Reduced-Intensity Stem Cell Transplant for Non-Malignant Disorders

(HSCT+RIC Trial)

Overseen By Paul Szabolcs, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Paul Szabolcs

Disqualifiers: Active malignancy, Severe aplastic anemia, 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

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The objective of this study is to evaluate the efficacy of using a reduced-intensity condition (RIC) regimen with umbilical cord blood transplant (UCBT), double cord UCBT, matched unrelated donor (MUD) bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) in patients with non-malignant disorders that are amenable to treatment with hematopoietic stem cell transplant (HSCT). After transplant, subjects will be followed for late effects and for ongoing graft success.

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 reduced-intensity stem cell transplant using Alemtuzumab and Fludarabine generally safe for humans?

Alemtuzumab, used in stem cell transplants, can cause delayed immune recovery and increase the risk of viral infections. There are reports of serious side effects like acute kidney failure and blood clotting issues when used with Fludarabine, although these are rare. Safety varies, and careful monitoring is essential. ^{1 2 3 4 5}

What makes the Reduced-Intensity Stem Cell Transplant treatment for non-malignant disorders unique?

This treatment is unique because it combines multiple drugs, including Alemtuzumab, Fludarabine, Hydroxyurea, Melphalan, and Thiotepa, to create a reduced-intensity regimen that may be less harsh on the body compared to traditional high-dose chemotherapy. This approach is particularly novel for non-malignant disorders, where standard treatments may not be well-established. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Alemtuzumab in the clinical trial for Reduced-Intensity Stem Cell Transplant for Non-Malignant Disorders?

Alemtuzumab has been effectively used as an immunosuppressant in post-transplant induction therapy, showing good outcomes in renal transplantation by depleting lymphocytes, which are a type of white blood cell. ^{1 2 11 12 13}

Who Is on the Research Team?

Paul Szabolcs, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for patients with non-cancerous disorders like juvenile arthritis, bone marrow failure, primary immunodeficiency, anemia, and metabolic diseases. Participants must have proper organ function, no active malignancy or severe aplastic anemia, not be pregnant or nursing mothers, and should not have had a stem cell transplant in the last 6 months.

Inclusion Criteria

Adequate organ function as measured by: Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m2, Hepatic transaminases (ALT/AST) ≤ 4 x upper limit of normal (ULN), Adequate cardiac function by echocardiogram or radionuclide scan (shortening fraction > 26% or ejection fraction > 40% or > 80% of normal value for age), Pulmonary evaluation testing demonstrating CVC or FEV1/FVC of ≥ 50% of predicted for age and/or resting pulse oximeter ≥ 92% on room air or clearance by the pediatric or adult pulmonologist. For adult patients DLCO (corrected for hemoglobin) should be ≥ 50% of predicted if the DLCO can be obtained, Written informed consent and/or assent according to FDA guidelines, Negative pregnancy test if pubertal and/or menstruating, HIV negative, A non-malignant disorder amenable to treatment by stem cell transplantation

I have a suitable donor for my stem cell transplant.

Exclusion Criteria

I have been diagnosed with severe aplastic anemia.

I had a stem cell transplant from a donor within the last 6 months.

I have an active cancer or myelodysplastic syndrome.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Reduced Intensity Conditioning (RIC)

Participants undergo reduced-intensity conditioning with Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan, and Thiotepa prior to allogenic HSCT

4-6 weeks

Transplantation

Participants receive umbilical cord blood, bone marrow, or peripheral blood stem cell transplantation

1 week

Follow-up

Participants are monitored for safety, effectiveness, and late effects after transplantation

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Fludarabine
• Hydroxyurea
• Melphalan
• Thiotepa

Trial Overview The study tests a reduced-intensity conditioning regimen before umbilical cord blood transplant (UCBT), bone marrow transplant (BMT) from unrelated donors or peripheral blood stem cell transplant (PBSCT). It aims to see how well these transplants work for treating various non-malignant disorders.

How Is the Trial Designed?

