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

75 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug regimen including Busulfan, Busulfex, Myleran, Campath, Alemtuzumab, and Lemtrada for nonmalignant diseases?

Research shows that Alemtuzumab (Campath) has been effective in improving outcomes in patients with advanced mycosis fungoides/Sézary syndrome, a type of skin lymphoma, and is used to prevent complications in bone marrow transplants. Additionally, Busulfan, when monitored for dosage, has been used successfully in conditioning regimens for stem cell transplants, suggesting potential effectiveness in similar settings. ^{1 2 3 4 5}

What safety data exists for the RIC Regimen using Alemtuzumab (Campath) in humans?

Alemtuzumab (Campath) has been associated with delayed immune recovery, viral reactivations, and leukemia relapse. Some patients experienced severe infusion-related reactions and immunosuppression. Rarely, it has caused acute kidney failure and blood clotting issues. ^{1 2 3 4 6}

What makes the RIC regimen with Busulfan and Campath unique for nonmalignant diseases?

The RIC regimen using Busulfan and Campath is unique because it combines two drugs that are typically used in cancer treatment to address nonmalignant diseases. Busulfan is a chemotherapy drug that helps suppress the immune system, while Campath (Alemtuzumab) is an antibody that targets specific immune cells, making this combination potentially effective for conditions where immune suppression is needed. ^{7 8 9 10 11}

What is the purpose of this trial?

This is a Phase II pilot study to evaluate engraftment and toxicity of patients with non-malignant diseases using a reduced intensity conditioning regimen in the setting of allogeneic transplant for non malignant diseases. Bone Marrow or cord blood will be acceptable as a stem cell source. Recently, reduced intensity conditioning (RIC) regimens have been used for both adult patients with leukemias and pediatric patients with non-malignant diseases. These regimens are better tolerated, resulting in less transplant related morbidity and mortality. Stable mixed chimerism, while insufficient for eradication of leukemias, may be sufficient to cure patients with non-malignant diseases.

Research Team

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

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

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

Mycosis fungoides/Sézary syndrome: a report of three cases treated with Campath-1H as salvage treatment. [2018]

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

Nursing care of patients receiving Campath. [2021]

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

Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Treatment of patients with advanced mycosis fungoides and Sézary syndrome with alemtuzumab. [2021]

7. England pubmed.ncbi.nlm.nih.gov

A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer. [2020]

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

Risk of malignancy in rheumatoid arthritis patients initiating biologics: an historical propensity score matched cohort study within the French nationwide healthcare database. [2022]

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

Personalized rheumatic medicine through dose reduction reduces the cost of biological treatment - a retrospective intervention analysis. [2020]

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

Guselkumab dosing interval optimization in adult patients with moderate-to-severe psoriasis switching from ustekinumab. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: a Review. [2022]