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出境医 / 临床实验 / Bendamustine With or Without Cyclophosphamide in Preventing GVHD in Patients Undergoing Stem Cell Transplant
Bendamustine With or Without Cyclophosphamide in Preventing GVHD in Patients Undergoing Stem Cell Transplant
Study Description
Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hematopoietic and Lymphoid System Neoplasm | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Bendamustine Drug: Cyclophosphamide Biological: Filgrastim-sndz Drug: Fludarabine Drug: Melphalan Drug: Mycophenolate Mofetil Biological: Rituximab Drug: Tacrolimus Radiation: Total-Body Irradiation | Phase 1 Phase 2 |
Detailed Description:
PRIMARY OBJECTIVE:
I. Evaluate the safety of substituting the standard post-transplant cyclophosphamide (PT-CY) given on day +3 and +4 with post-transplant bendamustine (PT-BEN) in patients undergoing HLA-mismatched hematopoietic cell transplantation.
SECONDARY OBJECTIVES:
I. To evaluate treatment-related mortality. II. To assess acute and chronic graft-versus-host disease (GVHD). III. To assess overall survival, progression-free survival and relapse rates. IV. To evaluate the risk of acute cystitis. V. To evaluate immune reconstitution after transplantation.
OUTLINE: This is a dose-escalation study of bendamustine. Patients are assigned to 1 of 2 treatment schedules.
SCHEDULE I (NON-LYMPHOMA): Patients receive fludarabine intravenously (IV) over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo total body irradiation (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 orally (PO) once daily (QD) or twice daily (BID) for 6 months and mycophenolate mofetil PO thrice daily (TID) until day 100. Beginning day 7, patients receive filgrastim-sndz subcutaneously (SC) QD until blood cell levels return to normal.
SCHEDULE II (LYMPHOID MALIGNANCIES): 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.
After completion of study treatment, patients are followed weekly for 3 months, every 3 months in year 1, and every 6 months in year 2.
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 40 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Post-Transplant Bendamustine (PT-BEN) for GVHD Prophylaxis |
| Actual Study Start Date : | March 13, 2020 |
| Estimated Primary Completion Date : | July 1, 2022 |
| Estimated Study Completion Date : | July 1, 2022 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Schedule I (non-lymphoma)
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.
|
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo stem cell transplantation
Other Names:
Drug: Bendamustine Given IV
Other Name: SDX-105
Drug: Cyclophosphamide Given IV
Other Names:
Biological: Filgrastim-sndz Given SC
Other Names:
Drug: Fludarabine Given IV
Other Name: Fluradosa
Drug: Melphalan Given IV
Other Names:
Drug: Mycophenolate Mofetil Given PO
Other Names:
Drug: Tacrolimus Given IV and PO
Other Names:
Radiation: Total-Body Irradiation Undergo TBI
Other Names:
|
|
Experimental: Schedule II (lymphoid malignancies)
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.
|
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo stem cell transplantation
Other Names:
Drug: Bendamustine Given IV
Other Name: SDX-105
Drug: Cyclophosphamide Given IV
Other Names:
Biological: Filgrastim-sndz Given SC
Other Names:
Drug: Fludarabine Given IV
Other Name: Fluradosa
Drug: Mycophenolate Mofetil Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Tacrolimus Given IV and PO
Other Names:
Radiation: Total-Body Irradiation Undergo TBI
Other Names:
|
Outcome Measures
Primary Outcome Measures :
- Maximum tolerated dose level (MTDL) (Phase I) [ Time Frame: Up to 30 days ]Will employ the time-to-event Bayesian optimal interval design to find the MTDL. After the trial is completed, the MTDL will be selected based on isotonic regression as specified in Yuan et al. Specifically, MTDL will be selected as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, the higher dose level when the isotonic estimate is lower than the target toxicity rate will be selected and the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate will be selected.
- Dose-limiting toxicity (Phase I) [ Time Frame: Up to 100 days ]
- Incidence of adverse events (Phase II) [ Time Frame: Up to 2 years ]The trial is continuously monitored for toxicity per the statistical design.
Eligibility Criteria
| Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patient with hematologic malignancies.
- Donor: Mismatched or haplo-identical.
- Zubrod performance 0 to 2 or Karnofsky of at least 60.
