Low-Dose Cyclophosphamide for Graft-versus-Host Disease

Recruiting at 1 trial location

Overseen By Christopher G Kanakry, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Active non-hematopoietic malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 4-6 weeks

260 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Blood cancers (such as leukemias or lymphomas) often do not respond to standard treatments. A transplant of blood stem cells from a healthy donor can help people with these cancers. Sometimes these transplants cause serious side effects, including a common immunologic problem called graft-versus-host disease. A drug called cyclophosphamide given early after the transplant (post-transplantation cyclophosphamide, PTCy) can reduce these complications. But sometimes this drug has its own negative effects. Furthermore, studies in mice suggest that an intermediate, rather than very high, dose of this drug may best protect against graft-versus-host disease. Objective: To find out if a lower dose of PTCy is more helpful for people who undergo blood stem cell transplants. Eligibility: People aged 18 and older who have a blood cancer and are eligible for a transplant of blood stem cells from another person. Healthy donors are also needed but must be related to the individual needing the transplant. Design: Participants will undergo screening. Transplant recipients will have imaging scans and tests of their heart and lung function. They will be assessed for the status of their cancer, including bone marrow taken from their pelvis and possibly also scans and/or fluid drawn from the spine depending on the disease type. Donors will be screened for general health. They will give several tubes of blood. They will give an oral swab and saliva and stool samples for research. Recipients will be in the hospital at least 4 to 6 weeks. They will have a temporary catheter inserted into a vein in the chest or neck. Medications will be given and blood will be drawn through the catheter. The transplanted stem cells will be given through the catheter. Participants will receive medications both before and after the transplant. Participants will return to the clinic at least once a week for 3 months after leaving the hospital. Follow-up visits will continue periodically for 5 years.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot be on any other investigational agents, and prior experimental therapies must be completed at least 2 weeks before starting the trial.

What data supports the effectiveness of the drug Cyclophosphamide for treating graft-versus-host disease?

Research shows that using Cyclophosphamide after transplantation can reduce the risk of severe graft-versus-host disease, which is a common complication after receiving a donor's bone marrow or stem cells. Studies have found that this approach helps improve survival rates without significant complications. ^{1 2 3 4 5}

Is low-dose cyclophosphamide safe for preventing graft-versus-host disease?

Research shows that low-dose cyclophosphamide, when used after transplantation, is generally safe and helps prevent graft-versus-host disease with low rates of severe side effects and transplant-related mortality. ^{3 4 6 7 8}

What makes the drug combination of Cyclophosphamide, Mycophenolate Mofetil, and Sirolimus unique for treating graft-versus-host disease?

This treatment is unique because it uses low-dose cyclophosphamide, which has shown effectiveness in preventing graft-versus-host disease with fewer side effects compared to high-dose regimens, and combines it with mycophenolate mofetil and sirolimus to enhance immune suppression and improve outcomes. ^{5 6 7 9 10}

Research Team

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with certain blood cancers eligible for a stem cell transplant from a related donor can join. Excluded are those with active non-blood cancer, severe allergies to similar drugs, uncontrolled illnesses, breastfeeding women, or anyone on other experimental treatments.

Inclusion Criteria

Ability of participant to understand and the willingness to sign a written informed consent document

My organs are functioning well.

I have a related donor over 12 years old willing to donate and participate in research.

Exclusion Criteria

Active breastfeeding

I have an active cancer that is not related to blood or skin cancer.

Uncontrolled intercurrent illness that in the opinion of the Site PI would make it unsafe to proceed with transplantation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive reduced intensity conditioning, peripheral blood stem cell transplantation, and GVHD prophylaxis with PTCy, MMF, and sirolimus

4-6 weeks

In-hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation for acute GVHD and primary graft failure

3 months

Weekly visits (in-person)

Long-term Follow-up

Participants continue to be monitored periodically for 5 years to assess long-term outcomes such as chronic GVHD and overall survival

5 years

Treatment Details

Interventions

• Cyclophosphamide
• Mycophenolate Mofetil
• Sirolimus

Trial Overview The trial is testing if lower doses of cyclophosphamide after stem cell transplants work better for preventing graft-versus-host disease. It includes other medications and procedures like imaging scans, heart and lung tests, and follow-ups for up to five years.

