Bendamustine +/- Cyclophosphamide to Prevent GVHD Post Stem Cell Transplant for Blood Cancers

Overseen By Issa F. Khouri, M D

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnant, HIV positive, Active infection, others

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

Compensation: Varies

Number of Visits: 4

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and examine the side effects of bendamustine, with or without cyclophosphamide, to prevent graft versus host disease (GVHD) in patients undergoing stem cell transplants for blood cancers. GVHD occurs when donor stem cells attack the patient's body, and the trial will test whether these drugs can prevent it. The trial includes different treatment schedules based on the type of blood cancer. Individuals with blood cancers who have a matched stem cell donor and meet specific health criteria may be suitable candidates for the trial. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in GVHD prevention.

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 has shown that bendamustine, when used in stem cell transplants, carries a low risk of severe side effects. Studies indicate that serious conditions like severe graft versus host disease (GVHD) occur in about 10% of patients, suggesting the treatment is generally well-tolerated. However, bendamustine does carry a risk of non-melanoma skin cancers, so monitoring for skin changes is important.

For cyclophosphamide, research has found it effective in preventing GVHD after a stem cell transplant. It improves survival rates without increasing the risk of severe GVHD. Using cyclophosphamide with other treatments has led to better survival and GVHD prevention.

Both drugs are often used in cancer treatments, indicating a known safety record. However, like all treatments, they have some risks and side effects. Discuss these with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they could offer a new way to prevent graft-versus-host disease (GVHD) after stem cell transplants for blood cancers. Unlike the standard approach of using medications like methotrexate and tacrolimus, this trial explores bendamustine and cyclophosphamide, which might work together to reduce GVHD risk more effectively. Bendamustine, in particular, has a unique mechanism that targets both cancer cells and immune cells, potentially offering a dual benefit of controlling the disease while minimizing transplant-related complications. Additionally, the study looks at combining these treatments in different schedules, which could optimize their effectiveness and tailor therapy to individual patient needs.

What evidence suggests that this trial's treatments could be effective in preventing GVHD after stem cell transplant for blood cancers?

Research has shown that bendamustine, a treatment in this trial, can help prevent graft-versus-host disease (GVHD), a condition where donor cells attack the patient's body. Some studies suggest that this treatment might also improve survival rates in animal studies. Cyclophosphamide, another treatment option in this trial, has effectively reduced the risk of GVHD in patients after stem cell transplants. Data from previous trials indicate that it increases survival rates and lessens severe GVHD. Both treatments show promise in preventing GVHD, a common issue after stem cell transplants. ^{4 6 7 8 9}

Who Is on the Research Team?

Issa F. Khouri

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for blood cancer patients who need a stem cell transplant and have good lung function (FVC and FEV1 >= 40%), heart function (ejection fraction >= 40%), and kidney function (creatinine clearance >= 30 ml/min). They must have a donor that's mismatched or haplo-identical, be relatively fit (Zubrod performance 0 to 2 or Karnofsky ≥60), not HIV positive, without active hepatitis B/C, unresolved toxicities from prior treatments, certain active diseases/infections, or pregnant/nursing.

Inclusion Criteria

Forced vital capacity (FVC) >= 40%. (at time of study entry)

I can take care of myself but may not be able to do heavy physical work.

The donor's tissue type is not a close match to yours.

Exclusion Criteria

I have no lasting side effects above mild from previous cancer treatments.

I am HIV positive.

I am unable or unwilling to sign the consent form.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Transplant Conditioning

Patients receive chemotherapy and total body irradiation to prepare for stem cell transplantation

6 days

Daily visits for chemotherapy administration

Stem Cell Transplantation

Patients undergo stem cell transplantation

1 day

1 visit for transplantation procedure

Post-Transplant Treatment

Patients receive post-transplant medications including tacrolimus, mycophenolate mofetil, and filgrastim to prevent GVHD and support recovery

6 months

Regular visits for medication administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Weekly for 3 months, every 3 months in year 1, every 6 months in year 2

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Cyclophosphamide

Trial Overview The study tests if bendamustine with/without cyclophosphamide can prevent GVHD after stem cell transplants. It includes chemotherapy drugs like melphalan and fludarabine, total-body irradiation before the transplant to kill cancer cells/make room for new cells in bone marrow, followed by tacrolimus and mycophenolate mofetil to potentially stop GVHD.

How Is the Trial Designed?

Group I: Schedule II (lymphoid malignancies) Experimental Treatment 9 Interventions

Patients receive fludarabine IV over 1 hour, bendamustine IV over 30-60 minutes on days -5 to -3 and undergo TBI on day -1 and stem cell transplantation over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal. CD20+ patients receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8.

Group II: Schedule I (non-lymphoma) Experimental Treatment 9 Interventions

Patients receive fludarabine IV over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo TBI on day -1 and stem cell transplantation IV over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal.

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

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Post-transplant bendamustine (PT-BEN) significantly reduces graft-versus-host disease (GvHD) and improves survival rates in murine models of haploidentical bone marrow transplantation (h-BMT), while still preserving the beneficial graft-versus-leukemia (GvL) effect.

PT-BEN is less myelosuppressive than post-transplant cyclophosphamide (PT-CY), leading to an increase in certain immune cells and enhancing the function of myeloid-derived suppressor cells, suggesting it could be a safer and more effective option for patients undergoing h-BMT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. Stokes, J., Hoffman, EA., Zeng, Y., et al.[2021]

In a phase II study involving patients with various types of lymphoid malignancies, bendamustine combined with etoposide and dexamethasone successfully mobilized stem cells, with all patients able to collect sufficient stem cells for transplantation.

