Clinical trial NCT03328936: 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
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Hematopoietic Cell Transplantation Recipient
Recurrent Plasma Cell Myeloma
Refractory Plasma Cell Myeloma
Lead sponsor: Ohio State University Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2017-11-01
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Complete response proportion
timeFrame: At 90 days
Secondary outcomes:
measure: Incidence of melphalan hydrochloride-related toxicities
timeFrame: Up to 3.5 years
measure: Minimal residual disease negative proportions
timeFrame: Pre-transplant
measure: Minimal residual disease negative proportions
timeFrame: up to 1 year
measure: Overall survival
timeFrame: time from randomization to death, assessed up to 3.5 years
measure: Progression free survival
timeFrame: Time from transplant to death, clinical relapse, progressive disease, and death in all treated patients, assessed up to 3.5 years
measure: Time to biochemical relapse
timeFrame: 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
measure: Time to progression
timeFrame: Time from start of melphalan hydrochloride until the criteria for disease progression are met, assessed up to 3.5 years
Other outcomes:
measure: Deoxyribonucleic acid (DNA) damage repair
timeFrame: Up to 3.5 years
measure: Half maximal inhibitory concentration (IC50)
timeFrame: Up to 3.5 years
measure: Melphalan hydrochloride pharmacokinetics (PK) parameters
timeFrame: Within 2 hours prior to start of melphalan hydrochloride infusion and at 5, 30, 45, and 60 minutes, and 3 and 6 hours
measure: p53 messenger ribonucleic acid
timeFrame: Up to 3.5 years
measure: Phosphorylated TP53
timeFrame: Up to 3.5 years
measure: PK/pharmacodynamics (PD) model
timeFrame: Up to 3.5 years
measure: XRCC1 rs25487 and XRCC3 rs861529 variant alleles
timeFrame: Up to 3.5 years
Locations:
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center
name: Ashley Rosko, MD
role: PRINCIPAL_INVESTIGATOR
References: