Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies
- Conditions
- Hematologic Neoplasms
- Interventions
- Procedure: Allogeneic HSCTProcedure: Total Body Irradiation (TBI)
- Registration Number
- NCT04959175
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Certain blood cancers can be treated with blood or bone marrow transplants. Sometimes the donor cells attack the recipient's body, called graft-versus-host disease (GVHD). The chemotherapy drug cyclophosphamide helps reduce the risk and severity of GVHD. Researchers want to learn if using a lower dose of cyclophosphamide may reduce the drug's side effects while maintaining its effectiveness. Such an approach is being used in an ongoing clinical study at the NIH with promising results, but this approach has not been tested for transplants using lower doses of chemotherapy/radiation prior to the transplant.
Objective:
To learn if using a lower dose of cyclophosphamide will help people have a successful transplant and have fewer problems and side effects.
Eligibility:
Adults ages 18-85 who have a blood cancer that did not respond well to standard treatments or is at high risk for relapse without transplant, and their donors.
Design:
Participants may be screened with the following:
Medical history
Physical exam
Blood and urine tests
Heart and lung tests
Body imaging scans (they may get a contrast agent)
Spinal tap
Bone marrow biopsy
Participants will be hospitalized for 4-6 weeks. They will have a central venous catheter placed in a chest or neck vein. It will be used to give medicines, transfusions, and the donor cells, and to take blood. In the week before transplant, they will get 2 chemotherapy drugs and radiation. After the transplant, they will get the study drug for 2 days. They will take other drugs for up to 2 months.
Participants must stay near NIH for 3 months after discharge for weekly study visits. Then they will have visits every 3-12 months until 5 years after transplant.
Participants and donors will give blood, bone marrow, saliva, cheek swab, urine, and stool samples for research.
- Detailed Description
Background:
With novel therapies for hematologic malignancies, an increasing number of older and/or less fit patients are achieving remissions, but these new therapies are not curative, making consolidation approaches with curative intent such as allogeneic transplantation necessary.
Frailty is a phenotype that predicts a patient s intolerance of physiologic stressors and may predict a patient s tolerance of intensive consolidative strategies.
Frailty phenotype, though increasing in incidence in older patients, can occur in younger patients and may predict poor survival after allogeneic transplantation.
We have yet to define the ideal allogeneic transplantation regimen for older patients or those with frailty or pre-frail phenotypes.
Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-matched-related, HLA-matched-unrelated, HLA-mismatched-unrelated, and HLA-haploidentical HCT; it has become the most widely adopted change to transplantation platforms over the last decade.
When clinically translated, the dose (50 mg/kg/day) of PTCy used was partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and was partly empirical.
In both MHC-haploidentical and MHC-disparate murine HCT models, a dose of 25 mg/kg/day was superior to 50 mg/kg/day on days +3 and +4 in terms of GVHD severity and mortality. Lower dosing of PTCy also was associated with less broad reductions of T-cell numbers after PTCy and lower toxicity than higher dosing.
In patients on an NIH study using myeloablative conditioning, a dose of 25 mg/kg/day has been associated with more rapid engraftment and potentially better immune function without an increase in severe acute GVHD.
Objectives:
Determine whether PTCy 25 mg/kg on days +3 and +4 can maintain adequate protection against grade III-IV acute GVHD and reduce toxicity associated with transplantation in older and/or unfit transplant recipients receiving reduced intensity conditioned allogeneic HCT.
Determine the frailty measures associated with outcomes after allogeneic transplantation.
Eligibility:
Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation.
Age 60-85 years, or age 18-60 years and unfit for myeloablative conditioning (MAC).
At least one potentially suitable HLA-matched related, HLA-haploidentical donor, HLA-matched unrelated, or \>=5/10 HLA-mismatched unrelated donor.
Karnofsky performance score \>=60
Adequate organ function
Design:
Open-label, multi-center, non-randomized, phase I/II study
There will be four separate arms: HLA-matched elderly, HLA-matched young/infirm, HLA-partially matched elderly, and HLA-partially matched young/infirm
All subjects will receive nonmyeloablative conditioning consisting of fludarabine, cyclophosphamide, and total body irradiation; GVHD prophylaxis with PTCy 25 mg/kg on days +3 and +4, MMF, and sirolimus; and bone marrow as the stem cell source
Subjects will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicities for the Simon two-stage design. Dose escalation of PTCy will be permitted within each arm if stopping rules are met at the 25 mg/kg/day on days +3 and +4 dose.
Frailty assessments will be performed prior to transplantation conditioning and serially after allogeneic transplantation.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 320
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Younger, HLA-matched Fludarabine Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-matched Cyclophosphamide Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-matched Allogeneic HSCT Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-matched Sirolimus Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-matched Total Body Irradiation (TBI) Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-mismatched Allogeneic HSCT Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-mismatched Fludarabine Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-matched Mycophenolate Mofetil Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-matched Allogeneic HSCT Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-matched Filgrastim Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-mismatched Total Body Irradiation (TBI) Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-mismatched Total Body Irradiation (TBI) Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-matched Cyclophosphamide Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-matched Total Body Irradiation (TBI) Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-mismatched Mycophenolate Mofetil Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-mismatched Allogeneic HSCT Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-mismatched Mesna Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-mismatched Fludarabine Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-mismatched Cyclophosphamide Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-matched Fludarabine Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-matched Mesna Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor Older, HLA-mismatched Mycophenolate Mofetil Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-mismatched Sirolimus Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-mismatched Filgrastim Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-mismatched Cyclophosphamide Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Older, HLA-mismatched Mesna Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-matched Mycophenolate Mofetil Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-matched Filgrastim Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-matched Sirolimus Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-matched Mesna Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor Younger, HLA-mismatched Filgrastim Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor Younger, HLA-mismatched Sirolimus Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor
- Primary Outcome Measures
Name Time Method determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60 60 days The fraction of evaluable patients who experience grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals. In addition, a cumulative incidence curve for this endpoint will be constructed.
- Secondary Outcome Measures
Name Time Method Grade II-IV acute GVHD at day 100 and 200 100 days/200 days Estimates will be determined using competing risk-based cumulative incidence curves. Grade II-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals.
Overall survival, progression-free survival, and disease-free survival at one year 1 year Estimates will be determined using Kaplan-Meier curves.
Rate of Fried s Frailty Phenotypes (FP) 1 year Frequency of different phenotypes
Chronic GVHD at one year 1 year Estimates will be determined using competing risk-based cumulative incidence curves. Graft failure, relapse, donor lymphocyte infusion, and non-relapse mortality will be competing risks for chronic GVHD.
Progression/relapse at one year 1 year Estimates will be determined using Kaplan-Meier curves. Relapse and non-relapse mortality will be competing risks for each other.
Non-relapse mortality at 100 days and one year 100 days and 1 year Estimates will be determined using competing risk-based cumulative incidence curves. Relapse and non-relapse mortality will be competing risks for each other.
Grade III-IV acute GVHD at day 100 and 200 100 days/200 days Estimates will be determined using competing risk-based cumulative incidence curves. Graft failure, relapse, donor lymphocyte infusion, non-relapse mortality, and chronic GVHD will be competing risks for acute GVHD. Grade III-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals.
Estimation of platelet engraftment, neutrophil engraftment. day 28 and day 100 Rate and timing will be evaluated descriptively, including fractions who attain each condition at day 28 and 100, along with 95% confidence intervals. Ranges and medians will be calculated only in engrafting participants.
Trial Locations
- Locations (2)
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States