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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a lower dose of cyclophosphamide effectively prevents graft-versus-host disease, a common complication of blood stem cell transplants for certain blood cancers. Participants will receive varying doses to identify the safest and most effective amount. The trial seeks individuals with blood cancers like leukemia or lymphoma who qualify for a blood stem cell transplant and have frequent relapses or poor responses to other treatments. Additionally, healthy related donors are needed to provide samples for research. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical advancements.

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.

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

Research has shown that using low-dose cyclophosphamide after a blood stem cell transplant can help prevent graft-versus-host disease (GVHD), a common issue where donor cells attack the recipient's body. In one study, patients had a 49% chance of surviving without GVHD and cancer relapse three years after receiving the experimental treatment, compared to a 14% chance with standard treatment. Another study found that one year after the transplant, about 83.8% of some patients were still alive.

While these results are promising, the treatment is still being tested in early clinical trials, and researchers continue to gather information on its safety. Cyclophosphamide is already approved for other uses, so its safety profile is well-known. However, its effects at lower doses remain under study. Some side effects can occur, but the goal is to find the safest dose that remains effective. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for graft-versus-host disease (GVHD) because they offer a fresh approach to managing this complex condition. Cyclophosphamide is being used at a lower dose, which aims to reduce toxicity while still effectively preventing GVHD. This differs from standard treatments like high-dose steroids or other immunosuppressive drugs, which can have significant side effects. Additionally, the combination with mycophenolate mofetil and sirolimus could provide a more balanced immune modulation, potentially leading to better outcomes with fewer complications. This multi-drug approach targets different pathways, which might offer a synergistic effect, making it a promising option for patients.

What evidence suggests that this trial's treatments could be effective for graft-versus-host disease?

This trial will evaluate low-dose post-transplant cyclophosphamide (PTCy) for preventing graft-versus-host disease (GVHD) in different contexts. Studies have shown that low-dose PTCy effectively prevents GVHD, a common issue after blood stem cell transplants. Specifically, research indicates that this approach offers a 49% chance of surviving without GVHD or cancer relapse over three years, compared to just 14% with standard treatments. Additionally, evidence suggests that this method results in low relapse rates and manageable side effects. Overall, these findings support the idea that low-dose PTCy can reduce serious transplant complications while remaining effective. Participants in this trial will join various treatment arms to assess the efficacy and safety of this approach. ^{1 2 3 6 7}

Who Is on the Research Team?

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 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 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 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 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 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]

Citations

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Low-dose Cyclophosphamide or CNI in the Prevention of ... Low-dose Cyclophosphamide or CNI in the Prevention of Acute Graft-versus-host Disease After gDLI. ClinicalTrials.gov ID NCT06490562. Sponsor Institute of ...

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Modifying Post-Transplant Cyclophosphamide Platform to ... Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv ...