Pharmacokinetic Study of Propylene Glycol-Free Melphalan HCl for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT02669615
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arm: 1
• Actual Duration (Months): 8.5
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

This study is a single-center, open-label study of high-dose Melphalan HCl (hydrochloric acid) for injection (propylene glycol-free Melphalan) conducted in 24 patients, who have symptomatic multiple myeloma and qualify for autologous stem-cell transplantation (ASCT).

There will be three distinct evaluation periods in this trial: a pretreatment period, a study period and a follow-up period.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Melphalan HCl for injection (propylene glycol free)	Phase 2

Detailed Description

OVERVIEW: This study is a single-center, open-label study of high-dose Melphalan HCl for injection (propylene glycol free Melphalan) conducted in 24 patients, who have symptomatic multiple myeloma and qualify for ASCT.

There will be three distinct evaluation periods in this trial: a pretreatment period, a study period and a follow-up period.

PRETREATMENT:

Pretreatment Period Evaluations (Days -30 to -3). Baseline assessments will be collected within 30 days of dosing with Melphalan HCl for injection (propylene glycol free), after the patient has signed the informed consent. These include clinical and laboratory assessments (e.g., medical history and physical examination, hematology, urine analysis, creatinine clearance), chest X-ray and vital signs.

STUDY TREATMENT:

1. During the study period, patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day

2. Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0).

3. Pharmacokinetic, efficacy and safety evaluations will be performed during the study period.

FOLLOW-UP:

ASCT Day +1 until Day+100. During the follow-up period, patients will return for daily laboratory tests (hematology and basic serum chemistry) and will be evaluated weekly by their physicians until the engraftment date, with the final end-of-study evaluation occurring up to seven days after engraftment date. During the follow-up period, the tests (e.g., physical examination, CBC, vital signs, full serum chemistry panel, bone marrow biopsy) will be performed weekly until engraftment (unless otherwise specified).

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-Label, Pharmacokinetic Study of Propylene Glycol-Free Melphalan HCl for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation
• Actual Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jun 9, 2017
• Actual Study Completion Date: Jul 19, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Melphalan HCl for injection (propylene glycol free) Patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0).

Drug: Melphalan HCl for injection (propylene glycol free); During the study period, patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.

Outcome Measures

Primary Outcome Measures

1. Cmax (Pharmacokinetics) [Day -2]

   Maximum observed plasma concentration. Derived from the individual raw data.

2. AUC0-t (Pharmacokinetics) [Day -2]

   Area under the plasma concentration-time curve to the last measurable time point (AUC0-t) calculated by the trapezoidal rule. The area under the concentration-time curve (AUC) is calculated to determine the total drug exposure over a period of time.

Secondary Outcome Measures

1. Transplant-Related Mortality (TRM) Following Autologous Stem-Cell Transplantation (ASCT) [100 days]

   TRM will be summarized descriptively (death within 100 days without relapse following ASCT).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with symptomatic multiple myeloma (MM) requiring treatment at or following diagnosis.

• Patients with MM, who qualify for ASCT therapy, and have received pretransplant therapy prior to transplantation.

• Adult patients (≥18 years of age) meeting local institutional criteria to receive a total Melphalan dose of 200 mg/m^2 as a conditioning regimen.

• Patients with an adequate autologous graft, which is defined as an unmanipulated, cryopreserved, peripheral blood cell graft containing at least 2 × 106 CD34+ cells/kg, based on patient weight.

• Patients with adequate organ function, as measured by:

• Cardiac: Left ventricular ejection fraction at rest >40% (documented within 30 days prior to Day -3).

• Hepatic: Bilirubin <2 × the upper limit of normal (ULN) and Alanine transaminase/Aspartate transaminase (ALT/AST) <3 × ULN.

• Renal: Creatinine clearance >40 mL/min (measured or calculated/estimated).

• Pulmonary: Adjusted 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 level [Hgb]) and documented within prior to day -3.

Exclusion Criteria:

• Patients with systemic AL amyloidosis (immunoglobulin light chain amyloidosis).

• Eastern Cooperative Oncology Group (ECOG) performance status ≥2.

• Patients with uncontrolled hypertension.

• Patients with a serious active bacterial, viral or fungal infection.

• Patients with prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent >5 years previously will be allowed. Cancer treated with curative intent <5 years previously will not be allowed unless approved by the medical monitor.