Participant Groups

Group I: Phase II Efficacy (Matched HCT) Experimental Treatment 9 Interventions

PTCy at shortest duration, safe dose (from Phase I)

Group II: Phase II Efficacy (Haplo HCT) Experimental Treatment 9 Interventions

PTCy at shortest duration, safe dose (from Phase I)

Group III: Phase I Pilot for Comparative Data (Matched HCT) Experimental Treatment 9 Interventions

Standard PTCy 50 mg/kg/day on days +3 and +4

Group IV: Phase I Pilot for Comparative Data (Haplo HCT) Experimental Treatment 9 Interventions

Standard PTCy 50 mg/kgday on days +3 and +4

Group V: Phase I Dose De-escalation (Matched HCT) Experimental Treatment 9 Interventions

PTCy at de-escalating doses to assess for safety and determine Phase II dose

Group VI: Phase I Dose De-escalation (Haplo HCT) Experimental Treatment 9 Interventions

PTCy at de-escalating doses to assess for safety and determine Phase II dose

Group VII: Donors (Haplo HCT) Active Control 1 Intervention

Research on collected samples

Group VIII: Donors (Matched HCT) Active Control 1 Intervention

Research on collected samples

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study involving 46 patients undergoing HLA-matched hematopoietic stem cell transplantation, the use of cyclophosphamide (CY) for T cell tolerization resulted in low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM), with overall survival rates of 89.1% at 1 year and 65.8% at 5 years.

Higher doses of non-CY-exposed residual T cells were associated with significantly lower relapse rates (19.3% vs. 58.1%), suggesting that optimizing T cell exposure could enhance long-term outcomes without increasing NRM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes. Grosso, D., Carabasi, M., Filicko-O'Hara, J., et al.[2021]

In a murine model of MHC-haploidentical hematopoietic cell transplantation, administering post-transplantation cyclophosphamide (PTCy) on days +3/+4 was found to be the most effective timing for preventing graft-versus-host disease (GVHD), outperforming other dosing schedules.

The study revealed that both the timing and dosage of PTCy are crucial for its efficacy, with lower doses given on days +1/+2 leading to accelerated death, highlighting the importance of optimizing PTCy protocols in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimized Timing of Post-Transplantation Cyclophosphamide in MHC-Haploidentical Murine Hematopoietic Cell Transplantation. Wachsmuth, LP., Patterson, MT., Eckhaus, MA., et al.[2021]

In a study of 12 patients undergoing unrelated donor allogeneic bone marrow transplantation, mycophenolate mofetil (MMF) combined with cyclosporine A (CsA) and methotrexate (MTX) effectively prevented acute graft versus host disease (GVHD), with only three cases of GVHD reported.

The main side effect observed was leukopenia, indicating that while MMF is effective in preventing acute GVHD, monitoring for blood cell counts is necessary for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination of mycophenolate mofetil with cyclosporine A and methotrexate as acute GVHD prophylaxis after unrelated donor allogeneic bone marrow transplantation]. Huang, H., Lin, M., Meng, H., et al.[2016]

In a study of 684 adults with hematologic malignancies, high-dose post-transplantation cyclophosphamide was found to effectively reduce severe graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation, leading to improved composite survival outcomes.

The one-year graft-versus-host disease-free, relapse-free survival rates were similar across different donor types and conditioning intensities, indicating that post-transplantation cyclophosphamide provides comparable efficacy regardless of the transplantation approach used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. McCurdy, SR., Kasamon, YL., Kanakry, CG., et al.[2018]

In a study of 39 patients undergoing allogeneic peripheral blood stem cell transplantation, the combination of mycophenolate mofetil (MMF) with cyclosporine (CsA) and methotrexate (MTX) significantly reduced the incidence of acute graft-versus-host disease (GVHD) to 7.6%, compared to 46.2% in the CsA + MTX group.

The MMF regimen also resulted in a lower incidence of severe mucositis (15.4% vs. 30.8% in the control group), demonstrating its efficacy without negatively impacting the engraftment process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination of mycophenolate mofetil with cyclosporine A and methotrexate for the prophylaxes of acute graft versus host disease in allogeneic peripheral stem cell transplantation]. Wang, J., Song, X., Zhang, W., et al.[2016]

In a study of 134 patients undergoing allogeneic stem cell transplant, adding low-dose mycophenolate mofetil to the standard regimen of cyclosporine and methotrexate significantly reduced the incidence of acute graft-versus-host disease (GVHD) from 40.9% to 21.6%.

