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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the drug cyclophosphamide to determine the best dose for individuals who have undergone a stem cell transplant as part of their blood cancer treatment. It targets patients aged 65 and older who have received a specific type of transplant using donor stem cells. The trial aims to assess how well cyclophosphamide can prevent the immune system from attacking the new stem cells. It suits those who have not had a stem cell transplant before and do not have myelofibrosis, a type of bone marrow cancer. Participants should be comfortable with medical procedures and not have conditions like claustrophobia. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking research.

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 cyclophosphamide is likely to be safe for humans?

A previous study found that administering cyclophosphamide after a stem cell transplant was safe for most people, with patients experiencing few serious side effects. Another study demonstrated that using cyclophosphamide post-transplant helped prevent graft-versus-host disease (GVHD), where new cells attack the body. This indicates that cyclophosphamide can safely integrate into the transplant process.

Research also shows that cyclophosphamide did not interfere with the transplant's success, allowing new cells to grow and function as expected. While side effects like nausea and hair loss can occur, they were generally manageable. Overall, cyclophosphamide has been used safely in similar situations, suggesting it could be a viable option for patients in this trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Cyclophosphamide is unique because it is administered shortly after a stem cell transplant for blood cancer, specifically on Day +3 and Day +4, which is different from the standard timing of chemotherapy. Most treatments for blood cancer involve chemotherapy either before or during the transplant process to prepare the body, but cyclophosphamide is given after the transplant to potentially reduce complications and improve outcomes. Researchers are excited about this approach because it might enhance the effectiveness of the transplant by targeting residual cancer cells and minimizing the risk of graft-versus-host disease, a common and serious post-transplant issue.

What evidence suggests that cyclophosphamide might be an effective treatment for blood cancer?

Research has shown that using cyclophosphamide after a stem cell transplant can help prevent graft-versus-host disease, which occurs when donor cells attack the patient's body. In this trial, all participants will receive cyclophosphamide on Day +3 and Day +4 following the transplant. Studies have found that post-transplant cyclophosphamide greatly improves patient outcomes by reducing this risk. It facilitates better compatibility between donor and patient cells, leading to a smoother recovery. These findings highlight the potential benefits of cyclophosphamide in enhancing transplant success and improving patient health. ^{2 6 7 8 9}

Who Is on the Research Team?

Ronald L. Paquette

Principal Investigator

Cedars-Sinai Medical Center

Are You a Good Fit for This Trial?

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

Patient and Donor sign the Informed Consent Form for the study

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

I am 70 years old or older.

Exclusion Criteria

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

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

I have high levels of antibodies against donor tissues.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38607399/

Long-term outcomes after haploidentical stem cell ... The introduction of posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements ...

2. clinicaltrials.gov clinicaltrials.gov/ct2/show/study/NCT03187756

Study of Nonmyeloablative Peripheral Blood Stem Cell ... This is an open label phase II single arm study of peripheral blood stem cell transplantation and posttransplantation cyclophosphamide, using HLA full match ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2892158/

High-dose, post-transplantation cyclophosphamide to ... High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation · Abstract.

4. withpower.com withpower.com/trial/phase-1-hematologic-neoplasms-6-2023-bc975

Cyclophosphamide After Stem Cell Transplant for Blood ... Research shows that Cyclophosphamide, when used after stem cell transplants, can effectively prevent graft-versus-host disease (a condition where the donor ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00856

Post-Transplant Cyclophosphamide-Based Graft-Versus ... Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for advanced hematologic malignancies.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10558021/

Post-Transplant Cyclophosphamide for the Prevention of ... Hematopoietic stem cells rich in this enzyme are resistant to cyclophosphamide, allowing for its use soon after HCT without impairing engraftment (Mayumi et al.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa2503189

Graft-versus-Host Disease Prophylaxis with ... The combination of post-transplantation cyclophosphamide and a calcineurin inhibitor led to longer GVHD-free, relapse-free survival than standard prophylaxis.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35285885/

Benefits and risks of haematopoietic stem cell ... We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide.

9. thelancet.com thelancet.com/journals/langas/article/PIIS2468-1253(23)00460-0/fulltext

Safety and efficacy of autologous haematopoietic stem-cell ... We report the findings of an open-label, multicentre, randomised controlled trial assessing the safety and efficacy of HSCT with an immune- ...