Evomela + Fludarabine + TBI for Multiple Myeloma

Overseen By Medical College of Wisconsin Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Medical College of Wisconsin

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 week

43 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, single-arm, phase II study to determine the safety of propylene glycol-free melphalan HCl (EVOMELA®), in combination with fludarabine and total-body irradiation-based reduced-intensity conditioning for haploidentical transplantation. In addition, the study evaluates the one-year progression-free survival of patients undergoing this treatment.

Do I need to stop taking my current medications for this trial?

The trial protocol 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.

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 idea that Evomela + Fludarabine + TBI for Multiple Myeloma is an effective treatment?

The available research shows that the combination of Evomela (Melphalan), Fludarabine, and Total Body Irradiation (TBI) is effective in treating multiple myeloma. In a study comparing different regimens, the combination with TBI (FluMelTBI-75) showed improved survival and disease control compared to a regimen without TBI. Specifically, patients who were not in complete remission had better outcomes with the TBI regimen. Additionally, this combination was better tolerated, with fewer side effects like mouth sores. This suggests that adding TBI to the treatment can enhance its effectiveness while reducing some side effects. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment Evomela + Fludarabine + TBI for Multiple Myeloma?

Research shows that melphalan, a component of Evomela, has been used effectively in treating multiple myeloma and other blood cancers. Additionally, combining fludarabine, melphalan, and total body irradiation (TBI) has shown improved survival and disease control in similar treatments, suggesting potential effectiveness for multiple myeloma. ^{1 2 3 4 5}

What safety data is available for the treatment of Evomela, Fludarabine, and TBI in Multiple Myeloma?

The combination of Fludarabine and Melphalan, with or without Total Body Irradiation (TBI), has been studied in various clinical trials. Regimen-related toxicities include renal, hepatic, mucosal, cardiac, and pulmonary issues, with some cases leading to death. Myelosuppression is a dose-limiting toxicity for Fludarabine, and neurotoxicity has been noted at high doses. The addition of TBI to Fludarabine and Melphalan regimens has been explored to improve outcomes, but it also presents risks of significant non-relapse mortality, especially in older patients or those with prior transplants. Overall, while these regimens can lead to durable remission, they are associated with considerable toxicity. ^{1 2 3 6 7}

Is the combination of Evomela, Fludarabine, and Total Body Irradiation generally safe for humans?

The combination of Evomela (Melphalan), Fludarabine, and Total Body Irradiation has been studied in various clinical trials, showing that while it can be effective, it also has significant risks. Common side effects include mucositis (painful inflammation and ulceration of the mucous membranes), cardiac and renal toxicity, and a risk of graft-versus-host disease (a condition where the donor cells attack the recipient's body). There is also a notable risk of non-relapse mortality, especially in older patients or those with prior transplants. ^{1 2 3 6 7}

Is the treatment Evomela, Fludarabine, and Total Body Irradiation promising for Multiple Myeloma?

The treatment using Evomela, Fludarabine, and Total Body Irradiation is considered promising for Multiple Myeloma because it combines different approaches to target the cancer cells effectively. Evomela and Fludarabine are drugs that help destroy cancer cells, while Total Body Irradiation uses radiation to kill cancer cells throughout the body. This combination aims to improve treatment outcomes by attacking the cancer in multiple ways. ^{8 9 10 11 12}

What makes the Evomela + Fludarabine + TBI treatment unique for multiple myeloma?

This treatment combines Evomela (a form of melphalan), Fludarabine, and Total Body Irradiation (TBI), which is a novel approach for multiple myeloma. It uses a combination of chemotherapy and radiation to target cancer cells throughout the body, which may offer a different mechanism of action compared to standard treatments that typically focus on chemotherapy alone. ^{8 9 10 11 12}

Research Team

Mehdi Hamadani

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

This trial is for adults with blood cancers like multiple myeloma who need a haploidentical transplant. They should have good heart and lung function, stable liver and kidney health, no uncontrolled infections or serious illnesses, and agree to use effective contraception.

Inclusion Criteria

Transplant recipient able to give informed consent

Your lung function is at least 50% of what is expected for someone of your age and size.

I do not have any ongoing serious infections.

Exclusion Criteria

My condition is active AML or MDS.

I do not have a suitable family or unrelated donor for a transplant.