• Female patients who are pregnant (positive human chorionic gonadotropin [ß-HCG]) or breastfeeding.

• Female patients of childbearing potential, who are unwilling to use adequate contraceptive techniques during and for one month following study treatment with Melphalan HCl for injection (propylene glycol free).

• Patients seropositive for HIV.

• Patients who are unwilling to provide informed consent.

• Patients receiving other concurrent anticancer therapy (including chemotherapy, radiation, hormonal treatment, or immunotherapy, but excluding corticosteroids) within 30 days prior to the ASCT or planning to receive any of these treatments prior to study discharge.

• Patients concurrently participating in any other clinical study.

• Patients who are hypersensitive or intolerant to any component of the study drug formulation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Medical College of Wisconsin

Investigators

• Principal Investigator: Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin

Study Documents (Full-Text)

• Study Protocol - Feb 20, 2016
• Statistical Analysis Plan - Feb 20, 2016

More Information

Publications

None provided.

• Responsible Party: Parameswaran Hari, Professor, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02669615
• Other Study ID Numbers: PRO00026736
• First Posted: Feb 1, 2016
• Last Update Posted: Oct 10, 2018
• Last Verified: Sep 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Parameswaran Hari, Professor, Medical College of Wisconsin: multiple myeloma; Melphalan HCl; Autologous Transplantation
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Melphalan

Study Results

Participant Flow

Arm/Group Title	Melphalan HCl for Injection (Propylene Glycol Free)
Arm/Group Description	Patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0). Melphalan HCl for injection (propylene glycol free): During the study period, patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Melphalan HCl for Injection (Propylene Glycol Free)
Arm/Group Description	Patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0). Melphalan HCl for injection (propylene glycol free): During the study period, patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 45.8%
>=65 years	13 54.2%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Sex: Female, Male (Count of Participants)
Female	9 37.5%
Male	15 62.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 20.8%
White	19 79.2%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Cmax (Pharmacokinetics)
Description	Maximum observed plasma concentration. Derived from the individual raw data.
Time Frame	Day -2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan HCl for Injection (Propylene Glycol Free)
Arm/Group Description	Patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0). Melphalan HCl for injection (propylene glycol free): During the study period, patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.
Measure Participants	24
Median (Full Range) [ng/ml]	7380

2. Primary Outcome

Title	AUC0-t (Pharmacokinetics)
Description	Area under the plasma concentration-time curve to the last measurable time point (AUC0-t) calculated by the trapezoidal rule. The area under the concentration-time curve (AUC) is calculated to determine the total drug exposure over a period of time.
Time Frame	Day -2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan HCl for Injection (Propylene Glycol Free)
Arm/Group Description	Patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0). Melphalan HCl for injection (propylene glycol free): During the study period, patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.
Measure Participants	24
Median (Full Range) [ng*min/ml]	533552

3. Secondary Outcome

Title	Transplant-Related Mortality (TRM) Following Autologous Stem-Cell Transplantation (ASCT)
Description	TRM will be summarized descriptively (death within 100 days without relapse following ASCT).
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan HCl for Injection (Propylene Glycol Free)
Arm/Group Description	Patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0). Melphalan HCl for injection (propylene glycol free): During the study period, patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.
Measure Participants	24
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	100 days post transplant
Arm/Group Title	Melphalan HCl for Injection (Propylene Glycol Free)
Arm/Group Description	Patients will receive 200 mg/m^2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2. Blood samples for the pharmacokinetic (PK) evaluation of melphalan will be collected after melphalan dosing (day -2). Following one day of rest after the myeloablative Melphalan conditioning (day -1), patients will receive an autologous graft with a minimum cell dose of 2 × 106 CD34+ cells/kg of patient body weight (day 0). Melphalan HCl for injection (propylene glycol free): During the study period, patients will receive 200 mg/m2 of Melphalan HCl for injection (propylene glycol free) as a one-time infusion on day 2.
All Cause Mortality
	Melphalan HCl for Injection (Propylene Glycol Free)
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Serious Adverse Events
	Melphalan HCl for Injection (Propylene Glycol Free)
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Other (Not Including Serious) Adverse Events
	Melphalan HCl for Injection (Propylene Glycol Free)
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
leukopenia	24/24 (100%)	24

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.