The combination therapy also resulted in a lower incidence of grade II-IV acute GVHD (15.2% in the mycophenolate mofetil group compared to 33% in the control group), indicating that mycophenolate mofetil enhances the efficacy of standard GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Low-Dose, Short-Course Mycophenolate Mofetil With Cyclosporine and Methotrexate for Graft-Versus-Host Disease Prophylaxis in Allogeneic Stem Cell Transplant. Ramzi, M., Haghighat, S., Namdari, N., et al.[2022]

In a study of 35 patients undergoing allogeneic peripheral blood stem cell transplantation (alloPBSCT), a combination of post-transplant cyclophosphamide and standard immunosuppressants effectively reduced the incidence of acute and chronic graft-versus-host disease (GVHD) to 17% and 7%, respectively, with no severe grade IV GVHD cases reported.

The approach resulted in an impressive 2-year nonrelapse mortality rate of just 3% and maintained overall survival at 77%, demonstrating that this strategy not only controls GVHD but also preserves the beneficial graft-versus-tumor effect essential for combating hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors. Carnevale-Schianca, F., Caravelli, D., Gallo, S., et al.[2018]

In a study of 242 adult patients with acute myeloid leukemia (AML) undergoing their first allogeneic stem cell transplant, the combination of sirolimus and post-transplant cyclophosphamide (Sir-PTCy) was found to be a safe and effective method for preventing graft-versus-host disease (GvHD).

The use of Sir-PTCy resulted in low rates of transplant-related mortality, relapse, and both acute and chronic GvHD across various donor types, indicating its potential as a reliable prophylactic strategy in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia. Lazzari, L., Balaguer-Roselló, A., Montoro, J., et al.[2022]

High-dose posttransplantation cyclophosphamide, when combined with tacrolimus and mycophenolate mofetil, has been shown to effectively prevent graft-versus-host disease (GvHD) in patients receiving allogeneic blood or marrow transplants, even with HLA-mismatched donors.

This treatment strategy takes advantage of the drug's ability to target proliferating alloreactive T cells while sparing nonalloreactive T cells, making it a promising option for improving GvHD prophylaxis and expanding donor options for patients, including those with conditions like sickle cell anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cyclophosphamide for graft-versus-host disease prevention. Luznik, L., Jones, RJ., Fuchs, EJ.[2021]

High-dose cyclophosphamide used as a single-agent prophylaxis after myeloablative allogeneic bone marrow transplantation significantly reduced the incidence of acute graft-versus-host disease (GVHD), with rates of 43% for grades II-IV and 10% for grades III-IV among 117 patients.

The treatment also demonstrated promising long-term outcomes, with a 2-year overall survival rate of 55% and a low cumulative incidence of chronic GVHD at 10%, indicating its efficacy and safety in patients with advanced hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Luznik, L., Bolaños-Meade, J., Zahurak, M., et al.[2022]

References

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

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes. [2021]

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

Optimized Timing of Post-Transplantation Cyclophosphamide in MHC-Haploidentical Murine Hematopoietic Cell Transplantation. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Combination of mycophenolate mofetil with cyclosporine A and methotrexate as acute GVHD prophylaxis after unrelated donor allogeneic bone marrow transplantation]. [2016]

4. Italy pubmed.ncbi.nlm.nih.gov

Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. [2018]

5. China pubmed.ncbi.nlm.nih.gov

[Combination of mycophenolate mofetil with cyclosporine A and methotrexate for the prophylaxes of acute graft versus host disease in allogeneic peripheral stem cell transplantation]. [2016]

6. Turkey pubmed.ncbi.nlm.nih.gov

Combination of Low-Dose, Short-Course Mycophenolate Mofetil With Cyclosporine and Methotrexate for Graft-Versus-Host Disease Prophylaxis in Allogeneic Stem Cell Transplant. [2022]

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

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia. [2022]

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

High-dose cyclophosphamide for graft-versus-host disease prevention. [2021]

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

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. [2022]