Transplant Approach for Sickle Cell Disease

(SUN-RAY Trial)

Recruiting at 1 trial location

Overseen By Robert Nickel, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's National Research Institute

Disqualifiers: HIV, Hepatitis B/C, 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: 10

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment method for individuals with sickle cell disease who face specific blood compatibility challenges with their donors. The researchers aim to determine if adding daratumumab, an immunotherapy, to the transplant process can prevent complications while ensuring safety. The trial uses a combination of medications and irradiation before a stem cell transplant from a compatible sibling. Participants may qualify if they have sickle cell disease with frequent severe pain episodes or complications like stroke and have a matching sibling donor with certain blood type differences. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in sickle cell treatment.

Will I have to stop taking my current medications?

The trial information does not specify if 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 is safe when administered under the skin for children undergoing transplants for sickle cell disease, indicating it is generally well-tolerated in similar situations. Studies have found that daratumumab is effective and mostly safe, with most patients experiencing successful treatment for related conditions. However, some have experienced side effects such as sickle cell crises and liver problems.

Sirolimus has improved anemia without major safety concerns, though dose-related effects may occur, making it important to stay within recommended limits.

Total body irradiation, used in very low doses here, has proven safe in similar transplant situations. It is part of standard procedures for certain types of transplants and contributes to good survival rates in patients.

Overall, each of these treatments has demonstrated a reasonable safety profile in similar settings, but like any medical treatment, risks and side effects can occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment protocol for sickle cell disease because it combines innovative elements that differ from standard care approaches. Unlike conventional treatments, which usually involve hydroxyurea or blood transfusions, this approach integrates a unique conditioning regimen using alemtuzumab and daratumumab before hematopoietic cell transplantation (HCT). These drugs help to prepare the body for the transplant by targeting specific immune cells, potentially reducing the risk of complications. Additionally, the use of low-dose total body irradiation with gonadal shielding and sirolimus for graft-versus-host disease (GVHD) prophylaxis helps to protect healthy tissues and improve patient outcomes. This multifaceted strategy aims to enhance the effectiveness and safety of transplants for patients with sickle cell disease, offering new hope for long-term remission.

What evidence suggests that this trial's treatments could be effective for sickle cell disease?

In this trial, participants will receive different treatment regimens to improve transplant outcomes for sickle cell disease. Research has shown that daratumumab, which participants will receive, effectively treats pure red cell aplasia, with 93% of patients improving within 14 days. Alemtuzumab, another treatment in this trial, is often used in transplants and effectively reduces immune reactions and supports new blood cell growth. Sirolimus, also part of the trial regimen, increases fetal hemoglobin and prevents graft-versus-host disease (GVHD), where a transplant attacks the body. Total body irradiation, carefully used in the trial, has improved transplant success rates in sickle cell disease, leading to good long-term outcomes. Each treatment aims to make transplants safer and more effective for sickle cell patients. ^{1 2 6 7 8}

Who Is on the Research Team?

Robert Nickel, MD

Principal Investigator

Children's National Research Institute

Are You a Good Fit for This Trial?

This trial is for individuals with Sickle Cell Anemia or Disease who have antibodies against donor red blood cells. They're looking at whether a new treatment can help them receive transplants from siblings without complications.

Inclusion Criteria

I have a sickle cell genotype with significant symptoms or treatments in the past year.

I am between 2 and 24 years old with sickle cell disease and have a sibling donor who is a perfect match but has a different blood type, or I have antibodies against donor blood types.

I have sickle cell disease with complications or treatments as described.

Exclusion Criteria

My lung function is low, and I may have severe asthma.

I have a sibling donor match for a blood or marrow transplant without major blood type issues.

Life expectancy less than 6 months

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Participants receive daratumumab intravenously on days -49, -42, -35, and -28 prior to HCT

7 weeks

4 visits (in-person)

Conditioning

Participants undergo conditioning with alemtuzumab and low dose total body irradiation

1 week

5 visits (in-person)

Transplantation

Hematopoietic cell transplant (HCT) is performed

1 day

1 visit (in-person)

Post-transplant Treatment

Sirolimus is given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including immune reconstitution and donor chimerism testing

1 year

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Daratumumab
• Sirolimus
• Total Body Irradiation

Trial Overview The study tests if daratumumab, along with alemtuzumab, low-dose total body irradiation, and sirolimus before sibling donor transplant, can prevent complications in patients with anti-donor antibodies.

How Is the Trial Designed?

