Melphalan for Lymphoma

Overseen By Gunjan Shah, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Disease progression, Pregnant, Allergies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

40 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether it is practical to use a newer way to calculate melphalan dose given (called population PK model) in BEAM chemotherapy before AHCT. Standard dose is fixed for everybody and is calculated using height and weight. The population PK model, tested in this study, uses information based on people who have previously received melphalan and aims to calculate an optimal dose separately for each person. Study researchers think that the dose calculated using the population PK model may still be effective but have less side effects than the standard melphalan dose.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Melphalan for treating lymphoma?

Research shows that high-dose melphalan, when used in combination with autologous stem cell transplantation, is effective in treating multiple myeloma, a type of blood cancer. This suggests that melphalan may also be effective for other similar blood-related cancers, such as lymphoma, due to its ability to achieve high response rates and improve survival in these conditions. ^{1 2 3 4 5}

What makes the drug Melphalan unique for treating lymphoma?

Melphalan, particularly in its propylene glycol-free formulation known as EVOMELA, is unique because it improves solubility and stability without the need for propylene glycol, which can cause complications. This formulation is used as a high-dose conditioning regimen for stem cell transplantation, offering a safer alternative with a high response rate and manageable side effects. ^{2 3 4 5 6}

Research Team

Parastoo Dahi, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults aged 18-79 with lymphoma (including T-cell, B-cell, Hodgkin's, Non-Hodgkin's) who are responding to chemotherapy and scheduled for a stem cell transplant. They must have good heart function, kidney function, lung capacity, and a sufficient dose of stem cells available. Pregnant women or those with disease progression since last therapy cannot participate.

Inclusion Criteria

My cancer responded to chemotherapy.

My heart pumps blood effectively.

My stem cell transplant will use at least 2 million CD34+ cells per kg of my body weight.

Exclusion Criteria

Pregnant or lactating females

Disease progression by IWG Working Group since last therapy

Any known allergy or allergic reactions to Captisol

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive BEAM chemotherapy with pharmacokinetic directed melphalan dosing

7 days

Daily visits for chemotherapy administration

Autologous Hematopoietic Cell Transplantation (AHCT)

Participants undergo autologous hematopoietic cell transplantation following chemotherapy

1 day

1 visit (in-patient)

Follow-up

Participants are monitored for safety and effectiveness after transplantation

1 year

Treatment Details

Interventions

• Melphalan
• Population PK Model

Trial Overview The study tests if calculating the melphalan chemotherapy dose using a population PK model before autologous hematopoietic cell transplant (AHCT) is practical. This method aims to tailor doses individually based on previous patient data rather than using standard fixed doses.

Participant Groups

Group I: Cohort 2: Pharmacokinetic directed melphalan Experimental Treatment 1 Intervention

In cohort 2, carmustine will be on Day -7, cytrabine and etoposide on Day -6 to Day -3, and melphalan (70mg/m2 /day IV) will be administered on day -2 followed by PK samples to determine the melphalan dose on day -1 using the population PK model. PK samples will be collected again after the dose on day -1 to confirm the total melphalan AUC of 8.5 (+/- 1.5) mg\*h/L. Six peripheral blood samples of 5 ml in lithium heparin tubes will be collected at 5, 15, 30, 40, 75, and 150 minutes after the melphalan, for PK testing. The first four time points are +/- 2 min and the last two time points are +/- 5 minutes.

Group II: Cohort 1: Pharmacokinetic directed melphalan Experimental Treatment 1 Intervention

This is a feasibility study of pharmacokinetic (PK)-directed Captisol Enabled (CE) melphalan dosing to target an AUC of 8.5 (+/- 1.5) using a population PK model in lymphoma patients receiving BEAM \[carmustine (BCNU) (B), etoposide (E), cytarabine (Ara-C) (A), and melphalan (M)\], followed by autologous hematopoietic cell transplantation (AHCT). This study will enroll patients with lymphoma planned for BEAM-AHCT. Carmustine IV will be given on day -6, followed by etoposide IV and cytarabine IV from day -5 to -2 as per the MSK inpatient or outpatient standard of care. The calculated melphalan dose based on population PK model to achieve the proposed melphalan target exposure \[8.5 (+/- 1.5) mg\*h/L\], will be administered on day -1, and six peripheral blood samples of 5 ml in lithium heparin tubes will be collected at 5, 15, 30, 40, 75, and 150 minutes after the melphalan, for PK testing to determine if the goal AUC was achieved.

