Stem Cell Transplantation for Osteopetrosis

Overseen By Lisa Burke

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnancy, Myeloablative chemotherapy, 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

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests stem cell transplantation to determine its effectiveness for individuals with severe osteopetrosis (a condition causing overly dense bones) and other inherited metabolic disorders. The goal is to replace unhealthy cells with healthy donor cells while minimizing side effects. Various treatment plans will be tested, so participants may receive different medications to prepare for the transplant. Individuals with severe osteopetrosis or specific inherited conditions affecting metabolism and the nervous system may be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in medical care.

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 shows that treatments like the stem cell transplants in this trial have been studied for safety. One study found that using the drugs busulfan and fludarabine resulted in minimal side effects and excellent outcomes. Specifically, patients with higher busulfan levels had successful transplants with few side effects.

Another study found that patients who received busulfan before their stem cell transplant had good results, and the treatment was well-tolerated. This suggests the treatment is likely safe.

However, some patients may experience bone health issues, such as reduced bone density, which are known risks and are closely monitored during treatment.

Overall, while there are some risks, past studies have shown that these treatments are generally well-tolerated. Participants should discuss any concerns with their healthcare providers to make informed decisions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the stem cell transplantation approach for osteopetrosis because it offers a potentially transformative solution for this challenging condition. Unlike current treatments, which mostly focus on managing symptoms or complications, stem cell transplantation targets the root cause by aiming to replenish and repair the defective bone marrow cells responsible for the disease. This method could significantly improve bone density and overall health outcomes by harnessing the body's ability to generate healthy cells. By using specially matched donor cells, it also offers a tailored approach that could lead to more effective and enduring results compared to conventional therapies.

What evidence suggests that this trial's treatments could be effective for osteopetrosis?

Research has shown that stem cell transplants can help treat severe osteopetrosis. In this trial, participants will join different treatment arms, each involving specific regimens. Some arms will use the drugs busulfan and fludarabine before a bone marrow transplant. Studies have found that this combination can increase survival rates. For inherited metabolic disorders, stem cell transplants with fludarabine have demonstrated a high survival rate of 96%. Specifically, in osteopetrosis cases, five out of seven patients were completely cured with this method. These findings suggest that stem cell transplants could be a promising treatment for these conditions. ^{1 6 7 8 9}

Who Is on the Research Team?

Paul Orchard, M.D.

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

This trial is for patients aged 0-55 with various inherited metabolic disorders like Hurler syndrome, Hunter syndrome without severe neurologic disease, and severe osteopetrosis. Participants must have a suitable stem cell donor, good organ function, and no recent myeloablative chemotherapy or uncontrolled infections.

Inclusion Criteria

I have been diagnosed with severe Osteopetrosis.

My condition is listed as eligible for this trial.

I have been diagnosed with MNGIE.

Exclusion Criteria

I do not have any uncontrolled infections, including HIV or mold infections in the last 30 days.

I haven't had intense chemotherapy within the last 4 months.

Pregnancy - menstruating females must have a negative serum or urine pregnancy test within 14 days of study treatment start

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo conditioning with busulfan and fludarabine, with busulfan therapeutic drug monitoring

1-2 weeks

Transplantation

Participants receive allogeneic hematopoietic cell transplantation

1 week

Follow-up

Participants are monitored for donor hematopoietic engraftment and transplant-related outcomes

100 days

Long-term Follow-up

Participants are monitored for post-HSCT changes in disease and other long-term outcomes

1 year

What Are the Treatments Tested in This Trial?

Interventions

• cALD HR-D (High-Risk, Regimen C)
• cALD HR-D (High-Risk, Regimen D)
• cALD SR-A (Standard-Risk, Regimen A)
• cALD SR-B (Standard-Risk, Regimen B)
• IMD Preparative Regimen
• Osteopetrosis Haploidentical Only Preparative Regimen
• Osteopetrosis Only Preparative Regimen
• Stem Cell Transplantation

Trial Overview The study tests the effectiveness of busulfan- and fludarabine-based conditioning regimens with busulfan drug monitoring in achieving successful stem cell engraftment while minimizing transplant-related mortality in patients with inherited metabolic disorders and osteopetrosis.

