The Lowest Effective Dose of Post-Transplantation Cyclophosphamide in Combination With Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning and Peripheral Blood Stem Cell Transplantation

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05436418

Collaborator

(none)

220

Enrollment

Location

Arms

58.1

Anticipated Duration (Months)

3.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:

Blood cancers (such as leukemias or lymphomas) often do not respond to standard treatments. A transplant of blood stem cells from a healthy donor can help people with these cancers. Sometimes these transplants cause serious side effects, including a common immunologic problem called graft-versus-host disease. A drug called cyclophosphamide given early after the transplant (post-transplantation cyclophosphamide, PTCy) can reduce these complications. But sometimes this drug has its own negative effects. Furthermore, studies in mice suggest that an intermediate, rather than very high, dose of this drug may best protect against graft-versus-host disease.

Objective:

To find out if a lower dose of PTCy is more helpful for people who undergo blood stem cell transplants.

Eligibility:

People aged 18 and older who have a blood cancer and are eligible for a transplant of blood stem cells from another person. Healthy donors are also needed but must be related to the individual needing the transplant.

Design:

Participants will undergo screening. Transplant recipients will have imaging scans and tests of their heart and lung function. They will be assessed for the status of their cancer, including bone marrow taken from their pelvis and possibly also scans and/or fluid drawn from the spine depending on the disease type.

Donors will be screened for general health. They will give several tubes of blood. They will give an oral swab and saliva and stool samples for research.

Recipients will be in the hospital at least 4 to 6 weeks.

They will have a temporary catheter inserted into a vein in the chest or neck. Medications will be given and blood will be drawn through the catheter.

The transplanted stem cells will be given through the catheter. Participants will receive medications both before and after the transplant.

Participants will return to the clinic at least once a week for 3 months after leaving the hospital. Follow-up visits will continue periodically for 5 years.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Blood Stem Cell Transplantation Hematopoietic Stem Cell Transplantation	Drug: Melphalan Drug: Sirolimus Radiation: Total Body Irradiation (TBI) Drug: Cyclophosphamide Drug: Mycophenolate Mofeti Drug: Fludarabine Procedure: Allogeneic HSCT	Phase 1/Phase 2

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 protection against GVHD severity and mortality. Lower dosing of PTCy also was associated with less broad reduction of T-cell numbers after PTCy and lower toxicity than higher dosing.
In patients on an NIH study using myeloablative conditioning and bone marrow as the graft source, a dose of 25 mg/kg/day on days +3/+4 has been associated with more rapid engraftment, less toxicity, and potentially better immune function without an increase in acute GVHD.
The optimal dosing of PTCy potentially may differ depending on the graft source (bone marrow versus peripheral blood stem cells) and HLA disparity (HLA-matched vs. HLA-partially mismatched).

Objective:

Phase I: Determine the lowest effective dose of post-transplantation cyclophosphamide (PTCy) in combination with sirolimus and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning and peripheral blood stem cell transplantation (PBSCT), as assessed by primary graft failure AND Grade III-IV acute GVHD as the dose limiting toxicities (DLTs). This lowest effective dose will be evaluated in parallel for HLA-matched and HLA-haploidentical HCT in different arms of the study.
Phase II: Evaluate the efficacy of PTCy, at the lowest dose determined for each HLA-matching arm from phase I, as assessed by 1-year GVHD-free relapse-free survival (GRFS) rate.

Eligibility:

-Recipient Participant:

Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation
Age >= 50 years or 18-49 years but considered ineligible for myeloablative conditioning.
At least one potentially suitable HLA-haploidentical or 10/10 (HLA-A, B, C, DR, DQ) related or unrelated donor.
Karnofsky performance score >= 70
Adequate organ function

Design:

Open-label, multi-center, non-randomized, phase I/II study.
All recipient participants will receive reduced intensity conditioning, peripheral blood stem cell (PBSC) HCT, and GVHD prophylaxis with PTCy, MMF, and sirolimus.
There will be two parallel arms: one using HLA-haploidentical donors and one using HLA-matched related or unrelated donors.
A small pilot of 5 evaluable participants per arm will receive the standard PTCy 50 mg/kg/day on days +3/+4 to obtain a limited amount of comparative clinical, pharmacokinetic, and T-cell immunophenotyping data.
Then the study will proceed to a novel phase I time-to-event Bayesian optimal interval (TITE-BOIN) trial design to find the lowest acceptable dose of PTCy for each arm. Primary graft failure and grade III-IV aGVHD at day +100 post-transplant are defined PTCy dose-limiting toxicities.
Three dose levels of PTCy: 35, 25, and 15 mg/kg/day on days +3 and +4 are planned in each arm of phase I.
Recipient participants will be evaluated for development of grade III-IV acute GVHD (aGVHD) and primary graft failure at day +100 as the dose-limiting toxicities. Once the optimal PTCy dose for PBSC transplantation is determined for each arm, we will conduct a phase II expansion for each arm to estimate the efficacy of PTCy in combination with sirolimus and mycophenolate mofetil as GVHD prophylaxis. 1-year GRFS rate will be the primary endpoint during the phase II part.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

220 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Trial to Determine the Lowest Effective Dose of Post-Transplantation Cyclophosphamide in Combination With Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning and Peripheral Blood Stem Cell Transplantation

Anticipated Study Start Date :

Aug 30, 2022

Anticipated Primary Completion Date :

Jun 25, 2027

Anticipated Study Completion Date :

Jul 2, 2027

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Donors (Haplo HCT) Research on collected samples
No Intervention: Donors (Matched HCT) Research on collected samples
Experimental: Phase I Dose De-escalation (Haplo HCT) PTCy at de-escalating doses to assess for safety and determine Phase II dose	Drug: Melphalan Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes. Drug: Sirolimus Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions. Radiation: Total Body Irradiation (TBI) Haplo HCT only: A dose of 200 cGy will be administered on day -1. Drug: Cyclophosphamide based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion. Drug: Mycophenolate Mofeti 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. Drug: Fludarabine Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2 Procedure: Allogeneic HSCT Stem cell transplant
Experimental: Phase I Dose De-escalation (Matched HCT) PTCy at de-escalating doses to assess for safety and determine Phase II dose	Drug: Melphalan Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes. Drug: Sirolimus Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions. Radiation: Total Body Irradiation (TBI) Haplo HCT only: A dose of 200 cGy will be administered on day -1. Drug: Cyclophosphamide based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion. Drug: Mycophenolate Mofeti 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. Drug: Fludarabine Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2 Procedure: Allogeneic HSCT Stem cell transplant
Experimental: Phase I Pilot for Comparative Data (Haplo HCT) Standard PTCy 50 mg/kgday on days +3 and +4	Drug: Melphalan Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes. Drug: Sirolimus Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions. Radiation: Total Body Irradiation (TBI) Haplo HCT only: A dose of 200 cGy will be administered on day -1. Drug: Cyclophosphamide based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion. Drug: Mycophenolate Mofeti 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. Drug: Fludarabine Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2 Procedure: Allogeneic HSCT Stem cell transplant
Experimental: Phase I Pilot for Comparative Data (Matched HCT) Standard PTCy 50 mg/kg/day on days +3 and +4	Drug: Melphalan Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes. Drug: Sirolimus Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions. Radiation: Total Body Irradiation (TBI) Haplo HCT only: A dose of 200 cGy will be administered on day -1. Drug: Cyclophosphamide based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion. Drug: Mycophenolate Mofeti 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. Drug: Fludarabine Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2 Procedure: Allogeneic HSCT Stem cell transplant
Experimental: Phase II Efficacy (Haplo HCT) PTCy at shortest duration, safe dose (from Phase I)	Drug: Melphalan Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes. Drug: Sirolimus Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions. Radiation: Total Body Irradiation (TBI) Haplo HCT only: A dose of 200 cGy will be administered on day -1. Drug: Cyclophosphamide based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion. Drug: Mycophenolate Mofeti 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. Drug: Fludarabine Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2 Procedure: Allogeneic HSCT Stem cell transplant
Experimental: Phase II Efficacy (Matched HCT) PTCy at shortest duration, safe dose (from Phase I)	Drug: Melphalan Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes. Drug: Sirolimus Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions. Radiation: Total Body Irradiation (TBI) Haplo HCT only: A dose of 200 cGy will be administered on day -1. Drug: Cyclophosphamide based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion. Drug: Mycophenolate Mofeti 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. Drug: Fludarabine Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2 Procedure: Allogeneic HSCT Stem cell transplant

Outcome Measures

Primary Outcome Measures

Phase II: Evaluate the efficacy of PTCy, at the lowest dose determined for each HLA-matching arm from phase I, as assessed by 1-year GVHD-free relapse-free survival (GRFS) rate. [1 year]
1-year GRFS and 95% CI per arm will be estimated using Kaplan-Meier curves.
Phase I: Determine the lowest effective dose of PTCy in combination with sirolimus and mycophenolate mofetil as GVHD prophylaxis after reduced intensity conditioning and PBSCT, as assessed by primary graft failure AND Grade III-IV acute GVHD as ... [60 days]
Number of evaluable subjects and DLT will be summarized per dose level in each arm.

