RIC Regimen for Nonmalignant Diseases

(RIC Trial)

Overseen By Patricia Hankins, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Uncontrolled infections, others

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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment plan called reduced intensity conditioning (RIC) to determine its effectiveness for certain non-cancerous blood disorders. The goal is to see if this approach can lead to successful and less risky bone marrow or cord blood transplants. People with conditions like sickle cell disease or immune system disorders, who often face serious health challenges, might be suitable candidates. Participants will receive a combination of medications, such as Busulfan (a chemotherapy drug) and Campath (an immunotherapy drug), to prepare their bodies for the transplant. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

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 has shown that alemtuzumab and busulfan, part of the treatment under study, have been used for other conditions and have known side effects. Alemtuzumab causes infusion reactions in 95% of patients and infections in 74% of cases. Thyroid problems occurred in 30% of patients using alemtuzumab. These side effects are significant but can often be managed with medical care.

Busulfan is generally well-tolerated and considered safe. Its side effects can be managed, and it effectively controls symptoms. The method of administering busulfan, such as through an IV, can affect the risk of treatment-related issues and overall survival.

This study is in Phase 2, meaning researchers are still testing the treatment's efficacy and safety. By this phase, treatments have demonstrated some safety in earlier trials. However, researchers continue to monitor for any side effects. Prospective participants should discuss these potential risks with the study team to understand their implications. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a fresh approach to managing nonmalignant diseases requiring bone marrow or cord blood transplants. Unlike the standard of care that typically involves high-dose chemotherapy, these regimens use reduced-intensity conditioning (RIC), which is less aggressive, potentially leading to fewer side effects. The treatments combine Busulfan or Campath (Alemtuzumab) with other drugs like Fludarabine and Cyclosporine, offering a unique mechanism of action that may better prepare patients for transplant with reduced toxicity. This approach could improve outcomes and make transplants accessible to patients who cannot tolerate conventional high-dose regimens.

What evidence suggests that this trial's treatments could be effective for non-malignant diseases?

In this trial, participants will receive different treatment regimens as part of a reduced intensity conditioning (RIC) plan for non-cancerous diseases. One arm involves Alemtuzumab (Campath), which previous studies have shown to reduce disease activity and slow progression in conditions like multiple sclerosis. Another arm includes Busulfan, which has been used safely and effectively in children with non-cancerous conditions, improving survival rates and enabling successful integration of donor cells. Research suggests that these treatments in the RIC plan may be well-tolerated and lead to positive outcomes, such as stable mixed chimerism, potentially curing these conditions. ^{1 6 7 8 9}

Who Is on the Research Team?

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for young people aged between 6 months and 25 years with certain non-cancerous diseases like severe immune disorders, blood conditions (like sickle cell disease), or bone marrow failure. They must have a heart that pumps well, normal-ish kidney function, liver tests not too high, and no ongoing serious infections.

Inclusion Criteria

I am between 6 months and 25 years old.

My heart, kidneys, and liver meet the health requirements, and I don't have any active infections.

I have IPEX syndrome, Sickle cell, Thalassemia major, or Bone marrow failure.

Exclusion Criteria

I do not have any untreated infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants undergo a reduced intensity conditioning regimen with Alemtuzumab, Fludarabine, and Melphalan or Busulfan, depending on the protocol

3 weeks

Inpatient treatment

Transplant

Bone marrow or cord blood infusion is performed

1 day

Inpatient procedure

Post-Transplant Monitoring

Participants are monitored for engraftment and early outcomes

100 days

Follow-up

Participants are monitored for event-free survival, including graft failure, disease recurrence, or death

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Campath

Trial Overview

The study is testing different levels of Campath (a medication used to prepare the body for transplant) and a smaller dose of Busulfan (chemotherapy) in patients getting donor stem cells from bone marrow or cord blood. The goal is to see if these reduced intensity treatments help the body accept new stem cells with fewer complications.

How Is the Trial Designed?

Group I: RIC:Intermediate Campath Experimental Treatment 1 Intervention

Day Treatment Day - 14 to-10 Inpatient: Alemtuzumab (Campath) IV or SQ (subcutaneously) Day - 7 to -3 Fludarabine IV Day - 2 Melphalan 140 mg/m2 IV Day - 1 Cyclosporine infusion starts Day 0 Transplant: Bone marrow or cord blood infusion

Group II: RIC: Mini Busulfan Experimental Treatment 1 Intervention

Day Treatment Day - 8 Alemtuzumab (Campath) IV or SQ (subcutaneously) Day - 7 Alemtuzumab (Campath) IV or SQ (subcutaneously) Day - 6 Alemtuzumab (Campath) IV or SQ (subcutaneously) Busulfan IV Fludarabine IV Day - 5 Alemtuzumab (Campath) IV or SQ (subcutaneously) Busulfan IV Fludarabine IV Day - 4 Alemtuzumab (Campath) IV or SQ (subcutaneously) Fludarabine IV Day - 3 Fludarabine IV Day - 2 Fludarabine IV Cyclosporine infusion Day - 1 Rest Day 0 Transplant: Bone marrow or cord blood infusion

Group III: RIC: Distal Campath Experimental Treatment 1 Intervention

Day Treatment Day - 22 Inpatient: Alemtuzumab (Campath) test dose IV or SQ (subcutaneously) (subcutaneously) over 2 hours Day - 21 to-19 Alemtuzumab IV/ SQ (subcutaneously) Day - 7 to -3 Readmission to hospital Fludarabine IV Day - 2 Melphalan IV Day - 1 Begin cyclosporine infusion Day 0 Transplant: Bone marrow or cord blood infusion

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Published Research Related to This Trial

In a phase II study involving 8 patients with advanced cutaneous T-cell lymphoma, alemtuzumab showed a modest overall response rate of 38%, with some patients achieving partial remission, but responses were short-lived, lasting less than 3 months.

The treatment was associated with significant toxicity, including severe cytopenias and infectious complications, indicating that while alemtuzumab has some biological activity, its safety profile and limited efficacy suggest the need for further research into combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with advanced mycosis fungoides and Sézary syndrome with alemtuzumab. Kennedy, GA., Seymour, JF., Wolf, M., et al.[2021]

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]

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]

Disease-modifying antirheumatic drugs (DMARDs) are essential for treating immune-mediated inflammatory diseases (IMIDs), but they carry a risk of malignancy, which is a significant concern for patients, especially since many IMIDs already have a higher background risk of cancer.

Some conventional synthetic DMARDs, like chloroquine, hydroxychloroquine, and methotrexate, have shown potential antineoplastic properties, suggesting they could be beneficial for patients with both IMIDs and existing malignancies, which may help guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: a Review. Hsieh, CH., Huang, YW., Tsai, TF.[2022]

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