How Is the Trial Designed?

Group I: cALD SR-B (Standard-Risk, Regimen B) Experimental Treatment 3 Interventions

See intervention descriptions.

Group II: cALD SR-A (Standard-Risk, Regimen A) Experimental Treatment 3 Interventions

See intervention descriptions.

Group III: cALD HR-D (High-Risk, Regimen D) Experimental Treatment 3 Interventions

See intervention descriptions.

Group IV: cALD HR-C (High-Risk, Regimen C) Experimental Treatment 3 Interventions

See intervention descriptions.

Group V: OP and IMD -Haplo-Identical Only Experimental Treatment 2 Interventions

Severe Osteopetrosis (OP) and Inhterited Metabolic Disorders (IMD) -Haplo-Identical Only See intervention descriptions.

Group VI: OP - Except Haplo-Identical Experimental Treatment 2 Interventions

Severe Osteoperosis (OP) - Except Haplo-Identical See intervention descriptions.

Group VII: IMD - Except Haplo-identical Experimental Treatment 2 Interventions

Inherited Metabolic Disease (IMD) - Except Haplo-Identical See intervention descriptions.

cALD HR-D (High-Risk, Regimen C) is already approved in United States, European Union for the following indications:

Approved in United States as Busulfan and Fludarabine Conditioning Regimen for:

• Inherited Metabolic Disorders
• Severe Osteopetrosis

Approved in European Union as Busulfan and Fludarabine Conditioning Regimen for:

• Inherited Metabolic Disorders
• Severe Osteopetrosis

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Published Research Related to This Trial

In a study of 394 acute myeloid leukemia patients undergoing allogeneic stem cell transplantation, the fludarabine plus melphalan (FM) regimen showed a significantly lower relapse incidence compared to fludarabine plus busulfan (FB), indicating better control of the disease.

Despite the differences in relapse rates, both FM and FB regimens resulted in similar overall survival rates, suggesting that while FM may be more effective in preventing relapse, both treatments are comparably effective in terms of long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Baron, F., Labopin, M., Peniket, A., et al.[2015]

In a study of adult patients with acute myeloid leukemia (AML) receiving reduced-intensity conditioning (RIC) before allogeneic hematopoietic cell transplantation (allo-HCT), the Flu+Mel regimen showed a significantly lower risk of relapse compared to the Flu+ivBu regimen, indicating better disease control potential.

Patients receiving the Flu+ivBu regimen experienced significantly lower non-relapse mortality compared to those on Flu+poBu and Flu+Mel, suggesting that while both RIC regimens are effective, Flu+ivBu may be less toxic for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity stem cell transplantation for acute myeloid leukemia with fludarabine-based conditioning with intravenous busulfan versus melphalan. Yamashita, T., Takami, A., Uchida, N., et al.[2022]

In a study of 9 pediatric patients with hemophagocytic lymphohistiocytosis (HLH) treated with a busulfan and fludarabine-based reduced-intensity conditioning (RIC) regimen, all patients achieved successful neutrophil and platelet engraftment, indicating effective treatment.

The 8-year overall survival rate was 78%, with no early treatment-related mortality within 100 days, suggesting that this RIC regimen is a safe and effective option for HCT in pediatric HLH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis. Suh, JK., Koh, YK., Kang, SH., et al.[2022]

The reduced intensity conditioning regimen using busulfan, fludarabine, and rabbit ATG (Bu/Flu/rATG) was well tolerated in 19 pediatric patients, leading to an excellent overall survival rate of 89% and event-free survival of 74% after 2 years.

However, the study faced a significant challenge with a 21% graft failure rate, particularly in patients receiving transplants from mismatched unrelated donors, which ultimately led to the premature closure of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML. Horn, B., Baxter-Lowe, LA., Englert, L., et al.[2013]

A new preparative regimen for allogeneic stem cell transplantation was tested on 30 patients, primarily aimed at reducing regimen-related toxicity (RRT) while ensuring effective engraftment; 89% of evaluable patients achieved over 90% donor cell chimerism by day 100.