Melphalan is already approved in European Union, United States for the following indications:

Approved in European Union as Alkeran for:

• Multiple myeloma
• Malignant lymphoma
• Acute lymphoblastic leukemia
• Acute myeloblastic leukemia
• Childhood neuroblastoma
• Ovarian cancer
• Mammary adenocarcinoma

Approved in United States as Alkeran for:

• Multiple myeloma
• High-dose conditioning before hematopoietic stem cell transplant
• Uveal melanoma with unresectable hepatic metastases

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

In a study involving BALB/c mice, melphalan treatment at doses of 250 and 400 micrograms cured plasmacytoma but caused long-term immune impairments, including reduced T-cell numbers and IL-2 production, lasting up to one year after treatment.

Mice without plasmacytoma maintained normal immune functions after melphalan treatment, indicating that the presence of the tumor influences the drug's long-term effects on immune health and survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late immune and haemopoietic functions in plasmacytoma-bearing mice cured by melphalan. Sagi, O., Witz, IP., Ramot, B., et al.[2019]

EVOMELA, a new formulation of melphalan that is free from propylene glycol, has been shown to be safe and effective for high-dose conditioning in autologous stem cell transplantation for multiple myeloma, with a 100% overall response rate in a study of 61 patients.

The study reported low incidences of severe side effects, such as grade 3 mucositis (10%) and stomatitis (5%), indicating that EVOMELA has an acceptable safety profile compared to traditional formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. Hari, P., Aljitawi, OS., Arce-Lara, C., et al.[2017]

In a study of 514 multiple myeloma patients, the propylene glycol-free formulation of melphalan (PGF-mel) showed similar efficacy to the conventional propylene glycol-based formulation (PG-mel) in terms of relapse rates after high-dose melphalan with autologous hematopoietic cell transplantation.

However, PGF-mel was associated with fewer severe adverse events like mucositis and febrile neutropenia, leading to a preference for PG-mel despite the potential benefits of PGF-mel, due to cost considerations and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Khan, AM., Yucebay, F., Zhao, Q., et al.[2023]

Intravenous (IV) melphalan shows promising efficacy in treating certain cancers, particularly in previously untreated patients with rhabdomyosarcoma, and has demonstrated high response rates in high-dose regimens for non-Hodgkin's lymphoma and multiple myeloma, despite significant toxicity.

Compared to oral melphalan, IV administration provides higher and more predictable blood levels, but further clinical trials are needed to better understand its effectiveness at lower doses and to identify which patient groups may benefit the most.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The systemic administration of intravenous melphalan. Sarosy, G., Leyland-Jones, B., Soochan, P., et al.[2017]

Melphalan is a key treatment for multiple myeloma and ovarian cancer, with oral melphalan combined with prednisone being the standard therapy for elderly patients since the 1960s.

Recent advancements in understanding drug resistance have led to the development of novel therapies like thalidomide, lenalidomide, and bortezomib, which can enhance the effectiveness of melphalan and change treatment approaches for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melphalan and its role in the management of patients with multiple myeloma. Falco, P., Bringhen, S., Avonto, I., et al.[2020]

Melphalan flufenamide (melflufen) is a new alkylating drug approved for treating relapsed or refractory multiple myeloma in adults who have undergone at least four prior therapies, demonstrating its efficacy in a challenging patient population.

The drug works by rapidly entering cells and converting into active alkylating agents that damage DNA, which is a common mechanism of action for cancer treatments, and it is currently being studied for other blood disorders and cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melphalan Flufenamide (Melflufen): First Approval. Dhillon, S.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Late immune and haemopoietic functions in plasmacytoma-bearing mice cured by melphalan. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

The systemic administration of intravenous melphalan. [2017]

5. England pubmed.ncbi.nlm.nih.gov

Melphalan and its role in the management of patients with multiple myeloma. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Melphalan Flufenamide (Melflufen): First Approval. [2021]