Secondary Outcome Measures

Estimate rates of symptomatic BK virus cystitis. (Phase I and II) [100 days]
To evaluate symptomatic BK virus cystitis using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing the outcome.
Estimate rates of hematopoietic recovery/engraftment. (Phase I and II) [day 28, 42, and 100]
Rate and timing of neutrophil and platelet engraftment also will be evaluated descriptively, including fractions who attain each condition at day 28, 42, and 100, along with 95% confidence intervals. Ranges and medians will be calculated only in engrafting subjects.
Estimate rates of Grade II-IV and III-IV acute GVHD at 100 days (Phase I and II) [100 days]
To evaluate for grades II-IV and III-IV acute GVHD at 100 days using Kaplan-Meier curves or competing risk-based cumulative incidence curves. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.
Estimate non-relapse mortality at one year (Phase II only) [1 year]
To evaluate non-relapse mortality at one year, estimates will be determined using competing risk-based cumulative incidence curves. Relapse and non-relapse mortality will be competing risks for each other.
Estimate overall survival and progression-free survival at one year (Phase II only) [1 year]
To evaluate survival at one year, estimates will be determined using Kaplan-Meier curves.
Estimate incidence progression/relapse at one year (Phase II only) [1 year]
To evaluate relapse at one year, estimates will be determined using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. Relapse and non-relapse mortality will be competing risks for each other.
Describe and characterize cytokine release syndrome (CRS) (Phase I and II) [1 year]
To evaluate CRS incidence, frequency and severity using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. Relapse/progression and NRM will be competing risks.
Estimate rates of CMV reactivation requiring preemptive therapy. (Phase I and II) [100 days]
To evaluate CMV reactivation requiring preemptive therapy using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.
Estimate rates of any chronic GVHD and moderate/severe chronic GVHD at one year (Phase I and II) [1 year]
To evaluate for all chronic and moderate/severe chronic GVHD at one year using Kaplan-Meier curves or competing risk-based cumulative incidence curves. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

INCLUSION CRITERIA:

Recipient

Participants must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation limited to 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 (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
AML of any risk in second or subsequent morphologic complete remission
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, relapsed 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 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 >= 50 years or age 18-49 years and also meeting one of the following criteria:
Prior myeloablative HCT
Prior exposure to inotuzumab, gemtuzumab, or other agent that increases the risk for sinusoidal obstruction syndrome.
Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI) >= 3
Karnofsky performance score <80
Co-morbidity considered by the treating physician to be exclusionary of myeloablative conditioning
At least one potentially suitable HLA-haploidentical or 10/10 (HLA-A, B, C, DR, DQ) related or unrelated donor for HCT
Karnofsky performance score >= 70
Adequate organ function defined as possessing all of the following:
Cardiac ejection fraction >= 45% by 2D ECHO;
Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of

= 50% predicted;

Estimated serum creatinine clearance of >= 60 ml/minute/1.73m^2 calculated using eGFR in the clinical lab;
Total bilirubin <= 2X the upper limit of normal;
Alanine aminotransferase and aspartate aminotransferase <= 3X the upper limit of normal.
Women of child-bearing potential (WOCBP) and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-transplant.
WOCBP must have a negative serum or urine pregnancy test within 7 days prior to initiation of conditioning regimen.
Ability of participant to understand and the willingness to sign a written informed consent document.

Donor

Related donor (age >= 12) deemed suitable and eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, saliva, oral swab, 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.
Ability of participant or parent/legal guardian to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Recipient

Participants 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.
Active breastfeeding.
Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is: metastatic, or 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 non-melanoma skin cancers.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents.
Uncontrolled intercurrent illness (e.g., severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance, active infectious hepatitis, uncontrolled dental infection) that in the opinion of the Site PI would make it unsafe to proceed with transplantation.

Donor

None