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 (Bullet)5/10 HLA-mismatched unrelated donor.
Karnofsky performance score (Bullet)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.
Title
- Brief Title: Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies
- Official Title: Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies
Clinical Trial IDs
- ORG STUDY ID:
10000359
- SECONDARY ID:
000359-C
- NCT ID:
NCT04959175
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Mycophenolate Mofetil | | Older, HLA-matched |
Fludarabine | | Older, HLA-matched |
Sirolimus | | Older, HLA-matched |
Filgrastim | | Older, HLA-matched |
Cyclophosphamide | | Older, HLA-matched |
Mesna | | Older, HLA-matched |
Purpose
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 (Bullet)5/10 HLA-mismatched unrelated donor.
Karnofsky performance score (Bullet)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.
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 (Bullet)5/10 HLA-mismatched unrelated donor.
Karnofsky performance score (Bullet)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.
Trial Arms
Name | Type | Description | Interventions |
---|
Donors | No Intervention | Collection of research samples on bone marrow donors | |
Older, HLA-matched | Experimental | Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor | - Mycophenolate Mofetil
- Fludarabine
- Sirolimus
- Filgrastim
- Cyclophosphamide
- Mesna
|
Older, HLA-mismatched | Experimental | Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor | - Mycophenolate Mofetil
- Fludarabine
- Sirolimus
- Filgrastim
- Cyclophosphamide
- Mesna
|
Younger, HLA-matched | Experimental | Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor | - Mycophenolate Mofetil
- Fludarabine
- Sirolimus
- Filgrastim
- Cyclophosphamide
- Mesna
|
Younger, HLA-mismatched | Experimental | Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor | - Mycophenolate Mofetil
- Fludarabine
- Sirolimus
- Filgrastim
- Cyclophosphamide
- Mesna
|
Eligibility Criteria
-INCLUSION CRITERIA - Recipient
1. Subjects must have a histologically or cytologically confirmed hematologic malignancy
with standard indication for allogeneic hematopoietic cell transplantation including,
but not limited to, one of the following:
- Acute myeloid leukemia in morphologic complete remission (<5% blasts in the bone
marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
- B-cell acute lymphoblastic leukemia in first or subsequent complete remission
- T-cell acute lymphoblastic leukemia in first or subsequent complete remission
- 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 DIPSS
- Chronic myelomonocytic leukemia
- Chronic myelogenous leukemia resistant to or intolerant of >=3 tyrosine kinase
inhibitors or with history of accelerated phase or blast crisis
- B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of
completion of primary treatment, after autologous transplantation or has
progressed through at least 2 lines of therapy
- Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or
refractory 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 higher60 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)
2. Age 60-85 years, or age 18-60 years and unfit for myeloablative conditioning. Reasons
for unfitness for myeloablative conditioning include:
- Prior myeloablative HCT
- Prior exposure to inotuzumab, gemtuzumab, or other agent that increases the risk
for sinusoidal obstruction syndrome.
- Significant organ dysfunction (e.g., creatinine or liver enzymes above the upper
limit of normal or EGFR <=70 ml/min/1.73sq.m; prior sinusoidal obstruction
syndrome, hepatic fibrosis, hepatic steatosis, or nodular regenerative
hyperplasia; reduced ejection fraction <55% or focal hypokinesis, FEV1 or
adjusted DLCO <75% of predicted)
- Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI) >= 3
- Subject refusal of MAC (including subjects insistent on trying to maintain
fertility)
- Pre-frail or frail by Fried s frailty phenotype
- Karnofsky performance score <80
- Significant life-threatening toxicities associated with prior chemotherapy
- Co-morbidity considered by the treating physician to be exclusionary of MAC
3. At least one potentially suitable HLA-matched related, HLA-haploidentical first degree
or collateral related, HLA-matched unrelated, or >=5/10 HLA-mismatched unrelated
donor.
4. Karnofsky performance score >=60
5. Ability of subject to understand and the willingness to sign a written informed
consent document.
6. Adequate organ function defined as possessing all of the following:
- Cardiac ejection fraction >=35%;
- Forced expiratory volume-1, forced vital capacity, and diffusing capacity of the
lung for carbon monoxide (corrected for hemoglobin) all of >=40% predicted;
- Serum creatinine clearance of >=45 ml/minute calculated using the Cockcroft-Gault
equation;
- Total bilirubin <=2X the upper limit of normal;
- Alanine aminotransferase and aspartate aminotransferase <=5X the upper limit of
normal.
