Transplant Conditioning Regimen for Blood Disorders

Recruiting at 20 trial locations

Overseen By Stephanie Hyde, CCRP

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Disqualifiers: HIV, Invasive infection, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

220 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for individuals with specific blood disorders, using a combination of Campath (Alemtuzumab), Fludarabine, and Melphalan. The goal is to determine if this regimen can prepare the body to accept donor bone marrow without completely destroying the patient's own marrow. The study will also examine any major side effects within the first 100 days after the transplant. It is open to individuals under 21 years old with non-cancerous blood disorders, such as thalassemia or hemoglobinopathy, who require a bone marrow transplant. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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?

Previous studies have linked alemtuzumab (Campath) to serious side effects, such as immune system problems and reactions during IV administration. Cases of stroke and blood vessel tears have also occurred. However, it effectively reduces severe acute GVHD (graft-versus-host disease) after stem cell transplants, which is encouraging.

Research on fludarabine shows it is generally well-tolerated, with low rates of serious issues like non-cancer-related death and infections. It has been used safely before bone marrow transplants.

Melphalan, another drug in this trial, often reduces blood cell production, lowering immunity and increasing bleeding risks. Still, it is considered safe for transplant preparation.

These drugs are already used in other treatments, indicating some understanding of their safety. However, as this is an early trial phase, the full safety in this specific use is still under study. Participants should consider these findings and discuss them with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores a unique transplant conditioning regimen for blood disorders using a combination of Campath, Fludarabine, and Melphalan. Unlike typical conditioning regimens, which often rely on more aggressive chemotherapy, this approach aims to be less toxic while still effectively preparing the body for a bone marrow transplant. By using drugs like Campath, which targets specific immune cells, the regimen may reduce the risk of transplant complications and improve outcomes for patients with non-malignant blood disorders. This trial could lead to a safer, more targeted way to prepare patients for transplantation, offering hope for better recovery and fewer side effects.

What evidence suggests that this trial's treatments could be effective for blood disorders?

Research has shown that Campath, also known as alemtuzumab, successfully prepares patients for bone marrow transplants. In this trial, participants in different strata will receive various conditioning regimens. Some studies report survival rates between 20% and 60% for Campath, depending on different factors. Fludarabine, another treatment option in this trial, has demonstrated promising results, with a 100% survival rate at an average follow-up of about 10 months and an 81.8% survival rate after one year. Melphalan is also effective, especially in high doses, and is often used for patients receiving stem cell transplants. These treatments together aim to weaken the immune system just enough to allow donor cells to take hold without completely destroying the bone marrow. ^{3 6 7 8 9}

Who Is on the Research Team?

Shalini Shenoy, M.D.

Principal Investigator

Washington University School of Medicine (in St. Louis)

Are You a Good Fit for This Trial?

This trial is for children and young adults under 21 with non-cancerous blood, bone marrow, or metabolic disorders. They must have a matched donor for bone marrow or umbilical cord blood transplant and be in good health otherwise. Pregnant individuals, those with HIV, or active infections cannot participate.

Inclusion Criteria

My Hemoglobin S level is below 30%.

I have a non-cancerous condition and am getting a fully matched bone marrow transplant.

Negative pregnancy test

Exclusion Criteria

I have a serious infection.

Pregnancy/lactating

HIV positive

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Participants undergo a reduced-intensity conditioning regimen to maximize host immunosuppression without myeloablation

2-3 weeks

Transplantation

Hematopoietic stem cell transplantation is performed to achieve donor cell engraftment

1 week

Follow-up

Participants are monitored for safety, effectiveness, and incidence of graft-versus-host disease

100 days

Long-term Follow-up

Participants are monitored for chronic graft-versus-host disease, donor engraftment, immune reconstitution, and overall survival

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Campath
• Fludarabine
• Melphalan

Trial Overview

The study tests a new transplant conditioning regimen that uses Campath (an immunosuppressive drug), Fludarabine (a chemotherapy agent), and Melphalan (another chemotherapy) to prepare patients' bodies to accept donor cells without fully destroying their own bone marrow.

