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Melphalan Hydrochloride in Treating Participants With Newly-Diagnosed Multiple Myeloma Undergoing Donor Stem Cell Transplantation

Primary Purpose

Plasma Cell Myeloma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Autologous Hematopoietic Stem Cell Transplantation
Filgrastim-sndz
Melphalan Hydrochloride
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Plasma Cell Myeloma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with non-relapsed multiple myeloma in complete response (CR), partial remission (PR), very good partial remission (VGPR), or symptomatic stable disease (no evidence of progression) including patients with light chain multiple myeloma (MM) detected in the serum by free light chain assay OR
  • Patients with non-secretory multiple myeloma (absence of a monoclonal protein [M protein] in serum as measured by electrophoresis [serum protein electrophoresis (SPEP)] and immunofixation (serum immunofixation electrophoresis [SIFE]) and the absence of Bence Jones protein in the urine [urine protein electrophoresis (UPEP)] defined by use of conventional electrophoresis and immunofixation [urine immunofixation electrophoresis (UIFE) techniques]) but with measurable disease on imaging studies like magnetic resonance imaging (MRI), computed tomography (CT) scan or positron emission tomography (PET) scan.
  • Patients who have received at least two cycles of initial systemic therapy and are within 2 to 12 months of the first dose. Mobilization therapy is not considered initial therapy.
  • Karnofsky performance score 70% or higher.
  • Left ventricular ejection fraction at rest > 40% within 3 months of registration.
  • Bilirubin < 2 x the upper limit of normal (except patients with Gilbert syndrome in whom bilirubin level of > 2 x upper normal limit will be allowed)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upper limit of normal.
  • Creatinine clearance of >= 40 mL/min, estimated or calculated using the Cockcroft-Gault equation.
  • Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC) > 50% of predicted value (corrected for hemoglobin) within 3 months of registration.
  • All female and male subjects of reproductive potential must consent to the use of effective contraceptive methods as advised by the study doctor during treatment.
  • Signed informed consent form.

Exclusion Criteria:

  • Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms).
  • Patients seropositive for the human immunodeficiency virus (HIV).
  • Patients with history of 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.
  • Patients participating in an investigational new drug protocol within 14 days before enrollment.
  • Female patients who are pregnant (positive beta-human chorionic gonadotropin [b-HCG]) or breast feeding.
  • Prior hematopoietic cell transplantation allogeneic or autologous (A prior autologous HCT will be allowed as long as it was part of tandem transplantation).
  • Prior organ transplant requiring immunosuppressive therapy

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group 1 (melphalan hydrochloride, HSCT, filgrastim)

Group 2 (melphalan hydrochloride, HSCT, filgrastim)

Arm Description

PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 30-60 minutes on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10^9/L.

PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10^9/L.

Outcomes

Primary Outcome Measures

Incidence of toxicity of melphalan hydrochloride
Toxicity will be defined as grade 4 mucositis or any grade 4 or 5 non-hematologic or non-infectious toxicity occurring within 30 days from the start of infusion.
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
The investigators will determine pharmacokinetic parameters such as Cmax for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
The investigators will determine pharmacokinetic parameters such as, Clearance for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
The investigators will determine pharmacokinetic parameters such as Half-life for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
The investigators will determine pharmacokinetic parameters such as AUC (area under the curve) for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).

Secondary Outcome Measures

Progression-free survival (PFS)
PFS will be computed from the date of Evomela injection to the last time of follow-up or the event of interest (progression or death). Unadjusted PFS distributions will be estimated by the Kaplan and Meier method.
Incidence of treatment related mortality (TRM)
TRM will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of TRM from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the Bayesian Model Averaging continual reassessment method (BMA-CRM).
Rate of minimal residual disease (MRD)
MRD negative is defined as absence of phenotypically aberrant clonal plasma cells by nerve growth factor (NGF) on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10^5 nucleated cells or higher. MRD will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of MRD from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the BMA-CRM.
Complete response rate (CR)
CR will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of CR from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the BMA-CRM.

