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?

This trial tests a new method for performing stem cell transplants in individuals with certain non-cancerous blood and immune system disorders. Researchers use a lighter treatment approach before the transplant to determine if it is more effective and causes fewer side effects. The trial targets individuals with severe immune deficiencies, certain inherited metabolic disorders, or blood diseases like sickle cell disease that lead to frequent pain crises or strokes. Participants should have a non-cancerous disorder that could benefit from a stem cell transplant and must not have undergone a transplant in the past six months. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatments in this study have varying safety levels. Alemtuzumab effectively reduces severe acute graft-versus-host disease (GVHD), a common issue in stem cell transplants, and demonstrates good survival rates, indicating it is generally well-tolerated.

Fludarabine, widely studied, is associated with a low occurrence of acute GVHD and high survival rates, suggesting it is safe for most patients.

Hydroxyurea, commonly used for blood disorders, is known to be safe, particularly for conditions like sickle cell disease.

Melphalan helps control disease and has acceptable side effects in older patients. However, it may pose risks for patients with kidney problems, who might experience more severe side effects.

Thiotepa is generally well-tolerated, but concerns exist about a higher chance of disease recurrence. While it is safe, there is a risk of relapse.

These treatments have undergone thorough testing, showing they are generally safe, but each has specific potential side effects to consider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for non-malignant disorders rely on high-intensity chemotherapy or radiotherapy, which can be harsh on the body. Researchers are excited about this reduced-intensity stem cell transplant approach because it uses a gentler conditioning regimen with Alemtuzumab, Fludarabine, Hydroxyurea, Melphalan, and Thiotepa. This combination aims to prepare the body for allogeneic stem cell transplantation with less toxicity and fewer side effects, making it more tolerable for patients. By reducing the intensity, there's hope for a safer procedure that still effectively supports the transplant process, potentially broadening access to this therapy for more patients.

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

This trial will evaluate a conditioning regimen that includes Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan, and Thiotepa before allogenic hematopoietic stem cell transplantation (HSCT). Studies have shown that Alemtuzumab effectively maintains positive treatment results over five years for certain conditions. Fludarabine improves outcomes for patients undergoing bone marrow replacement, with appropriate dosages linked to better survival rates. Hydroxyurea effectively manages blood disorders like sickle cell disease over the long term. Melphalan is used before transplants to destroy bone marrow cells and has proven effective in this role. Lastly, Thiotepa has demonstrated good survival rates after transplants, improving outcomes in various treatment settings. ^{6 7 8 9 10}

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

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 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]

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]

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]

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 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 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]

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]

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 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 (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]

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