Bendamustine +/- Cyclophosphamide to Prevent GVHD Post Stem Cell Transplant for Blood Cancers
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Disqualifiers: Pregnant, HIV positive, Active infection, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase I/II trial studies the side effects and best dose of bendamustine when given with or without cyclophosphamide in preventing graft versus host disease (GVHD) in patients undergoing stem cell transplant. Drugs used in chemotherapy, such as bendamustine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total body irradiation before or after a stem cell transplant helps kills cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Sometimes, the transplanted cells from a donor can attack the body's normal cells called GVHD. Giving tacrolimus, mycophenolate mofetil, and filgrastim after the transplant may stop this from happening.
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 Bendamustine in preventing GVHD after stem cell transplant for blood cancers?
Research shows that Bendamustine, when used after a stem cell transplant, can reduce the risk of graft-versus-host disease (GVHD) while maintaining the beneficial effects against leukemia. It has been found to improve survival rates and is less suppressive on bone marrow compared to other treatments like cyclophosphamide.
12345Is Bendamustine with or without Cyclophosphamide safe for humans?
Bendamustine, used alone or with other drugs, has been studied in various conditions and is generally considered safe, though some serious side effects like fever, bone pain, and kidney issues have been reported. Cyclophosphamide is widely used in transplants to prevent complications and is also generally safe, but it can have side effects. Both drugs have been used in clinical settings with careful monitoring for safety.
24678How is the drug Bendamustine +/- Cyclophosphamide unique in preventing GVHD after stem cell transplant for blood cancers?
This treatment is unique because Bendamustine, when used after a stem cell transplant, can reduce the risk of graft-versus-host disease (GVHD) while preserving the beneficial graft-versus-leukemia (GvL) effect, and it is less likely to suppress bone marrow compared to the commonly used Cyclophosphamide.
12479Eligibility Criteria
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)
The donor's tissue type is not a close match to yours.
I can take care of myself but may not be able to do heavy physical work.
+7 more
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.
+5 more
Trial Timeline
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Schedule II (lymphoid malignancies)Experimental Treatment9 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 Treatment9 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. [2021]Advances in haploidentical bone marrow transplantation (h-BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft-versus-host disease (GvHD) with the administration of post-transplant cyclophosphamide (PT-CY) has substantially improved the efficacy and applicability of T cell-replete h-BMT. However, higher frequency of disease recurrence remains a major challenge in h-BMT with PT-CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft-versus-leukaemia (GvL) effect in h-BMT. To this end, we evaluated the impact of bendamustine (BEN), given post-transplant, on GvHD and GvL using clinically relevant murine h-BMT models. We provide results indicating that post-transplant bendamustine (PT-BEN) alleviates GvHD, significantly improving survival, while preserving engraftment and GvL effects. We further document that PT-BEN can mitigate GvHD even in the absence of Treg. Our results also indicate that PT-BEN is less myelosuppressive than PT-CY, significantly increasing the number and proportion of CD11b(+) Gr-1(hi) cells, while decreasing lymphoid cells. In vitro we observed that BEN enhances the suppressive function of myeloid-derived suppressor cells (MDSCs) while impairing the proliferation of T- and B-cells. These results advocate for the consideration of PT-BEN as a new therapeutic platform for clinical implementation in h-BMT.
Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation. [2023]Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.
Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. [2021]Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.
[Efficacy and Safety of Bendamustine in the Conditioning Regiment for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma]. [2023]To investigate the clinical efficacy and safety of bendamustine in the conditioning regimen for autologous stem cell transplantation in patients with lymphoma.
Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies. [2022]Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan) and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine) in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C), followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs). Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP) in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies.
Bendamustine hydrochloride - a renaissance of alkylating strategies in anticancer medicine. [2017]Alkylating drugs represent one of the oldest classes of anticancer medicine used in a broad variety of clinical indications. Bendamustine hydrochloride (Ribomustine, Treanda) is a newer alkylating agent which has already been under intensive clinical investigation and has gained emerging interest due to its unique pharmacological properties, particularly in resistant or refractory diseases. This article provides basic information on the molecular mechanisms of action of bendamustine and its pharmacological characteristics and an overview on published clinical trials where bendamustine is analyzed as a single agent as well as in combination therapies for the treatment of solid tumors and hematologic malignancies.
Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. [2015]Bendamustine (Treanda(®); Pharmachemie BV, The Netherlands for Cephalon, Inc., PA, USA) is a unique cytotoxic agent with both alkylating and antimetabolite properties. A growing body of evidence demonstrates its efficacy in a number of hematologic malignancies, and as such, it has been US FDA approved for the treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma that has not responded to, or progressed within 6 months of, a rituximab-based regimen. Bendamustine has efficacy both as a single agent as well as in combination with other chemotherapeutics and immunotherapeutics. Here, we will discuss in the detail the molecular properties, clinical efficacy and safety profile of bendamustine.
Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. [2023]Chemotherapeutic agents without cross-resistance to prior therapies may enhance PBSC collection and improve patient outcomes by exacting a more potent direct antitumor effect before autologous stem cell transplant. Bendamustine has broad clinical activity in transplantable lymphoid malignancies, but concern remains over the potential adverse impact of this combined alkylator-nucleoside analog on stem cell mobilization. We performed a prospective, nonrandomized phase II study including 34 patients with multiple myeloma (MM) (n=34; International Staging System (ISS) stages I (35%), II (29%) and III (24%); not scored (13%)) to evaluate bendamustine's efficacy and safety as a stem cell mobilizing agent. Patients received bendamustine (120 mg/m2 IV days 1, 2), etoposide (200 mg/m2 IV days 1-3) and dexamethasone (40 mg PO days 1- 4) (bendamustine, etoposide and dexamethasone (BED)) followed by filgrastim (10 μg/kg/day SC; through collection). All patients (100%) successfully yielded stem cells (median of 21.60 × 106/kg of body weight; range 9.24-55.5 × 106/kg), and 88% required a single apheresis. Six nonhematologic serious adverse events were observed in 6 patients including: neutropenic fever (1, grade 3), bone pain (1, grade 3) and renal insufficiency (1, grade 1). In conclusion, BED safely and effectively mobilizes hematopoietic stem cells.
Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. [2022]Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may adversely affect stem cell collection. Here we describe the lymphoma subset of a prospective, non-randomized phase II study of bendamustine, etoposide, and dexamethasone (BED) as a mobilization agent for lymphoid malignancies.