Group I: Recipients with red cell alloantibodies (non-ABO) against donor antigens Experimental Treatment 4 Interventions

Patients in this cohort are treated pre-HCT with Daratumumab, intravenously, on days -49, -42, -35 and -28. The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY on day -2 with gonadal shielding. Sirolimus will be given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism. G-CSF, at 5 mcg/kg/day, will be given post stem cell infusion until neutrophil engraftment is achieved.

Group II: Recipients with a major ABO incompatible donor Experimental Treatment 4 Interventions

Patients in this cohort are treated pre-HCT with Daratumumab, intravenously, on days -49, -42, -35 and -28. The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY on day -2 with gonadal shielding. Sirolimus will be given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism. G-CSF, at 5 mcg/kg/day, will be given post stem cell infusion until neutrophil engraftment is achieved.

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

Approved in United States as Campath for:

• Chronic lymphocytic leukemia
• Multiple sclerosis

Approved in European Union as Lemtrada for:

• Multiple sclerosis

Approved in European Union as Campath for:

• Chronic lymphocytic leukemia

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Children's Hospital at Montefiore

Collaborator

Trials

2

Recruited

70+

Alberta Children's Hospital

Collaborator

Trials

58

Recruited

44,700+

Ann & Robert H Lurie Children's Hospital of Chicago

Collaborator

Trials

275

Recruited

5,182,000+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Levine Children's Hospital

Collaborator

Trials

4

Recruited

560+

Doris Duke Charitable Foundation

Collaborator

Trials

65

Recruited

264,000+

Janssen Pharmaceuticals

Industry Sponsor

Trials

87

Recruited

208,000+

Joaquin Duato

Janssen Pharmaceuticals

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Pharmaceuticals

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

A radiation-free conditioning regimen using fludarabine, carmustine, and thiotepa was tested in 30 high-risk or relapsed patients undergoing allogeneic hematopoietic cell transplantation, showing a 2-year overall survival rate of 52%.

This approach is particularly beneficial for less-fit patients with hematologic malignancies affecting the central nervous system, offering a potentially curative alternative to traditional total body irradiation, despite concerns about neurologic toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation-free allogeneic conditioning with fludarabine, carmustine, and thiotepa for acute lymphoblastic leukemia and other hematologic malignancies necessitating enhanced central nervous system activity. Christopoulos, P., Bertz, H., Ihorst, G., 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 study of 265 patients aged 40 and older with acute lymphoblastic leukemia undergoing reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation, no significant differences in key outcomes such as relapse rates, nonrelapse mortality, and overall survival were found between those receiving TBI-based and thiotepa-based regimens.

While TBI-based regimens were associated with a higher incidence of chronic graft-versus-host disease (43% vs. 29%), multivariate analysis indicated that thiotepa-based regimens are a valid alternative to TBI, as they did not show differences in major transplantation outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa-Based Regimens Are Valid Alternatives to Total Body Irradiation-Based Reduced-Intensity Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Battipaglia, G., Labopin, M., Mielke, S., et al.[2023]

Alemtuzumab, when used in reduced-intensity conditioning for allogeneic stem cell transplantation, significantly reduces the incidence of graft-versus-host disease (GvHD) and treatment-related mortality (TRM), improving patient outcomes in hematological diseases.

However, while it effectively prevents GvHD, alemtuzumab can lead to increased disease relapse and slower immune recovery, necessitating careful monitoring for opportunistic infections and managing the risk of disease recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in allogeneic hematopoetic stem cell transplantation. Poiré, X., van Besien, K.[2021]

Alemtuzumab (CAMPATH-1H) is an effective monoclonal antibody for depleting T-cells in stem cell transplantation, significantly reducing the risk of graft-versus-host disease (GVHD) while maintaining low rates of graft rejection.

Current protocols for using alemtuzumab, either added to stem cell infusions or administered before transplantation, show excellent control of GVHD and have been associated with reduced transplant-related mortality, particularly from infections, although further clinical trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in stem cell transplantation. Hale, G.[2021]

Patients receiving alemtuzumab induction therapy after renal transplantation showed significantly higher stability rates (96.6%) compared to those on conventional immunosuppressive therapy (75.7%), indicating better outcomes with alemtuzumab.