7. Nonmyeloablative conditioning is toxic to the developing human fetus and is
teratogenic. For this reason, the following measures apply:
- Women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for at least one year post-transplant.
- Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately.
- WOCBP must have a negative serum or urine pregnancy test within 7 days prior to
enrollment.
8. For NIH treated subjects only: subjects requiring standard therapies to prepare for
HCT should be referred in remission, if possible. However, these diseases are often
aggressive and require swift evaluation for HCT while concurrently attempting to
establish disease control through the administration of standard therapies. If ongoing
therapy for the underlying disease outside of the NIH is not in the best interest of
the subject according to the clinical judgment of the NIH PI, then the subject may
receive standard treatment for his/her underlying hematologic malignancy as a bridge
to HCT on this protocol, prior to starting the research phase of the study. If it
becomes apparent that the subject will not be able to proceed to HCT, then he/she must
come off study. Subjects receiving standard therapy will be told about the therapy,
associated risks, potential benefits, alternatives to the proposed therapy, and the
availability of receiving the same treatment elsewhere, outside of a research
protocol.
EXCLUSION CRITERIA - Recipient:
1. Subjects who are receiving any other investigational agents. Prior experimental
therapies must have been completed at least 2 weeks prior to the date of beginning
conditioning.
2. Poorly controlled malignant indication for transplantation such as:
- Leukemia not having achieved morphologic remission (i.e. bone marrow blasts >5%
or active extramedullary disease)
- Lymphoma not having achieved at least a partial response to prior chemotherapy or
radiation
3. Uncontrolled intercurrent illness that in the opinion of the site PI would make it
unsafe to proceed with transplantation.
4. The potential for some of the study medications to be transmissible via breast milk of
nursing mothers is unknown. Because there is unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother, breastfeeding must be
discontinued.
5. Active malignancy of non-hematopoietic type which is: metastatic, relapsed/refractory
to treatment, or locally advanced and not amenable to curative treatment, or limited
disease treated with curative intent treatment within the last 2 years. This excludes
nonmelanoma skin cancers.
INCLUSION CRITERIA - Related Donor:
Related donor (age >=12) deemed suitable and eligible, and willing to donate, per clinical
evaluations, who are additionally willing to donate blood, bone marrow, and stool for
research.
Related donors will be evaluated in accordance with existing institutional Standard
Policies and Procedures for determination of eligibility and suitability for clinical
donation.
Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for at
least 60 days after donation.
EXCLUSION CRITERIA - Related Donor:
None
Maximum Eligible Age: | 85 Years |
Minimum Eligible Age: | 12 Years |
Eligible Gender: | All |
Healthy Volunteers: | Accepts Healthy Volunteers |
Primary Outcome Measures
Measure: | determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60 |
Time Frame: | 60 days |
Safety Issue: | |
Description: | 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
Measure: | Grade III-IV acute GVHD at day 100 and 200 |
Time Frame: | 100 days/200 days |
Safety Issue: | |
Description: | 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. |
Measure: | Grade II-IV acute GVHD at day 100 and 200 |
Time Frame: | 100 days/200 days |
Safety Issue: | |
Description: | 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. |
Measure: | Rate of Fried s Frailty Phenotypes (FP) |
Time Frame: | 1 year |
Safety Issue: | |
Description: | Frequency of different phenotypes |
Measure: | Chronic GVHD at one year |
Time Frame: | 1 year |
Safety Issue: | |
Description: | 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. |
Measure: | Progression/relapse at one year |
Time Frame: | 1 year |
Safety Issue: | |
Description: | Estimates will be determined using Kaplan-Meier curves. Relapse and non-relapse mortality will be competing risks for each other. |
Measure: | Non-relapse mortality at 100 days and one year |
Time Frame: | 100 days and 1 year |
Safety Issue: | |
Description: | Estimates will be determined using competing risk-based cumulative incidence curves. Relapse and non-relapse mortality will be competing risks for each other. |
Measure: | Overall survival, progression-free survival, and disease-free survival at one year |
Time Frame: | 1 year |
Safety Issue: | |
Description: | Estimates will be determined using Kaplan-Meier curves. |
Measure: | Estimation of platelet engraftment, neutrophil engraftment. |
Time Frame: | day 28 and day 100 |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- myeloablative conditioning
- Chronic Graft-Versus-Host Disease
- hematopoietic cell transplantation
- Fludarabine
- TOTAL BODY IRRADIATION
Last Updated
September 1, 2021