Optimizing PTCy Dose and Timing
- Conditions
- Hematologic NeoplasmsGraft Versus Host Disease
- Interventions
- Registration Number
- NCT03983850
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Stem cell or bone marrow transplants can cure or control blood cancers. Sometimes the donor cells see the recipient's body as foreign. This can cause complications. A high dose of the drug cyclophosphamide (PTCy) can help reduce these risks. Researchers want to see if a lower dose of PTCy can have the same benefits. Based on encouraging results from the first part of the study, researchers now are investigating whether a lower dose of PTCy can allow other immunosuppression to be decreased.
Objective:
To see if a lower dose of PTCy and now also shorter duration of another immunosuppressant called mycophenolate mofetil will help people with blood cancers have a more successful transplant and fewer side effects.
Eligibility:
People ages 15-65 with leukemia, lymphoma, or multiple myeloma that is not curable with standard therapy and is at high risk of returning without transplant, and their healthy adult relatives
Design:
Transplant participants will be screened with:
Blood, urine, breathing, and heart tests
Scans
Chest x-ray
Bone marrow samples: A needle inserted into the participant s pelvis will remove marrow and a bone fragment.
Transplant recipients will stay at the hospital and be prepped with chemotherapy over 6 days for the transplant. They will get stem cells through a catheter in the chest or neck. They will get the cyclophosphamide chemotherapy. They will stay in the hospital about 4 more weeks. They will have blood transfusions. They will have frequent blood tests and 2 bone marrow samples within 1 year after the transplant.
Donor participants will be screened with:
Blood, urine, and heart tests
Chest x-ray
Scans
Donor participants will have bone marrow taken from their pelvis or stem cells taken from their blood. For the blood donation, blood will be taken from a vein in one arm, move through a machine to remove white blood cells, and be returned through a vein in the other arm.
Participation will last up to 5 years....
- Detailed Description
Background:
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)-haploidentical HCT
When clinically translated, the dose (50 mg/kg) and timing (days +3 and +4) of PTCy used were partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and were 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
In the MHC-haploidentical HCT model, a dose of 25 mg/kg on day +4 was equivalent to 25 mg/kg/day on days +3 and +4
In addition to better GVHD prevention, lower dosing of PTCy is associated with less broad reduction of T-cell numbers after PTCy
Mycophenolate mofetil (MMF), used as adjunct immunosuppression with standard dose PTCy, can have substantial gastrointestinal toxicity and can impede immune reconstitution and pathogen-specific immunity.
Objectives:
Determine whether a dose of PTCy 25 mg/kg on day +3 and +4 or on day +4 only can maintain adequate protection against grade III-IV acute GVHD.
Determine whether a reduced duration of MMF, in combination with PTCy 25 mg/kg/day on days +3 and +4, can maintain adequate protection against grade III-IV acute GVHD.
Eligibility:
Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including one of the following:
Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission
AML of any risk in second or subsequent morphologic complete remission
B-cell acute lymphoblastic leukemia in first or subsequent complete remission
T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics
Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)
Primary myelofibrosis of intermediate-2 or higher risk by the Dynamic International Prognostic Scoring System (DIPSS)
Chronic myelomonocytic leukemia
Chronic myelogenous leukemia resistant to or intolerant of \>=3 tyrosine kinase inhibitors or with prior history of accelerated phase or blast crisis
B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment
Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors
Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T-cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines
Hematologic malignancy of dendritic cell or histiocytic cell type
Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD)
Age 15-65.
At least one potentially suitable HLA-haploidentical donor.
Karnofsky performance score \>=60
Adequate organ function
Design:
Open-label, single-center, non-randomized, phase I/II study
All patients will receive myeloablative conditioning, HLA-haploidentical bone marrow HCT, and GVHD prophylaxis with PTCy, MMF (depending on cohort), and sirolimus.
A small pilot of 5 evaluable patients will receive the standard PTCy 50 mg/kg on days +3/+4 to obtain a limited amount of comparative pharmacokinetic and T-cell immunophenotyping and repertoire data.
Then the study will proceed to a small, two-level \[1) 25 mg/kg/day on days +3 and +4, 2) 25 mg/kg on day +4 only\] phase I dose de-escalation study based on the standard 3+3 approach
Patients will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity and then phase II will proceed with the shorter duration of the days of treatment (+3/+4 or +4) which is associated with 0-1 of 6 patients with grade III-IV aGVHD at day +60 and with the least amount of toxicity
Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with this decreased PTCy exposure, will be used in the phase II portion of the study which will enroll an additional 14 patients to see if this lower PTCy exposure is associated with a similar rate of grade III-IV acute GVHD as is expected with 50 mg/kg on days +3/+4
Following completion of the phase II portion of the trial evaluating PTCy 25 mg/kg/day on days +3/+4, a dose de-escalation will be conducted to determine if the dose of MMF (standardly days +5 to +35) may be reduced without meaningful impact on avoidance of grade III-IV acute GVHD. The tested dose levels will be 1) MMF from days +5 to +18 and 2) no MMF. This will be followed by a second Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with decreased MMF exposure, which will expand on the lowest MMF dose that is associated with acceptable toxicity and enroll an additional 14 patients to see if this lower MMF is associated with a similar rate of grade III-IV acute GVHD as is expected with full 30 day MMF treatment.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 400
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase I Dose De-escalation Fludarabine PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients) Phase I Dose De-escalation Sirolimus PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients) Phase I duration de-escalation of MMF Fludarabine MMF at de-escalating duration (days +5 to +18 only, no MMF)) Phase I Dose De-escalation Busulfan PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients) Phase I duration de-escalation of MMF Sirolimus MMF at de-escalating duration (days +5 to +18 only, no MMF)) Phase I Dose De-escalation Cyclophosphamide PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients) Phase I Dose De-escalation Mycophenolate Mofetil PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients) Phase I duration de-escalation of MMF Cyclophosphamide MMF at de-escalating duration (days +5 to +18 only, no MMF)) Phase II efficacy of reduced duration MMF Busulfan MMF at duration identified from de-escalation evaluation. Phase I Pilot for Comparative Data Cyclophosphamide Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data Phase II Efficacy Busulfan PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients) Phase II efficacy of reduced duration MMF Mycophenolate Mofetil MMF at duration identified from de-escalation evaluation. Phase I Pilot for Comparative Data Fludarabine Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data Phase I duration de-escalation of MMF Busulfan MMF at de-escalating duration (days +5 to +18 only, no MMF)) Phase I duration de-escalation of MMF Mycophenolate Mofetil MMF at de-escalating duration (days +5 to +18 only, no MMF)) Phase I Pilot for Comparative Data Busulfan Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data Phase I Pilot for Comparative Data Mycophenolate Mofetil Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data Phase I Pilot for Comparative Data Sirolimus Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data Phase II Efficacy Fludarabine PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients) Phase II Efficacy Cyclophosphamide PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients) Phase II Efficacy Mycophenolate Mofetil PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients) Phase II efficacy of reduced duration MMF Fludarabine MMF at duration identified from de-escalation evaluation. Phase II Efficacy Sirolimus PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients) Phase II efficacy of reduced duration MMF Cyclophosphamide MMF at duration identified from de-escalation evaluation. Phase II efficacy of reduced duration MMF Sirolimus MMF at duration identified from de-escalation evaluation.
- Primary Outcome Measures
Name Time Method aGVHD protection from a reduced duration of MMF, in combination with PTCy 25 mg/kg/day 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. The MMF duration level patients may be compared with the PTCy dose level patients which serves as a baseline for standard duration MMF.
aGVHD protection from PTCy 25 mg/kg 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.
- Secondary Outcome Measures
Name Time Method Determine, at the PTCy dose or MMF duration used in phase II cohorts, the cumulative incidences 100 days Rate and timing of neutrophil and platelet engraftment also 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 patients. 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. 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
determine the shortest MMF duration without unacceptable acute GVHD to be used during phase II 60 days The phase II MMF duration level patients may be compared with the phase II PTCy dose level patients which serves as a baseline for standard duration MMF.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States