Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies

NCT04959175 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10000359000359-C
• Study Type: interventional
• Target: 320
• Locations: 1 country
• Sites: 2

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.

Conditions

Hematologic Neoplasms

Keywords

myeloablative conditioning; Chronic Graft-Versus-Host Disease; hematopoietic cell transplantation; Fludarabine; TOTAL BODY IRRADIATION

Outcome Measures

Primary Outcomes (1)

• determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60

  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.

  60 days

Secondary Outcomes (8)

• Grade III-IV acute GVHD at day 100 and 200

  100 days/200 days

• Grade II-IV acute GVHD at day 100 and 200

  100 days/200 days

• Rate of Fried s Frailty Phenotypes (FP)

  1 year

• Chronic GVHD at one year

  1 year

• Progression/relapse at one year

  1 year

Study Arms (5)

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

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

Older, HLA-mismatched

EXPERIMENTAL

Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor

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

Younger, HLA-matched

EXPERIMENTAL

Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor

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

Younger, HLA-mismatched

EXPERIMENTAL

Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor

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

Interventions

Fludarabine DRUG

30 mg/m2 IV infusion over 30-60 minutes once daily for 5 days (Pre-Transplant days -6 through -2).

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Sirolimus DRUG

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 +60 with no taper. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Allogeneic HSCT PROCEDURE

Stem cell transplant

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Mycophenolate Mofetil DRUG

15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Filgrastim DRUG

begins on day +5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously, until the absolute neutrophil count is \> 1,000/mm3 over the course of three days or \> 5,000/mm3 on one day. Rounding to the nearest vial is allowed. G-CSF may be stopped early or not administered if required by the clinical circumstance. Additional G-CSF may be administered as warranted.

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Cyclophosphamide DRUG

Pre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant (Pre-Transplant days -6 and -5). Post-transplant: 25 mg/kg/day or 35 mg/kg/day (Post-transplant days +3 and +4).

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Mesna DRUG

25 or 35 mg/kg (equal to the cyclophosphamide dose) as IV infusion concomitant with cyclophosphamide. Mesna may or may not be given with the pre-transplant cyclophosphamide depending on institutional practice.

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Total Body Irradiation (TBI) PROCEDURE

400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice daily. Pre-Transplant Day -1 (or Day 0 prior to graft administration)

Older, HLA-matched; Older, HLA-mismatched; Younger, HLA-matched; Younger, HLA-mismatched

Eligibility Criteria

• Age: 12 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Age 60-85 years, or age 18-60 years and unfit for myeloablative conditioning. Reasons for unfitness for myeloablative conditioning include:
• Prior myeloablative HCT

You may not qualify if:

• 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.
• 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
• Uncontrolled intercurrent illness that in the opinion of the site PI would make it unsafe to proceed with transplantation.
• 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.
• 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.
• Related (age \>=12) and unrelated (age \>=18) donors deemed eligible (i.e., evaluated at NIH 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.
• None

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hematologic Neoplasms; Bronchiolitis Obliterans Syndrome

Interventions

Mycophenolic Acid; fludarabine; Sirolimus; Filgrastim; Cyclophosphamide; Mesna; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

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

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: July 10, 2021
• First Posted: July 13, 2021
• Study Start: September 23, 2021
• Primary Completion (Estimated): April 27, 2027
• Study Completion (Estimated): April 30, 2027
• Last Updated: June 11, 2026

Record last verified: 2026-06-09

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: Data from this study may be requested by contacting the PI.

Locations

US (2)