Transplant Conditioning Regimen for Blood Disorders

Recruiting at 16 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

Trial Summary

What is the purpose of this trial?

The hypothesis for this study is that a preparative regimen that maximizes host immunosuppression without myeloablation will be well tolerated and sufficient for engraftment of donor hematopoietic cells. It is also to determine major toxicities from these conditioning regimens, within the first 100 days after transplantation.

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 effectiveness of the drug regimen for blood disorders?

The combination of Campath (Alemtuzumab), Fludarabine, and Melphalan has been shown to be a reasonable preparative regimen for reduced-intensity transplantation, with a low nonrelapse mortality rate, although issues with graft-versus-host disease (GVHD) remain. In pediatric cases, Campath-1H effectively reduced the risk of serious GVHD without increasing life-threatening infections or relapse compared to conventional regimens. ^{1 2 3 4 5}

What makes the transplant conditioning regimen with Campath, Fludarabine, and Melphalan unique?

This regimen is unique because it combines three drugs—Campath (alemtuzumab), Fludarabine, and Melphalan—to prepare patients for a blood stem cell transplant, which is not a standard treatment for many blood disorders. Each drug has a specific role: Campath targets immune cells, Fludarabine suppresses the immune system, and Melphalan is a chemotherapy agent, together creating a comprehensive approach to conditioning before transplantation. ^{6 7 8 9 10}

Research Team

Shalini Shenoy, M.D.

Principal Investigator

Washington University School of Medicine (in St. Louis)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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 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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

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

2. United States 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. [2017]

3. United States 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. [2017]

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

Pretransplant conditioning with Campath-1H (alemtuzumab) in pediatric matched unrelated hematopoietic stem cell transplants: an institutional experience. [2017]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Capecitabine in the treatment of colorectal cancer. [2015]

7. Japan pubmed.ncbi.nlm.nih.gov

[FOLFIRI regimen for metastatic or recurrent colorectal cancer]. [2013]

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

Prospective phase II trial of iriontecan, 5-fluorouracil, and leucovorin in combination as salvage therapy for advanced colorectal cancer. [2019]

9. Greece 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. [2018]

10. Greece pubmed.ncbi.nlm.nih.gov

Irinotecan plus capecitabine as first-line chemotherapy in advanced colorectal cancer. [2018]