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

NCT05436418 | Recruiting Phase 1

• 2 other identifiers: 10000613000613-C
• Study Type: interventional
• Target: 260
• Locations: 1 country
• Sites: 2

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.

Conditions

Hematopoietic Stem Cell Transplantation; Peripheral Blood Stem Cell Transplantation

Keywords

Reduced Intensity Conditioning; Systemic Immunosuppressive Therapy; Hematologic Malignancy; Acute Myeloid Leukemia; Calcineurin Inhibitor

Outcome Measures

Primary Outcomes (2)

• 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 GRFS and 95% CI per arm will be estimated using Kaplan-Meier curves.

  1 year

• 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 ...

  Number of evaluable subjects and DLT will be summarized per dose level in each arm.

  60 days

Secondary Outcomes (9)

• Estimate rates of symptomatic BK virus cystitis. (Phase I and II)

  100 days

• Estimate rates of hematopoietic recovery/engraftment. (Phase I and II)

  day 28, 42, and 100

• Estimate rates of Grade II-IV and III-IV acute GVHD at 100 days (Phase I and II)

  100 days

• Estimate non-relapse mortality at one year (Phase II only)

  1 year

• Estimate overall survival and progression-free survival at one year (Phase II only)

  1 year

Study Arms (8)

Donors (Haplo HCT)

NO INTERVENTION

Research on collected samples

Donors (Matched HCT)

NO INTERVENTION

Research on collected samples

Phase I Dose De-escalation (Haplo HCT)

EXPERIMENTAL

PTCy at de-escalating doses to assess for safety and determine Phase II dose

Drug: Melphalan; Drug: Sirolimus; Radiation: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Mycophenolate Mofeti; Drug: Fludarabine; Procedure: Allogeneic HSCT; Drug: Mesna; Drug: Filgrastim

Phase I Dose De-escalation (Matched HCT)

EXPERIMENTAL

PTCy at de-escalating doses to assess for safety and determine Phase II dose

Drug: Melphalan; Drug: Sirolimus; Radiation: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Mycophenolate Mofeti; Drug: Fludarabine; Procedure: Allogeneic HSCT; Drug: Mesna; Drug: Filgrastim

Phase I Pilot for Comparative Data (Haplo HCT)

EXPERIMENTAL

Standard PTCy 50 mg/kgday on days +3 and +4

Drug: Melphalan; Drug: Sirolimus; Radiation: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Mycophenolate Mofeti; Drug: Fludarabine; Procedure: Allogeneic HSCT; Drug: Mesna; Drug: Filgrastim

Phase I Pilot for Comparative Data (Matched HCT)

EXPERIMENTAL

Standard PTCy 50 mg/kg/day on days +3 and +4

Drug: Melphalan; Drug: Sirolimus; Radiation: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Mycophenolate Mofeti; Drug: Fludarabine; Procedure: Allogeneic HSCT; Drug: Mesna; Drug: Filgrastim

Phase II Efficacy (Haplo HCT)

EXPERIMENTAL

PTCy at shortest duration, safe dose (from Phase I)

Drug: Melphalan; Drug: Sirolimus; Radiation: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Mycophenolate Mofeti; Drug: Fludarabine; Procedure: Allogeneic HSCT; Drug: Mesna; Drug: Filgrastim

Phase II Efficacy (Matched HCT)

EXPERIMENTAL

PTCy at shortest duration, safe dose (from Phase I)

Drug: Melphalan; Drug: Sirolimus; Radiation: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Mycophenolate Mofeti; Drug: Fludarabine; Procedure: Allogeneic HSCT; Drug: Mesna; Drug: Filgrastim

Interventions

Melphalan DRUG

Matched HCT: 100 mg/m\^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m\^2 IV on day -6 over approximately 20-30 minutes.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Sirolimus DRUG

Sirolimus: Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg)\^d, 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 and may be modified based on institutional practice.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Total Body Irradiation (TBI) RADIATION

Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Cyclophosphamide DRUG

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.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Fludarabine DRUG

Matched HCT: 25 mg/m\^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 40 mg/m\^2/day infused IV over approximately 30-60 minutes from day -5 to day -2

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Mycophenolate Mofeti DRUG

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.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Allogeneic HSCT PROCEDURE

Stem cell transplant

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Mesna DRUG

equal to the cyclophosphamide dose (50, 35, 25, or 15 mg/kg) as IV infusion concomitant with cyclophosphamide. Mesna is dosed in the same way as cyclophosphamide regarding ideal vs. actual body weight.b Dosing may be modified based on institutional standard practice.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Filgrastim DRUG

begins on day +5 at a dose of 5 mcg/kg/day (actual body weight; dose rounding is permitted e.g., nearest vial or syringe size) and is administered daily subcutaneously or IV until the absolute neutrophil count is \> 1000 cells/mm3 for three days or \> 5000 for one day.

Phase I Dose De-escalation (Haplo HCT); Phase I Dose De-escalation (Matched HCT); Phase I Pilot for Comparative Data (Haplo HCT); Phase I Pilot for Comparative Data (Matched HCT); Phase II Efficacy (Haplo HCT); Phase II Efficacy (Matched HCT)

Eligibility Criteria

• Age: 12 Years - 120 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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 nursing.
• 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
• Related (age \>=12) and unrelated (age \>=18) donors deemed eligible (i.e., evaluated at NIH, COH, and FHCC in accordance with existing institutional Standard Policies and Procedures or evaluated per the standards required by the IRB of the National Marrow Donor Program or applicable registry), and willing to donate research samples will be included.
• Ability of participant or parent/legal guardian to understand and the willingness to sign a written informed consent document.
• Donor
• None

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

City of Hope

Duarte, California, 91010, United States

NOT YET RECRUITING

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hematologic Neoplasms; Leukemia, Myeloid, Acute

Interventions

Melphalan; Sirolimus; Whole-Body Irradiation; Cyclophosphamide; fludarabine; Mesna; Filgrastim

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques; Phosphoramide Mustards; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Proteins; Biological Factors

Study Officials

• Christopher G Kanakry, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amy H Chai

CONTACT

(240) 858-3755; amy.chai@nih.gov

Christopher G Kanakry, M.D.

CONTACT

(240) 760-6171; christopher.kanakry@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2022
• First Posted: June 29, 2022
• Study Start: November 18, 2022
• Primary Completion (Estimated): June 25, 2027
• Study Completion (Estimated): June 25, 2028
• Last Updated: April 27, 2026

Record last verified: 2026-04-23

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (2)