Group I: UCBT:transfusion dependent anemias or increased rejection risk Experimental Treatment 5 Interventions

Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan, and Thiotepa conditioning regimen prior to allogenic HSCT.

Group II: BMT, PBSCT and not transfusion dependent UCBT Experimental Treatment 5 Interventions

Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan, and Thiotepa conditioning regimen prior to allogenic HSCT.

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?

Paul Szabolcs

Lead Sponsor

Trials

8

Recruited

230+

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]

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]

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 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]

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]

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]

Alemtuzumab induction therapy in kidney transplantation significantly reduces the risk of biopsy-proven acute rejection (BPAR) compared to interleukin-2 receptor antibodies (IL-2RAs), with a relative risk of 0.54 based on a systematic review of 10 randomized controlled trials involving 1223 patients.

There was no significant difference in the risk of BPAR when comparing alemtuzumab to rabbit antithymocyte globulin (rATG), and other outcomes like graft loss and patient death were similar across induction methods, suggesting that safety and cost may guide the choice of induction therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Morgan, RD., O'Callaghan, JM., Knight, SR., et al.[2018]

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]

Capecitabine is an oral chemotherapy that selectively produces 5-fluorouracil in tumors, making it effective for treating metastatic colorectal cancer, showing comparable efficacy to traditional treatments.

In patients with metastatic breast cancer, capecitabine not only works for those who have not responded to other treatments but also improves survival when combined with docetaxel compared to docetaxel alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine: fulfilling the promise of oral chemotherapy. Hwang, JJ., Marshall, JL.[2019]

In a study of 107 patients with metastatic colorectal cancer, the combination of irinotecan plus bevacizumab showed similar efficacy to FOLFIRI plus bevacizumab, with median progression-free survival of 6.4 months versus 5.8 months, and overall survival of 16.6 months versus 16.5 months, respectively.

Omitting fluorouracil from the FOLFIRI regimen resulted in fewer adverse events, such as nausea and neutropenia, suggesting that irinotecan plus bevacizumab may be a safer second-line treatment option for patients who are refractory to fluoropyrimidines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. Matsubara, Y., Masuishi, T., Ogata, T., et al.[2023]

The modified FOLFIRI regimen, which includes irinotecan, 5-fluorouracil, and a low dose of leucovorin, demonstrated a 47.8% overall response rate in 44 patients with recurrent or metastatic colorectal cancer, indicating its efficacy as a first-line treatment.

The treatment was well-tolerated, with mild and manageable toxicities; only a few patients experienced severe side effects, such as Grade 3/4 leukopenia and diarrhea, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, continuous 5-fluorouracil, and low dose of leucovorin (modified FOLFIRI) as first line of therapy in recurrent or metastatic colorectal cancer. Lee, MA., Byun, JH., Shim, BY., et al.[2019]

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]

In a study of 109 patients with stage IV colon cancer receiving palliative chemotherapy, dose reductions due to side effects did not significantly affect overall survival, suggesting that lower doses can still be effective.

Patients who required dose reductions received more cycles of chemotherapy and had similar cumulative dosages compared to those on full doses, indicating that dose adjustments may allow for better treatment tolerance and potentially improved outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for metastatic colon cancer: No effect on survival when the dose is reduced due to side effects. Munker, S., Gerken, M., Fest, P., et al.[2023]

Citations

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. Japan 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. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Alemtuzumab induction in deceased donor kidney transplantation. [2017]

5. England pubmed.ncbi.nlm.nih.gov

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

6. 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]

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

Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. [2018]

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

Alemtuzumab in stem cell transplantation. [2021]

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

Capecitabine: fulfilling the promise of oral chemotherapy. [2019]

10. Germany pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. [2023]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

Irinotecan, continuous 5-fluorouracil, and low dose of leucovorin (modified FOLFIRI) as first line of therapy in recurrent or metastatic colorectal cancer. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Capecitabine in the treatment of colorectal cancer. [2015]

13. England pubmed.ncbi.nlm.nih.gov

Chemotherapy for metastatic colon cancer: No effect on survival when the dose is reduced due to side effects. [2023]