- Creatinine less than or equal to 1.6 mg/dL and creatinine clearance >= 30 ml/min. Creatine clearance will be calculated using the Cockcroft-Gault equation. (at time of study entry)
- Total bilirubin less than < 1.5 x upper limit of normal (UNL). (at time of study entry)
- Serum glutamate pyruvate transaminase (SGPT) < 2.5 x ULN. (at time of study entry)
- Ejection fraction >= 40%. (at time of study entry)
- Forced expiratory volume in one second (FEV1) >= 40%. (at time of study entry)
- Forced vital capacity (FVC) >= 40%. (at time of study entry)
- Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40%. (at time of study entry)
Exclusion Criteria:
- Pregnant or nursing women.
- Known to be human immunodeficiency virus (HIV) positive.
- Active and uncontrolled disease/infection.
- Unable or unwilling to sign consent.
- Current active hepatic or biliary disease (with exception of Gilbert's syndrome).
- Active hepatitis B or C.
- Toxicities (grade > 1) unresolved from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents radiation, or surgery.
- Patients with standard risk acute leukemia in first complete remission and patients with chronic myeloid leukemia in first chronic will be excluded during escalated phase.
Contacts and Locations
Locations
| United States, Texas | |
| M D Anderson Cancer Center | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Issa F. Khouri 713-745-0049 ikhouri@mdanderson.org | |
| Principal Investigator: Issa F. Khouri | |
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Issa F Khouri | M.D. Anderson Cancer Center |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | July 15, 2019 | ||||
| First Posted Date ICMJE | July 17, 2019 | ||||
| Last Update Posted Date | May 26, 2021 | ||||
| Actual Study Start Date ICMJE | March 13, 2020 | ||||
| Estimated Primary Completion Date | July 1, 2022 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
|
||||
| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE | Not Provided | ||||
| Original Secondary Outcome Measures ICMJE | Not Provided | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Bendamustine With or Without Cyclophosphamide in Preventing GVHD in Patients Undergoing Stem Cell Transplant | ||||
| Official Title ICMJE | Post-Transplant Bendamustine (PT-BEN) for GVHD Prophylaxis | ||||
| Brief Summary | 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. | ||||
| Detailed Description |
PRIMARY OBJECTIVE: I. Evaluate the safety of substituting the standard post-transplant cyclophosphamide (PT-CY) given on day +3 and +4 with post-transplant bendamustine (PT-BEN) in patients undergoing HLA-mismatched hematopoietic cell transplantation. SECONDARY OBJECTIVES: I. To evaluate treatment-related mortality. II. To assess acute and chronic graft-versus-host disease (GVHD). III. To assess overall survival, progression-free survival and relapse rates. IV. To evaluate the risk of acute cystitis. V. To evaluate immune reconstitution after transplantation. OUTLINE: This is a dose-escalation study of bendamustine. Patients are assigned to 1 of 2 treatment schedules. SCHEDULE I (NON-LYMPHOMA): Patients receive fludarabine intravenously (IV) over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo total body irradiation (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 orally (PO) once daily (QD) or twice daily (BID) for 6 months and mycophenolate mofetil PO thrice daily (TID) until day 100. Beginning day 7, patients receive filgrastim-sndz subcutaneously (SC) QD until blood cell levels return to normal. SCHEDULE II (LYMPHOID MALIGNANCIES): 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. After completion of study treatment, patients are followed weekly for 3 months, every 3 months in year 1, and every 6 months in year 2. |
||||
| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 1 Phase 2 |
||||
| Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment |
||||
| Condition ICMJE | Hematopoietic and Lymphoid System Neoplasm | ||||
| Intervention ICMJE |
|
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| Study Arms ICMJE |
|
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| Publications * | Not Provided | ||||
|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Recruiting | ||||
| Estimated Enrollment ICMJE |
40 | ||||
| Original Estimated Enrollment ICMJE | Same as current | ||||
| Estimated Study Completion Date ICMJE | July 1, 2022 | ||||
| Estimated Primary Completion Date | July 1, 2022 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
|
||||
| Sex/Gender ICMJE |
|
||||
| Ages ICMJE | 18 Years to 70 Years (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE | |||||
| Listed Location Countries ICMJE | United States | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT04022239 | ||||
| Other Study ID Numbers ICMJE | 2018-0972 NCI-2019-03900 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2018-0972 ( Other Identifier: M D Anderson Cancer Center ) |
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| Has Data Monitoring Committee | No | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE | Not Provided | ||||
| Responsible Party | M.D. Anderson Cancer Center | ||||
| Study Sponsor ICMJE | M.D. Anderson Cancer Center | ||||
| Collaborators ICMJE | National Cancer Institute (NCI) | ||||
| Investigators ICMJE |
|
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| PRS Account | M.D. Anderson Cancer Center | ||||
| Verification Date | May 2021 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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