Full Information

First Posted
January 24, 2018
Last Updated
October 23, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03417284
Brief Title
Melphalan Hydrochloride in Treating Participants With Newly-Diagnosed Multiple Myeloma Undergoing Donor Stem Cell Transplantation
Official Title
Prospective Phase I/II Trial to Jointly Optimize the Administration Schedule(s) and Dose(s) of Melphalan for Injection (Evomela) as a Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 9, 2019 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson 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
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I/II trial studies the side effects and best dose of melphalan hydrochloride in treating participants with newly-diagnosed multiple myeloma who are undergoing a donor stem cell transplantation. Giving chemotherapy before a donor stem cell transplantation helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant, they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving melphalan hydrochloride before a donor stem cell transplantation may work better than standard chemotherapy in helping to prevent multiple myeloma from coming back.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the optimal dose and schedule of melphalan for injection (melphalan hydrochloride [Evomela]) prior to autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma (MM). II. To collect the pharmacokinetic data and compare the exposure-response evaluations between the 2 infusion schedules. SECONDARY OBJECTIVES: I. To determine the incidence of treatment related mortality (TRM) at day 90 after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. II. To determine the rate of minimal residual disease (MRD) negative complete response (CR) rate at day 90 after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. III. To determine the progression-free survival (PFS) after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. OUTLINE: This is a phase I, dose escalation study of melphalan hydrochloride followed by a phase II study. PREPARATIVE REGIMEN: Participants are randomized to 1 of 2 groups. GROUP 1: Participants receive melphalan hydrochloride intravenously (IV) over 30-60 minutes on day -2. GROUP 2: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz subcutaneously (SC) once daily (QD) starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an absolute neutrophil count (ANC) of 0.5 x 10^9/L. After completion of study treatment, participants are followed up at 3 months, every 3 months for 1 year, and then annually for 1 year.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1 (melphalan hydrochloride, HSCT, filgrastim)
Arm Type
Experimental
Arm Description
PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 30-60 minutes on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10^9/L.
Arm Title
Group 2 (melphalan hydrochloride, HSCT, filgrastim)
Arm Type
Experimental
Arm Description
PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10^9/L.
Intervention Type
Procedure
Intervention Name(s)
Autologous Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
AHSCT, Autologous Hematopoietic Cell Transplantation, Autologous Stem Cell Transplantation, Stem Cell Transplantation, Autologous
Intervention Description
Undergo HSCT
Intervention Type
Biological
Intervention Name(s)
Filgrastim-sndz
Other Intervention Name(s)
Filgrastim Biosimilar Filgrastim-sndz, Zarxio
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Melphalan Hydrochloride
Other Intervention Name(s)
Alkeran, Alkerana, Evomela
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Incidence of toxicity of melphalan hydrochloride
Description
Toxicity will be defined as grade 4 mucositis or any grade 4 or 5 non-hematologic or non-infectious toxicity occurring within 30 days from the start of infusion.
Time Frame
Within 30 days after the start of infusion
Title
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
Description
The investigators will determine pharmacokinetic parameters such as Cmax for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
Time Frame
Up to 1 year
Title
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
Description
The investigators will determine pharmacokinetic parameters such as, Clearance for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
Time Frame
Up to 1 year
Title
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
Description
The investigators will determine pharmacokinetic parameters such as Half-life for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
Time Frame
Up to 1 year
Title
The Pharmacokinetics of melphalan hydrochloride parameters will assessed.
Description
The investigators will determine pharmacokinetic parameters such as AUC (area under the curve) for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis).
Time Frame
Up to 1 year
Secondary Outcome Measure Information:
Title
Progression-free survival (PFS)
Description
PFS will be computed from the date of Evomela injection to the last time of follow-up or the event of interest (progression or death). Unadjusted PFS distributions will be estimated by the Kaplan and Meier method.
Time Frame
From the date of Evomela injection up to 1 year
Title
Incidence of treatment related mortality (TRM)
Description
TRM will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of TRM from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the Bayesian Model Averaging continual reassessment method (BMA-CRM).
Time Frame
At day 90 post-transplant
Title
Rate of minimal residual disease (MRD)
Description
MRD negative is defined as absence of phenotypically aberrant clonal plasma cells by nerve growth factor (NGF) on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10^5 nucleated cells or higher. MRD will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of MRD from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the BMA-CRM.
Time Frame
At day 90 post-transplant
Title
Complete response rate (CR)
Description
CR will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of CR from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the BMA-CRM.
Time Frame
At 90 days post-transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with non-relapsed multiple myeloma in complete response (CR), partial remission (PR), very good partial remission (VGPR), or symptomatic stable disease (no evidence of progression) including patients with light chain multiple myeloma (MM) detected in the serum by free light chain assay OR Patients with non-secretory multiple myeloma (absence of a monoclonal protein [M protein] in serum as measured by electrophoresis [serum protein electrophoresis (SPEP)] and immunofixation (serum immunofixation electrophoresis [SIFE]) and the absence of Bence Jones protein in the urine [urine protein electrophoresis (UPEP)] defined by use of conventional electrophoresis and immunofixation [urine immunofixation electrophoresis (UIFE) techniques]) but with measurable disease on imaging studies like magnetic resonance imaging (MRI), computed tomography (CT) scan or positron emission tomography (PET) scan. Patients who have received at least two cycles of initial systemic therapy and are within 2 to 12 months of the first dose. Mobilization therapy is not considered initial therapy. Karnofsky performance score 70% or higher. Left ventricular ejection fraction at rest > 40% within 3 months of registration. Bilirubin < 2 x the upper limit of normal (except patients with Gilbert syndrome in whom bilirubin level of > 2 x upper normal limit will be allowed) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upper limit of normal. Creatinine clearance of >= 40 mL/min, estimated or calculated using the Cockcroft-Gault equation. Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC) > 50% of predicted value (corrected for hemoglobin) within 3 months of registration. All female and male subjects of reproductive potential must consent to the use of effective contraceptive methods as advised by the study doctor during treatment. Signed informed consent form. Exclusion Criteria: Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients seropositive for the human immunodeficiency virus (HIV). Patients with history of 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. Patients participating in an investigational new drug protocol within 14 days before enrollment. Female patients who are pregnant (positive beta-human chorionic gonadotropin [b-HCG]) or breast feeding. Prior hematopoietic cell transplantation allogeneic or autologous (A prior autologous HCT will be allowed as long as it was part of tandem transplantation). Prior organ transplant requiring immunosuppressive therapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qaiser Bashir
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
University of Texas MD Anderson Cancer Center Website

Learn more about this trial

Melphalan Hydrochloride in Treating Participants With Newly-Diagnosed Multiple Myeloma Undergoing Donor Stem Cell Transplantation

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