The mobilization regimen was found to be safe, with only three non-hematologic significant adverse events reported in one patient, indicating that bendamustine can be an effective option for stem cell mobilization in non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Greenbaum, AM., Green, DJ., Holmberg, LA., et al.[2022]

Bendamustine used as a conditioning regimen for autologous stem cell transplantation in 35 lymphoma patients resulted in successful hematopoietic reconstitution, with median times of 11 days for neutrophil and 12 days for platelet engraftment, and a high overall survival rate of 90.97% at 12 and 24 months.

The treatment was associated with manageable side effects, including nausea, vomiting, and diarrhea, with no transplant-related deaths reported, indicating that bendamustine is both effective and tolerable for patients undergoing this procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Bendamustine in the Conditioning Regiment for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma]. Fu, Y., Feng, YF., Liu, F., et al.[2023]

Bendamustine is a unique cancer treatment that combines alkylating and antimetabolite properties, making it effective against certain blood cancers like chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

It has been approved by the US FDA for patients whose cancer has not responded to or has progressed after rituximab treatment, and it can be used alone or in combination with other therapies, showing promising efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Ujjani, C., Cheson, BD.[2015]

Bendamustine hydrochloride is a newer alkylating agent that has shown promise in treating resistant or refractory cancers due to its unique pharmacological properties.

The article reviews clinical trials demonstrating bendamustine's effectiveness both as a standalone treatment and in combination therapies for various solid tumors and blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine hydrochloride - a renaissance of alkylating strategies in anticancer medicine. Eichbaum, M., Bischofs, E., Nehls, K., et al.[2017]

In a study of 34 patients with multiple myeloma, the combination of bendamustine, etoposide, and dexamethasone (BED) successfully mobilized hematopoietic stem cells in all participants, with a median yield of 21.60 million cells per kg of body weight.

The treatment was effective and safe, with 88% of patients needing only one apheresis session, although six patients experienced serious nonhematologic adverse events, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Green, DJ., Bensinger, WI., Holmberg, LA., et al.[2023]

Bendamustine (BEN) shows promise as an immunomodulatory agent in hematopoietic cell transplantation (HCT), consistently reducing graft-versus-host disease (GvHD) and enhancing graft-versus-leukemia (GvL) effects in murine models.

In vitro studies reveal that BEN alters key immune cell populations and functions, such as enhancing myeloid derived suppressor cells (MDSCs) and dendritic cells (DCs), which may lead to improved clinical outcomes in ongoing clinical trials for allogeneic HCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. Stokes, J., Molina, MS., Hoffman, EA., et al.[2021]

Bendamustine shows promising synergistic effects when combined with other anti-cancer drugs, such as alkylating agents and pyrimidine analogues, for treating resistant lymphoid malignancies, as demonstrated in various cancer cell lines.

The drug enhances the uptake of cytosine arabinoside (Ara-C) and increases the expression of transporters that facilitate this process, suggesting that its unique properties may improve the effectiveness of combination therapies in difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies. Hiraoka, N., Kikuchi, J., Yamauchi, T., et al.[2022]

A Phase Ia trial involving 44 patients with high-risk hematologic malignancies showed that partially replacing post-transplantation cyclophosphamide (PT-CY) with bendamustine (PT-BEN) was well tolerated and led to significantly earlier trilineage engraftment.

The PT-CY/BEN regimen demonstrated favorable trends in reducing chronic graft-versus-host disease (GVHD) and improving GVHD-free relapse-free survival (GRFS), suggesting it may be a promising alternative to standard PT-CY treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation. Katsanis, E., Stea, B., Kovacs, K., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12014643/

results from a phase Ia/Ib clinical trial - PMC Our preclinical studies indicate that pre- or post-transplant bendamustine (PT-BEN) may reduce GvHD, enhance graft-versus-leukemia (GvL) effects, and induce ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8038415/

Immunomodulatory Effects of Bendamustine in ... Bendamustine has been shown to reduce the side effects of the transplant, including graft-versus-host disease, where the donated cells attack the recipient's ...

3. withpower.com withpower.com/trial/phase-2-2-2020-41890

Cyclophosphamide to Prevent GVHD Post Stem Cell Transplant ... Post-transplant bendamustine (PT-BEN) significantly reduces graft-versus-host disease (GvHD) and improves survival rates in murine models of haploidentical bone ...

4. astctjournal.org astctjournal.org/article/S2666-6367(22)01230-1/fulltext

Feasibility and Efficacy of Partially Replacing Post ... Grade II acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after HLA-haploidentical ...

5. journals.lww.com journals.lww.com/hosct/fulltext/2024/17040/low_incidence_of_primary_graft_failure_with.3.aspx

Low incidence of primary graft failure with bendamustine, fl... Abstract. The outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) have improved with the implication of new in vivo and ex vivo graft ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11128657/

Post-marketing risk analysis of bendamustine: a real-world ... Our findings are consistent with clinical trial data suggesting an elevated risk of non-melanoma skin cancers in patients treated with ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7378358/

Bendamustine Conditioning Skews Murine Host DCs ... We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD. Keywords: graft-vs.-host ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04217317

CPI-613 in Combination With Bendamustine in Patients ... The purpose of this study is to determine if it is possible to give CPI-613 with the drug Bendamustine for 2 days every 28 days without causing severe side ...

9. fda.gov fda.gov/files/drugs/published/22-249S012-Bendamustine-hydrochloride-Clinical-PREA.pdf

Bendamustine hydrochloride 22-249S012 Clinical PREA The patient has evidence of active graft versus host disease. ▫ The ... integrated safety summary the applicant includes postmarketing data on ...