PK Study of Melphalan HCL & Alkeran for Injection of MA Conditioning in MM Patients of Autologous Transplantation

Study Overview
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Brief Summary
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To assess and compare the pharmacokinetics of Melphalan HCL for Injection (Propylene Glycol-Free) versus Alkeran for Injection in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT).

Detailed Description
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This study will be a multicenter, open-label, randomized, comparative, cross-over study of high-dose Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection conducted in 24 patients who have symptomatic MM and qualify for ASCT. During the Study Period, patients will be randomized to receive 100mg/m2 of either Melphalan HCl for Injection (Propylene Glycol-Free) or Alkeran for Injection on Day -3 and the alternate drug product on Day -2. Blood samples for pharmacokinetic (PK) evaluation will be withdrawn through an indwelling i.v. cannula each day of melphalan dosing (Day -3 and Day -2). Following one day of rest after the myeloablative conditioning (Day -1), patients will receive an autologous graft.

Official Title
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AA Phase IIA Open-Label, Randomized, PK Comparative, Cross-Over Study of Melphalan HCL for Injection (Propylene Glycol-Free) and Alkeran for Injection for Myeloablative Conditioning in MM Patients Undergoing Autologous Transplantation

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Melphalan HCL for Injection (Propylene Glycol-Free)/Alkeran for Injection
* Drug: Alkeran for Injection/Melphalan HCL for Injection (Propylene Glycol-Free)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with symptomatic MM requiring treatment at diagnosis or anytime thereafter. Patients with MM who qualify for ASCT therapy who have received appropriate primary induction therapy for transplantation. Adult patients (≥ 18 years old) who are 70 years of age or younger at time of transplant; patients greater than 70 years of age may qualify on a case-by-case basis if the patient meets local institutional criteria to receive a total melphalan dose of 200 mg/m2 as a conditioning regimen and if approved by the Medical Monitor. Patients with an adequate autologous graft which is defined as an unmanipulated, cryopreserved, peripheral blood stem cell graft containing at least 2 × 106 CD34+ cells/kg based upon patient weight. Patients with adequate organ function as measured by: Cardiac: Left ventricular ejection fraction at rest >40% (documented within 12 weeks prior to Day -3). Hepatic: Bilirubin <2 × the upper limit of normal (ULN) and ALT/AST <3 × ULN. Renal: Creatinine clearance >40 mL/minutes (measured or calculated/estimated). Pulmonary: DLCO, FEV1, FVC >50% of predicted value (corrected for Hgb) or O2 saturation > 92% on room air (documented within 12 weeks prior to Day -3) Exclusion Criteria: Patients who have never advanced beyond Stage 1 MM since diagnosis. Patients who have previously received more than one autologous stem cell transplant. Patients with plasma cell leukemia. Patients with MM and systemic AL amyloidosis. ECOG performance status ≥2. Patients with uncontrolled hypertension. Patients with an 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 ß-HCG) or breastfeeding. Female patients of childbearing potential who are unwilling to use adequate contraceptive techniques during and for 1 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 21 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Melphalan-Alkeran<br>Subjects begin with treatment Melphalan and crossover to treatment Alkeran | Drug: Melphalan HCL for Injection (Propylene Glycol-Free)/Alkeran for Injection<br>* Patients will be randomized to receive 100 mg/m2 of Melphalan HCL for Injection (Propylene Glycol-Free) on Day -3 and Alkeran for Injection on Day -2 prior to ASCT.<br>* Other names: Evomela;Drug: Alkeran for Injection/Melphalan HCL for Injection (Propylene Glycol-Free)<br>* Patients will be randomized to receive 100 mg/m2 of Alkeran for Injection on Day -3 and Melphalan HCL for Injection (Propylene Glycol-Free)on Day -2 prior to ASCT.<br>* Other names: L-PAM, L-Sarcolysin;|
| Other: Alkeran-Melphalan<br>Subjects begin with treatment Alkeran and crossover to treatment Melphalan. | Drug: Melphalan HCL for Injection (Propylene Glycol-Free)/Alkeran for Injection<br>* Patients will be randomized to receive 100 mg/m2 of Melphalan HCL for Injection (Propylene Glycol-Free) on Day -3 and Alkeran for Injection on Day -2 prior to ASCT.<br>* Other names: Evomela;Drug: Alkeran for Injection/Melphalan HCL for Injection (Propylene Glycol-Free)<br>* Patients will be randomized to receive 100 mg/m2 of Alkeran for Injection on Day -3 and Melphalan HCL for Injection (Propylene Glycol-Free)on Day -2 prior to ASCT.<br>* Other names: L-PAM, L-Sarcolysin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (0-t) | AUC (0-t) was one of the pharmacokinetic endpoints to confirm pharmacokinetic similarity between Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection in patients with multiple myeloma. Pharmacokinetic similarity was defined as a difference of 20% or less in the 90% confidence intervals (CIs) for the ratios of the pharmacokinetic parameters (calculated using log-transformed data) for the two formulations. The AUC results provided is the summary of Melphalan PK following Melphalan-Alkeran injection in Sequence 1 and Alkeran-melphalan injection in Sequence 2. | Day -3 and Day -2 | 
| Concentration-Max (Cmax) | Cmax was one of the pharmacokinetic endpoints to confirm pharmacokinetic similarity between Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection in patients with multiple myeloma. Pharmacokinetic similarity was defined as a difference of 20% or less in the 90% confidence intervals (CIs) for the ratios of the pharmacokinetic parameters (calculated using log-transformed data) for the two formulations. The Cmax results provided is the summary of Melphalan PK following Melphalan-Alkeran injection in Sequence 1 and Alkeran-melphalan injection in Sequence 2. | Day -3 and Day -2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Myeloablation Following Melphalan-alkeran Sequence and Alkeran-melphalan Sequence Followed by ASCT | ANC <0.5 × 109/L, absolute lymphocyte count (ALC) <0.1 × 109/L, platelet count <20,000/mm3, or bleeding requiring transfusion. The first of 2 consecutive days for which cell counts drop below these cutoff levels was recorded as the date of myeloablation. Since the two treatments were administered consecutively with 1 day rest, the time to myeloablation and myeloablation rate was measured after both treatments were administered. Comparison of sequence effect was not planned in the study and due to small sample size, it was not performed. | 30 days | 
| Determination of Engraftment Following Melphalan-alkeran Sequence and Alkeran-melphalan Sequence Followed by ASCT | Neutrophil engraftment was defined as the first day of 3 consecutive days where ANC (absolute neutrophil count) was higher than 500/ul. The two drug treatments in this cross-over design were administered on 2 subsequent days (Day -3 and Day -2). No per arm analysis was performed. Since the two treatments were administered consecutively with 1 day rest, the time to engraftment and engraftment rate was measured after both treatments were administered. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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autologous stem cell transplantation