How Is the Trial Designed?

Group I: Stratum 4 Experimental Treatment 3 Interventions

Recipient with non-malignant disorder, excluding hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB

Group II: Stratum 3 Experimental Treatment 3 Interventions

Recipient with hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB

Group III: Stratum 2 Experimental Treatment 3 Interventions

Recipient with transfusion dependent thalassemia. Related or unrelated. 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB

Group IV: Stratum 1 Experimental Treatment 2 Interventions

Recipients with non-malignant disorders, excluding thalassemia. Related or unrelated 8/8 HLA-matched bone marrow

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

Approved in European Union as Campath for:

• Chronic lymphocytic leukemia
• Multiple sclerosis

Approved in United States as Lemtrada for:

• Relapsing forms of multiple sclerosis

Approved in Canada as Campath for:

• Chronic lymphocytic leukemia
• Multiple sclerosis

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

St. Louis Children's Hospital

Collaborator

Trials

30

Recruited

83,200+

Published Research Related to This Trial

Alemtuzumab (Campath 1H), a monoclonal antibody targeting CD52 on B and T cells, is increasingly used as a conditioning agent for bone marrow transplantation, but it can have serious side effects.

In a case study of a 37-year-old woman, acute renal failure and disseminated intravascular coagulation (DIC) occurred after receiving Campath, leading to the abortion of her transplant and ongoing dialysis, highlighting the need for caution and further investigation into its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. Osborne, WL., Lennard, AL.[2017]

In a study of 17 pediatric patients undergoing matched unrelated hematopoietic stem cell transplantation (HSCT) with Campath-1H, the incidence of grade I-II acute graft versus host disease (GVHD) was only 29.4%, and no cases of chronic GVHD were observed, suggesting effective reduction of GVHD risk.

Despite a 35.3% relapse rate of primary disease, the overall survival rates were high at 100% at 100 days and 94% at one year, indicating that Campath-1H does not significantly increase the risk of life-threatening infections or relapse compared to conventional regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretransplant conditioning with Campath-1H (alemtuzumab) in pediatric matched unrelated hematopoietic stem cell transplants: an institutional experience. Nageswara Rao, AA., Kumar, R., Altaf, S., et al.[2017]

Capecitabine is an effective oral chemotherapy drug that converts to 5-fluorouracil in tumor tissue, making it easier to administer with a good safety profile, particularly in treating metastatic breast and colorectal cancers.

The addition of capecitabine to docetaxel in patients with metastatic breast cancer who had previously received anthracycline treatment significantly improved overall survival, highlighting its efficacy in combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine in the treatment of colorectal cancer. O'Neill, VJ., Cassidy, J.[2015]

The FOLFIRI regimen, which combines irinotecan (CPT-11) with 5-fluorouracil (5-FU) and Leucovorin (LV), has been established as a standard first-line chemotherapy for metastatic colorectal cancer since 2000, based on results from controlled randomized phase III trials.

This regimen requires careful supportive therapy to ensure safe administration, highlighting the importance of managing side effects while maximizing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[FOLFIRI regimen for metastatic or recurrent colorectal cancer]. Uemura, N., Yamada, Y.[2013]

The phase I clinical trial involving 21 patients with metastatic colorectal cancer demonstrated that the combination of CPT-11 with 5-FU and leucovorin is a safe outpatient treatment, with minimal hematologic toxicity and manageable side effects.

The study identified diarrhea as the dose-limiting toxicity at the maximum tolerated dose of 100 mg/m2 of CPT-11, while an 80 mg/m2 dose is recommended for further testing in phase II trials, showing some patients achieved partial responses to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of CPT-11 in combination with 5-fluorouracil plus leucovorin chemotherapy for patients with metastatic colorectal cancer. Yamaguchi, Y., Minami, K., Kawabuchi, Y., et al.[2018]

The study involved 25 patients with hematologic malignancies undergoing nonmyeloablative transplantation using a regimen that included Campath-1H, which aimed to reduce the risk of graft-versus-host disease (GVHD).

