Cyclophosphamide After Stem Cell Transplant for Blood Cancer

(GeriBMT Trial)

Overseen By Nadia Nassaj

Age: 65+

Sex: Any

Trial Phase: Phase 1

Sponsor: Ronald Paquette

Disqualifiers: Myelofibrosis, High titer antibodies, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

26 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this phase 1 study is to determine the optimal dose of the immune suppressive drug, cyclophosphamide, following standard allogeneic stem cell transplant in patients aged \>/= 65 years with hematologic malignancies.

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.

What data supports the effectiveness of the drug Cyclophosphamide after stem cell transplant for blood cancer?

Research shows that Cyclophosphamide, when used after stem cell transplants, can effectively prevent graft-versus-host disease (a condition where the donor cells attack the recipient's body) and improve survival rates in patients with blood cancers. It has been shown to help with engraftment (the process where transplanted cells start to grow and make healthy blood cells) and maintain disease control. ^{1 2 3 4 5}

Is cyclophosphamide safe for humans?

Cyclophosphamide, also known as Cytoxan or Endoxan, can cause side effects like hemorrhagic cystitis (bleeding in the bladder), myelosuppression (reduced bone marrow activity), and has potential carcinogenic (cancer-causing) effects. While many patients recover from these side effects, some may experience serious complications, so long-term monitoring is important. ^{1 2 5 6 7}

What makes cyclophosphamide unique as a drug for blood cancer treatment after stem cell transplant?

Cyclophosphamide is unique because it is used post-transplant to prevent graft-versus-host disease (GVHD), a condition where the donor cells attack the recipient's body. It is also known for its ability to penetrate tissues and target widely spread cancer cells, making it effective in treating various blood cancers. ^{1 2 3 6 8}

Research Team

Ronald L. Paquette

Principal Investigator

Cedars-Sinai Medical Center

Eligibility Criteria

This trial is for patients aged 70 or older with blood cancers who need a stem cell transplant and have a related donor that's a half-match for their immune system. They must be able to handle a specific pre-transplant treatment and both patient and donor must agree to the study rules.

Inclusion Criteria

I am 70 years old or older.

I have a family donor who is a half-match for my bone marrow transplant.

I am eligible for a stem cell transplant from a donor.

Exclusion Criteria

I have had a stem cell transplant using my own or a donor's cells.

I need sedation to undergo a cardiac MRI.

Inability to collect at least 3 x 10^6 CD34+ PBSCs/kg recipient weight from the donor

Timeline

Screening

Participants are screened for eligibility to participate in the trial

8 weeks

Transplant and Immediate Post-Transplant

Participants undergo allogeneic stem cell transplant followed by administration of cyclophosphamide on Day +3 and Day +4

1 week

In-patient stay for transplant and immediate post-transplant care

Treatment

Participants receive standard or reduced dose of cyclophosphamide post-transplant

4 weeks

Follow-up

Participants are monitored for safety and effectiveness with follow-up visits on Day +30, Day +100, Day +180, and Day +365

12 months

4 visits (in-person)

Treatment Details

Interventions

• Cyclophosphamide

Trial Overview The study is testing different doses of cyclophosphamide, an immune-suppressing drug, after standard stem cell transplants in elderly patients with blood cancers, to find the safest and most effective dose.

Participant Groups

Group I: Open Arm Experimental Treatment 1 Intervention

All patients will receive cyclophosphamide on Day +3 and Day +4 following transplant.

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?

Ronald Paquette

Lead Sponsor

Trials

2

Recruited

90+

Findings from Research

Cyclophosphamide, introduced in 1958, is a potent immunosuppressive agent used to treat various diseases, both malignant and non-malignant.

Despite its therapeutic benefits, cyclophosphamide is associated with significant urologic complications, including hemorrhagic cystitis, vesical fibrosis, and an increased risk of urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bladder carcinoma following cyclophosphamide therapy. A case report. Kiesswetter, H., Baloch, N., Flamm, J.[2019]

Endoxan (cyclophosphamide) is an effective chemotherapy drug that penetrates tissues well, making it useful for treating various cancers, particularly those of the reticulo-endothelial system, such as lymphomas and leukemias.

In laboratory tests, Endoxan demonstrated a dose-dependent ability to scavenge superoxide radicals and influence lipid peroxidation, suggesting it may have antioxidant properties that could enhance its therapeutic effects when used in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of endoxan on oxidative processes in model systems in vitro. Mileva, M., Traikov, L., Deliyska, B.[2014]

In a study of 12 children with graft failure, T-cell replete haploidentical hematopoietic stem cell transplantation (HSCT) using post-transplantation cyclophosphamide resulted in a high survival rate of 92%, with 10 out of 12 patients achieving complete donor chimerism after a median follow-up of 26 months.

The conditioning regimen was effective, leading to successful neutrophil and platelet engraftment in all patients, with low rates of acute and chronic graft-versus-host disease (GVHD), indicating a promising approach for treating graft failure in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders. Albert, MH., Sirin, M., Hoenig, M., et al.[2023]

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]

Cyclophosphamide (Cy) is an effective chemotherapy drug that works by converting into active metabolites, primarily phosphoramide mustard, which have cytotoxic and immunosuppressive effects, although its exact mechanism is not fully understood.

While Cy is effective for treating cancers and certain autoimmune diseases like Wegener's granulomatosis, it has significant side effects, including myelosuppression and potential carcinogenicity, prompting research into safer analogues like ifosfamide that may offer similar benefits with fewer harmful effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. Ahmed, AR., Hombal, SM.[2022]

In a study of 116 patients with Ewing's sarcoma treated with cyclophosphamide, 15% developed hemorrhagic cystitis, indicating a significant risk of this adverse effect associated with the chemotherapy.

While most patients recovered without major issues, there were serious complications in some cases, including significant blood loss and one patient requiring a cystectomy, highlighting the need for long-term monitoring and potential protective therapies for bladder health during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. Stillwell, TJ., Benson, RC., Burgert, EO.[2017]

In a study involving 36 patients, Endoxan showed significantly higher peak plasma concentrations of cyclophosphamide compared to Cytoxan and an investigational tablet, indicating it may be more effective in delivering the drug quickly.

While all formulations had similar bioavailability and toxicity profiles, the investigational formulation was associated with slightly lower overall toxicity, suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study. Stewart, DJ., Morgan, LR., Verma, S., et al.[2019]

In a study of 423 patients undergoing allogeneic stem cell transplantation, the addition of two immunosuppressive drugs to post-transplant cyclophosphamide (PT-Cy) significantly reduced the risk of extensive chronic graft-versus-host disease (cGVHD) and improved overall survival rates.

The combination of PT-Cy with two immunosuppressive agents was associated with a 51% reduction in non-relapse mortality, highlighting the enhanced efficacy of this treatment strategy in preventing severe complications after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. Ruggeri, A., Labopin, M., Bacigalupo, A., et al.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Bladder carcinoma following cyclophosphamide therapy. A case report. [2019]

2. Serbia pubmed.ncbi.nlm.nih.gov

Effects of endoxan on oxidative processes in model systems in vitro. [2014]

3. England pubmed.ncbi.nlm.nih.gov

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders. [2023]

4. 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]

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

Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. [2022]

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

Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. [2017]

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

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study. [2019]

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

Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. [2019]