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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method for dosing melphalan in individuals with lymphoma, a type of blood cancer. Traditionally, dosage is based on height and weight, but the trial tests a personalized approach using past patient data to potentially reduce side effects. Participants will receive melphalan as part of a chemotherapy regimen called BEAM, followed by a stem cell transplant. Individuals diagnosed with any type of lymphoma and planning to undergo this specific chemotherapy and transplant may be suitable for the study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this personalized dosing approach.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that melphalan, a chemotherapy drug, already treats multiple myeloma, a type of blood cancer, providing some safety information. Past studies identified lower blood cell counts as the most common side effect, typical for many chemotherapy drugs. This can lead to issues like a higher risk of infection or anemia, a condition where there aren't enough healthy red blood cells.

Evidence indicates that melphalan, when used in certain doses, has safety levels similar to other treatments, even for older or frail patients. However, the drug can cause severe bone marrow suppression, significantly reducing blood cell production in the bone marrow.

The trial's new approach aims to personalize the dose for each person, potentially reducing side effects compared to the standard fixed dose, though this is still under investigation. As this study is in the early phase, it focuses on safety and how the body processes the drug, indicating more needs to be learned about its safety in this specific setting. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about melphalan for lymphoma because it uses a personalized dosing approach called pharmacokinetic (PK) modeling to optimize treatment. Unlike standard chemotherapy treatments, which often use fixed doses, this method calculates the precise melphalan dose needed for each patient to achieve the desired drug exposure. This tailored approach aims to maximize effectiveness while minimizing side effects, offering a more targeted treatment option for lymphoma patients.

What evidence suggests that this population PK model is effective for lymphoma?

This trial will examine pharmacokinetic-directed melphalan dosing in two separate cohorts. Studies have shown that melphalan can help treat lymphoma when used in BEAM chemotherapy. Research suggests that higher doses of melphalan improve survival rates but may also increase side effects. Adjusting the dose based on individual drug processing might maintain effectiveness while reducing side effects. Studies of different melphalan types found no major differences in efficacy, allowing flexibility in administration. This approach aims to maximize benefits while minimizing risks for each participant. ^{6 7 8 9 10}

Who Is on the Research Team?

Parastoo Dahi, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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Comparison of Patient Outcomes With Two Different ...

We evaluated the differences in efficacy and safety of the 2 formulations as there are no prospective head-to-head trials.

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sciencedirect.com

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Comparison of Patient Outcomes With Two Different ...

Efficacy data analysis showed there was no difference in achieving myeloablation or neutrophil engraftment irrespective of which formulation was first ...

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clinical-lymphoma-myeloma-leukemia.com

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Original Study

Even with the longer follow-up in this study, no differences in PFS or OS were observed between the 2 melphalan formulations. With no difference in the primary ...

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accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2017/207155s001lbl.pdf

EVOMELA (melphalan) for injection - accessdata.fda.gov

The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with. Evomela were neutrophil count decreased, white blood ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40090795/

Melphalan 140 mg/m2 is Safe and Effective for Frail and ...

Our findings suggest equivalent efficacy and safety profiles between Mel140 and Mel200, supporting Mel140 as a viable option for older or frail MM patients.

8.

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evomela.com/wp-content/uploads/2019/05/Evomela-Prescribing-Information.pdf

WARNING: SEVERE BONE MARROW SUPPRESSION ...

The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with. Evomela were neutrophil count decreased, white blood ...

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clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(18)30903-0/fulltext

Safety and Toxicity of Oral Melphalan Use in Bone Marrow ...

Safety and Toxicity of Oral Melphalan Use in Bone Marrow Transplantation in Patients with Multiple Myeloma, in a Setting Without Venous Medication Supply.

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Melphalan (intra-arterial route, intravenous route)

Melphalan belongs to the group of medicines called alkylating agents (cancer medicines). ... Safety and efficacy have not been established.