While the regimen showed a low nonrelapse mortality rate of 12% and successful engraftment in most patients, acute GVHD occurred in 40% of cases, indicating that GVHD remains a significant challenge in this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study of a reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation for patients with hematologic malignancies using Campath-1H as part of a graft-versus-host disease strategy. Shore, T., Harpel, J., Schuster, MW., et al.[2017]

A population pharmacokinetic model for alemtuzumab was developed using data from 206 pediatric patients, revealing that body weight significantly affects the drug's clearance and distribution, which can lead to variable drug exposure.

The study suggests that the current standard dosing method may not be optimal for all children, and individualized dosing based on this model could improve treatment outcomes and reduce toxicity associated with alemtuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Admiraal, R., Jol-van der Zijde, CM., Furtado Silva, JM., et al.[2023]

In a phase II study involving 39 patients with advanced colorectal cancer, the combination of irinotecan and 5-fluorouracil showed promising efficacy, with 8 patients achieving an objective response and 12 experiencing disease stabilization, leading to surgical resection in some cases.

The treatment was generally well tolerated, with hematologic toxicity being the most common serious side effect (29% of patients), while the median duration of response was 14 months and median survival was 11 months, indicating a favorable outcome for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective phase II trial of iriontecan, 5-fluorouracil, and leucovorin in combination as salvage therapy for advanced colorectal cancer. Gil-Delgado, MA., Guinet, F., Castaing, D., et al.[2019]

The combination of irinotecan and capecitabine (XELIRI) was found to be effective in treating advanced colorectal adenocarcinoma, with a median survival of 16 months and a 30% partial response rate among 40 patients.

XELIRI was well-tolerated, with common side effects being leukopenia and gastrointestinal issues, making it a more convenient option compared to traditional intravenous chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan plus capecitabine as first-line chemotherapy in advanced colorectal cancer. Gennatas, C., Michalaki, V., Gennatas, S., et al.[2018]

In a study of 127 patients undergoing allogeneic hematopoietic cell transplantation, reducing the dose of alemtuzumab to 10 mg for graft-versus-host disease (GVHD) prophylaxis was feasible and did not significantly increase the risk of severe aGVHD compared to higher doses.

The study found that while there were no significant differences in the incidence of severe aGVHD across different alemtuzumab doses, the 20 mg dose showed a significant difference in the incidence of aGVHD grade II-IV compared to the 40 mg dose, suggesting that lower doses may be effective in preventing GVHD while minimizing potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel GVHD-prophylaxis with low-dose alemtuzumab in allogeneic sibling or unrelated donor hematopoetic cell transplantation: the feasibility of deescalation. Bertz, H., Spyridonidis, A., Wäsch, R., et al.[2017]

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13% of patients who took LEMTRADA experienced confirmed disability progression compared with 21% of those who took Rebif.

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Post-transplantation survival es- timates range from 20% to 60%, with variation related to MDS subtype, disease risk, cytogenetics, and conditioning in- tensity ...

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pmc.ncbi.nlm.nih.gov/articles/PMC8032381/

Safety of Alemtuzumab and Autologous Hematopoietic ...

We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for ...

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lemtrada.com/about/safety-side-effects

Safety & Side Effects: LEMTRADA® (alemtuzumab)

LEMTRADA can cause serious side effects including autoimmune problems, infusion reactions, stroke, tears in your arteries that supply blood to your brain.

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Campath (ALEMTUZUMAB) Package Insert

Safety data, except where indicated, are based on 149 patients with B-CLL enrolled in studies of Campath as a single agent administered at a ...

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Real-world safety and effectiveness of alemtuzumab as a ...

Alemtuzumab has been shown to reduce the incidence of severe acute GVHD among patients receiving HSCT with excellent disease-free survival.

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Safety in Immunomodulatory Functions of Alemtuzumab ...

The purpose of this study is to evaluate the safety of alemtuzumab after kidney transplantation as part of a multitherapy regimen to prevent kidney graft ...