I don't have any serious health or mental conditions that could stop me from completing the treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive reduced-intensity conditioning with EVOMELA®, fludarabine, and total-body irradiation for haploidentical transplantation

1 week

Daily visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of graft-versus-host disease and overall survival

1 year

Regular visits up to 1 year

Long-term follow-up

Participants are monitored for long-term outcomes such as chronic GVHD and overall survival

2 years

Treatment Details

Interventions

• Evomela
• Fludarabine
• Total Body Irradiation

Trial Overview The study tests EVOMELA® combined with Fludarabine and Total Body Irradiation as a conditioning treatment before haploidentical transplantation. It's an open-label phase II trial focusing on safety and one-year progression-free survival rates.

Participant Groups

Group I: MEL/FLU and Total-Body Irradiation (TBI) Experimental Treatment 3 Interventions

For patients who are \< 60 years. * Melphalan: 140 mg/m2/day IV on Day: -6 * Fludarabine: 40 mg/ m2/day IV Days: -5 -4, -3, -2 (Adults: creatinine clearance (CrCl) may be estimated by the Cockcroft Formula: CrCl = \[(140-age) x weight (kg) x 0.85 (for women only)\]/ \[72 x creat (mg/dl)\].) * TBI: 200 cGy Day: -1. For patients who are ≥60 years and/or Hematopoietic Cell Transplant-Co-morbidity Index (HCT-CI) score of \>3 (at the discretion of treating physician will have an option to receive): * Melphalan: 70 mg/m2/day IV on Day -6. * Fludarabine: 40 mg/m2/day IV Days -5, -4, -3, -2. * TBI: 200 cGy; Days -1.

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

Approved in United States as Evomela for:

• Multiple Myeloma

Approved in European Union as Alkeran for:

• Multiple Myeloma
• Malignant Lymphoma
• Lymphoblastic and Myeloblastic Leukemia
• Childhood Neuroblastoma
• Ovarian Cancer
• Mammary Adenocarcinoma
• Uveal Melanoma

Approved in Japan as Melphalan for:

• Multiple Myeloma
• Malignant Lymphoma
• Lymphoblastic and Myeloblastic Leukemia
• Childhood Neuroblastoma
• Ovarian Cancer
• Mammary Adenocarcinoma
• Uveal Melanoma

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Findings from Research

Melflufen, a derivative of melphalan, demonstrated significantly higher potency against lymphoma cells compared to melphalan, with IC50 values showing up to 49-fold superiority in cell lines and an average of 108-fold in primary cultures.

In preclinical studies, melflufen showed effective cytotoxicity with minimal side effects in a xenograft model, indicating its potential as a safer and more effective treatment option for relapsed or refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo activity of melflufen (J1)in lymphoma. Delforoush, M., Strese, S., Wickström, M., et al.[2019]

In a study of 31 patients with hematologic malignancies who were poor candidates for total body irradiation (TBI), the fludarabine-melphalan regimen resulted in successful engraftment for all patients, indicating its efficacy in stem cell transplantation.

However, the treatment was associated with significant regimen-related toxicities, including renal, hepatic, and mucosal issues, leading to seven regimen-related deaths, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. Van Besien, K., Devine, S., Wickrema, A., et al.[2013]

The addition of total body irradiation (TBI) and a reduction in melphalan dosage in the FluMelTBI-75 regimen led to improved overall survival (OS) and progression-free survival (PFS) compared to the standard FluMel regimen, based on a phase II trial involving 94 patients.

FluMelTBI-75 was better tolerated, showing a significant reduction in stomatitis and improved disease control for patients not in complete remission at the time of transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. Chen, GL., Hahn, T., Wilding, GE., et al.[2022]

The addition of 9 Gy of total body irradiation (TBI) to a reduced intensity regimen of fludarabine and melphalan in pediatric patients with advanced hematologic malignancies resulted in successful neutrophil and platelet engraftment, with 27 patients achieving neutrophil engraftment by a median of 16 days.

Despite some toxicities like oral mucositis and diarrhea, the treatment was generally well tolerated, and with a median follow-up of 52 months, 7 out of 22 patients with acute lymphoblastic leukemia (ALL) and 5 out of 6 patients with acute myeloid leukemia (AML) remained alive and in remission, indicating potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Petropoulos, D., Worth, LL., Mullen, CA., et al.[2013]

In the MagnetisMM-1 trial involving 88 patients with relapsed or refractory multiple myeloma, elranatamab demonstrated a significant overall response rate of 63.6%, with 38.2% of patients achieving a complete response or better, indicating its efficacy even in heavily pre-treated patients.