The ImmuKnow assay revealed that ATP levels, which reflect immune function, were significantly lower in the alemtuzumab group compared to the conventional group at 180 days post-transplant, suggesting that while alemtuzumab effectively maintains stability, it may also lead to reduced immune responsiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of the ImmuKnow assay to evaluate the effect of alemtuzumab-depleting induction therapy on cell-mediated immune function after renal transplantation. Zhou, H., Lin, J., Chen, S., et al.[2021]

In a phase 2 clinical trial involving 102 patients with Hodgkin and non-Hodgkin lymphoma, the modified BeEAM regimen using Bendamustine demonstrated a high overall survival rate of 87.3% and a disease-free survival rate of 66.7% at two years, indicating its efficacy as a conditioning treatment for autologous stem cell transplantation.

The treatment was found to be safe, with no transplant-related mortality and manageable toxicities, including mucositis and nausea, suggesting that Bendamustine can be a viable alternative to Carmustine in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the Efficacy of Modified BeEAM(Bendamustine, Etoposide, Cytarabine, Melphalan) Regimen as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Lymphoma: An Experience from Two Centers of a Developing Country. Ramzi, M., Vafaie, E., Haghighinejad, H., et al.[2023]

Total body irradiation (TBI) is effective in treating leukemia, but higher doses can lead to increased toxicities and immunosuppression, which complicates treatment outcomes.

Fractionated TBI is associated with reduced late toxicities compared to single-dose TBI, while targeted radiation methods, such as directed external beam irradiation, may enhance treatment efficacy without increasing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of total dose, fractionation, dose rate, and distribution of total body irradiation on bone marrow transplantation. Appelbaum, FR.[2021]

Cranial radiotherapy (CRT) has been effective in controlling meningeosis in acute leukemia, but recent studies suggest that in low-risk acute lymphoblastic leukemia (ALL), it can be safely replaced with high-dose methotrexate (HD-MTX) without increasing CNS relapse rates.

For medium and high-risk ALL, a combination of multidrug chemotherapy and limited CRT significantly reduces CNS relapse rates to below 5%, indicating that tailored treatment strategies are crucial for different risk levels in leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. Schrappe, M., Reiter, A., Riehm, H.[2019]

CAMPATH-1H (alemtuzumab) is effective in depleting lymphocytes and is licensed for treating chronic lymphocyte leukemia, showcasing its efficacy in managing blood cancers.

Short-term use of alemtuzumab has shown long-term benefits in various autoimmune conditions, suggesting it may help in reducing the need for ongoing immunosuppressive drugs in transplantation and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAMPATH: from concept to clinic. Waldmann, H., Hale, G.[2018]

In a study of 11 kidney transplant recipients, alemtuzumab induction led to a high patient and graft survival rate of 91% at one year, indicating its efficacy as an induction agent in renal transplantation.

The use of alemtuzumab was found to be safe, with no serious adverse events such as hyperlipidemia or new-onset diabetes, and no cases of acute rejection were observed, even among recipients of extended criteria donor kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab induction in deceased donor kidney transplantation. Shin, M., Song, SH., Kim, JM., et al.[2017]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9338787/

Alemtuzumab clearance, lymphocyte count, and T-cell ... Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39904467/

Comparison of outcomes following subcutaneous or ... We found that subcutaneous alemtuzumab administration elicited fewer infusion-related reactions than intravenously administered drug.

3. astctjournal.org astctjournal.org/article/S1083-8791(15)00597-2/fulltext

Nonmyeloablative Stem Cell Transplantation with ... No treatment-related mortality or graft-versus-host disease occurred after alemtuzumab/total body irradiation conditioning in sickle cell disease adults. •.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0966327425000073

Comparison of outcomes following subcutaneous or ... Conclusion. Subcutaneous administration of alemtuzumab for children undergoing transplant for sickle cell disease is safe and effective.

5. withpower.com withpower.com/trial/phase-3-anemia-sickle-cell-3-2018-e1c30

Transplant Method for Sickle Cell Disease (SUN Trial) Alemtuzumab has been shown to effectively deplete lymphocytes, which helps in immunosuppression during transplants, and has demonstrated clinical activity in ...

6. lemtrada.com lemtrada.com/about/clinical-study-relapses

LEMTRADA® (alemtuzumab) Clinical Study Results 13% of patients who took LEMTRADA experienced confirmed disability progression compared with 21% of those who took Rebif.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10920415/

Real-World Retrospective Analysis of Alemtuzumab Outcomes ... This study shows that alemtuzumab reduced the relapse rate and disability worsening in real-world clinical practice, with many patients ...

8. astctjournal.org astctjournal.org/article/S1083-8791(19)30136-3/fulltext

Nonmyeloablative Matched Sibling Donor Hematopoietic ... The study is a retrospective single center analysis of alemtuzumab/300 cGy total body irradiation (TBI) matched sibling donor peripheral blood hematopoietic ...