title

Phosphorylated TP53

Description

Will correlate with progression free survival.

Time Frame

Up to 3.5 years

Title

PK/pharmacodynamics (PD) model

Description

Will determine the parameter accuracy and precision of the newly integrated PK/PD model for absolute neutrophil count, mucositis, tachyarrhythmias, and disease progression.

Time Frame

Up to 3.5 years

Title

XRCC1 rs25487 and XRCC3 rs861529 variant alleles

Description

Will use Cox survival analysis, measure progression free survival of patients with XRCC1 rs25487 and XRCC3 rs861529 variant alleles compared to wild type.

Time Frame

Up to 3.5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ashley Rosko, MD

Organizational Affiliation

Ohio State University Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ohio State University Comprehensive Cancer Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

12. IPD Sharing Statement

Links:

URL

http://cancer.osu.edu

Description

The Jamesline

Learn more about this trial

Study of Personalized Melphalan Dosing in the Setting of Autologous Transplant

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