Elranatamab showed manageable safety with no dose-limiting toxicities during dose escalation, although some patients experienced cytopenias and cytokine release syndrome; the median progression-free survival was 11.8 months and overall survival was 21.2 months, suggesting promising durability of responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial. Bahlis, NJ., Costello, CL., Raje, NS., et al.[2023]

Fludara I.V. (fludarabine phosphate) has been tested in multiple phase I trials for solid tumors and acute leukemia, with myelosuppression identified as the main dose-limiting toxicity, particularly at higher doses for leukemia patients.

Despite severe neurotoxicity observed in acute leukemia patients at high doses, Fludara I.V. induces beneficial lymphopenia, which is effective in treating chronic lymphocytic leukemia and other lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trials with fludarabine phosphate. Von Hoff, DD.[2013]

The combination of fludarabine and melphalan with total body irradiation (Flu-Mel140-TBI) in 81 patients undergoing allogeneic stem cell transplantation showed a 3-year overall survival rate of 39.81%, indicating that this regimen is feasible and can provide durable disease control.

Despite the addition of TBI, there was no significant improvement in outcomes compared to previous reports of Flu-Mel140 alone, and the study highlighted considerable non-relapse mortality (29.9%) particularly in older patients and those with prior transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation. Modi, D., Chi, J., Kim, S., et al.[2021]

In a study of 85 patients with chronic plaque psoriasis, a PUVA regimen based on skin type resulted in a significantly higher clearance rate (95%) compared to a regimen starting with 50% of the minimal phototoxic dose (67.5%).

Both regimens led to common side effects, such as grades 2 or 3 erythema, but the study suggests that patients with skin types I and II may benefit from smaller dose increments to optimize treatment and minimize adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large increments in psoralen-ultraviolet A (PUVA) therapy are unsuitable for fair-skinned individuals with psoriasis. Kirby, B., Buckley, DA., Rogers, S.[2019]

Brodalumab, an anti-IL-17RA monoclonal antibody, has shown high efficacy in treating psoriasis by blocking IL-17 receptor A, which disrupts signaling from multiple IL-17 family members.

While brodalumab is effective, common side effects include nasopharyngitis and headaches, and there have been reports of suicidal ideation, although no causal link has been established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brodalumab for the treatment of psoriasis. Galluzzo, M., D'adamio, S., Bianchi, L., et al.[2022]

Brodalumab, an IL-17RA inhibitor, represents a significant advancement in psoriasis treatment, offering a new mechanism of action that addresses unmet patient needs for effective therapies.

While brodalumab has shown efficacy in achieving rapid and sustained skin clearance, common side effects include nasopharyngitis and headaches, with some reports of suicidal ideation, though no causal link has been established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic drug evaluation of brodalumab for the treatment of psoriasis. Galluzzo, M., Talamonti, M., D'adamio, S., et al.[2019]

Guselkumab is an approved treatment for moderate-to-severe plaque psoriasis, specifically designed to inhibit interleukin 23 (IL-23), which plays a key role in the inflammatory process of the disease.

By blocking IL-23 from binding to its receptor, guselkumab disrupts the IL-17 pathway, which is crucial for the activation of type 17 helper T cells, thereby reducing inflammation and symptoms in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guselkumab: First Global Approval. Markham, A.[2019]

In a 24-week study involving 210 subjects with moderate-to-severe plaque psoriasis, brodalumab demonstrated significantly higher efficacy than fumaric acid esters (FAE), with 81.0% of participants achieving PASI75 compared to 38.1% in the FAE group.

Brodalumab also showed a faster onset of action, with median times to PASI75 and PASI90 being 4.1 weeks and 7.4 weeks, respectively, while FAE took 16.4 weeks and 24.4 weeks, and had a lower rate of adverse events compared to FAE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 4, randomized, head-to-head trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate-to-severe plaque psoriasis (CHANGE). Pinter, A., Hoffmann, M., Reich, K., et al.[2021]

References

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

In vitro and in vivo activity of melflufen (J1)in lymphoma. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. [2013]

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

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. [2013]

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

Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial. [2023]

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

Phase I clinical trials with fludarabine phosphate. [2013]

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

Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Large increments in psoralen-ultraviolet A (PUVA) therapy are unsuitable for fair-skinned individuals with psoriasis. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Brodalumab for the treatment of psoriasis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic drug evaluation of brodalumab for the treatment of psoriasis. [2019]

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

Guselkumab: First Global Approval. [2019]

12. England pubmed.ncbi.nlm.nih.gov

A phase 4, randomized, head-to-head trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate-to-severe plaque psoriasis (CHANGE). [2021]