While the regimen showed minimal RRT and a low transplant-related mortality rate of 7% at 3 months, complications such as graft-versus-host disease (GVHD) occurred in 56% of patients, highlighting the need for further research to balance efficacy with safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience. Shaughnessy, PJ., Ornstein, D., Ririe, D., et al.[2019]

In a study of 378 high-risk non-Hodgkin lymphoma patients undergoing allogeneic stem-cell transplantation, the outcomes of reduced-intensity conditioning (FB2) were similar to those of myeloablative reduced-toxicity conditioning (FB3/FB4) in terms of overall survival and lymphoma-free survival.

The study found no significant advantage in using a myeloablative reduced-toxicity regimen, as both conditioning types showed comparable rates of severe acute graft versus host disease and overall survival, suggesting that reduced-intensity conditioning may be just as effective for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Le Bourgeois, A., Labopin, M., Blaise, D., et al.[2022]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

In a study of 70 patients undergoing allogeneic hematopoietic stem cell transplantation, targeting a higher busulfan area under the curve (AUC) of ≥19.7 mg*h/L did not improve overall survival (OS) or relapse-free survival (RFS) compared to a lower AUC of <19.7 mg*h/L.

There were no significant differences in non-relapsed mortality or the incidence of acute and chronic graft-versus-host disease between the two dosing groups, indicating that increasing busulfan intensity may not enhance safety or efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation. Mori, S., Guo, M., Rivera-Robles, N., et al.[2023]

Citations

1. withpower.com withpower.com/trial/phase-3-mucopolysaccharidosis-i-6-2014-074a6

Stem Cell Transplantation for Osteopetrosis This trial tests a treatment using busulfan and fludarabine to prepare patients with certain genetic disorders for a bone marrow transplant.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6861349/

Conditioning Regimens for Hematopoietic Cell ... Overall survival at 3 years was 62%, but there were high rates of acute (79%) and extensive chronic GvHD (47%) [35]. One had graft failure and ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26485304/

Improved Outcomes of Hematopoietic Stem Cell ... Results: The overall survival after conditioning with fludarabine was 96% (25/26) versus 58% (7/12) for the alternative regimens (P = 0.004), with ...

4. studyfinder.umn.edu studyfinder.umn.edu/studies?utf8=%E2%9C%93&search%5Bq%5D=MT2013-31&search%5Bhealthy_volunteers%5D=&commit=Search

UMN - StudyFinder The purpose of this study is to determine the safety and effectiveness of allogeneic hematopoietic cell transplant in persons with an inherited metabolic ...

5. malacards.org malacards.org/card/osteopetrosis

Osteopetrosis Integrated disease information for Osteopetrosis including associated genes, mutations, phenotypes, pathways, drugs, and more - integrated from 78 data ...

6. astctjournal.org astctjournal.org/article/S2666-6367(20)30050-6/fulltext

The Relationship Between Busulfan Exposure and ... All patients with busulfan exposure of >70 mg·h/L achieved the desired outcomes of transplant with minimal toxicity and excellent overall and event-free ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25879376/

Non-total body irradiation myeloablative conditioning with ... HSCT is the only curative treatment for MIOP. We prospectively investigated the outcome of HSCT using intravenous busulfan-based ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11907693/

Myeloablative Fractionated Busulfan With Fludarabine in ... The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning ...

9. researchgate.net researchgate.net/publication/336416547_High-Exposure_Targeted_Daily_Busulfan_and_Fludarabine-Based_Conditioning_for_Children_Undergoing_Hematopoietic_Stem_Cell_Transplantation_for_Inherited_Metabolic_Disorders_Outcomes_at_a_Single_Center

High-Exposure, Targeted Daily Busulfan and Fludarabine ... Recently, the Utrecht group reported highly favorable outcomes following a high-dose busulfan and fludarabine-based preparative regimen in ...