Optimizing PTCy Dose and Timing

NCT03983850 | Active Not Recruiting Phase 1

• 2 other identifiers: 19011219-C-0112
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 1

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....

Conditions

Graft Versus Host Disease; Hematologic Neoplasms

Keywords

Human Leukocyte Antigen; Busulfan; Fludarabine; Mycophenolate Mofetil; Sirolimus

Outcome Measures

Primary Outcomes (2)

• aGVHD protection from a reduced duration of MMF, in combination with PTCy 25 mg/kg/day

  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.

  60 days

• aGVHD protection from PTCy 25 mg/kg

  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.

  60 days

Secondary Outcomes (2)

• Determine, at the PTCy dose or MMF duration used in phase II cohorts, the cumulative incidences

  100 days

• determine the shortest MMF duration without unacceptable acute GVHD to be used during phase II

  60 days

Study Arms (6)

Donor Arm

NO INTERVENTION

Collection of bone marrow and/or PBSC (Up to 40 donors)

Phase I Dose De-escalation

EXPERIMENTAL

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)

Drug: Busulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Sirolimus

Phase I duration de-escalation of MMF

EXPERIMENTAL

MMF at de-escalating duration (days +5 to +18 only, no MMF))

Drug: Busulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Sirolimus

Phase I Pilot for Comparative Data

EXPERIMENTAL

Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data

Drug: Busulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Sirolimus

Phase II Efficacy

EXPERIMENTAL

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)

Drug: Busulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Sirolimus

Phase II efficacy of reduced duration MMF

EXPERIMENTAL

MMF at duration identified from de-escalation evaluation.

Drug: Busulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Sirolimus

Interventions

Busulfan DRUG

Busulfan should be administered intravenously via a central venous catheter as a three-hour infusion every 24 hours.

Phase I Dose De-escalation; Phase I Pilot for Comparative Data; Phase I duration de-escalation of MMF; Phase II Efficacy; Phase II efficacy of reduced duration MMF

Fludarabine DRUG

Fludarabine will be infused by IV over 60 minutes.

Phase I Dose De-escalation; Phase I Pilot for Comparative Data; Phase I duration de-escalation of MMF; Phase II Efficacy; Phase II efficacy of reduced duration MMF

Cyclophosphamide DRUG

IV cyclophosphamide will be administered over 2 hours. Slower rates of infusion may be used to decrease side effects. A fluid intake of greater than 2 L/day is recommended during and for 1 to 2 days after cyclophosphamide administration.

Phase I Dose De-escalation; Phase I Pilot for Comparative Data; Phase I duration de-escalation of MMF; Phase II Efficacy; Phase II efficacy of reduced duration MMF

Mycophenolate Mofetil DRUG

Any oral formulation should be taken on an empty stomach, 1 hour before or at least 2 hours after meals. Oral formulations should not be administered simultaneously with antacids. Avoid inhalation or direct contact with skin or mucous membranes of dry powder contained in capsules or suspension. IV solutions should be administered over at least two hours through either a peripheral or central vein and should not be administered by rapid or bolus injection.

Phase I Dose De-escalation; Phase I Pilot for Comparative Data; Phase I duration de-escalation of MMF; Phase II Efficacy; Phase II efficacy of reduced duration MMF

Sirolimus DRUG

Oral tablets should be administered approximately 4 hours after cyclosporine administration. Sirolimus is administered orally, once daily, without food. Patients unable to tolerate tablets may take the oral solution formulation.

Phase I Dose De-escalation; Phase I Pilot for Comparative Data; Phase I duration de-escalation of MMF; Phase II Efficacy; Phase II efficacy of reduced duration MMF

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:

• Patients 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
• 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 (no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration)
• 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
• 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. Patients \<18 years old must be at least 50 kg. Note: Because patients 15-17 years old and \<50 kg are not able to be cared for on the adult oncology wards and by the investigative team, they are excluded.

You may not qualify if:

• Patients who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 4 weeks prior to the date of beginning conditioning.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection excluding controlled fungal infection on appropriate treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, endocrinopathy (significant uncontrolled or untreated hypothyroidism, hyperthyroidism, or adrenal insufficiency), or active psychiatric illness/social situations that would limit compliance with study requirements
• Prior myeloablative conditioning for autologous or allogeneic HCT.
• Individuals who are pregnant or who intend to become pregnant during the study are excluded because myeloablative conditioning is toxic to the developing fetus with the potential for teratogenic or abortifacient effects.
• Nursing participants must be willing to discontinue nursing at the time of the study treatment initiation, as the potential for some of the study medications to be transmissible via nursing is unknown.
• 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.
• The severity of the hematologic malignancy does not warrant the potential toxicity of myeloablative allogeneic HCT as judged by the PI.
• Related donor deemed suitable and eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, bone marrow, 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.
• Ages \>= 12 years
• None

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Hyder MA, Dimitrova D, Sabina R, DeVries A, McCune JS, McAdams MJ, Flomerfelt FA, McKeown C, Sadler JL, Chai A, Hughes TE, Napier S, Stokes A, Sponaugle J, Rechache K, Parta M, Cuellar-Rodriguez J, Figg WD, Choo-Wosoba H, Steinberg SM, Kanakry JA, Kanakry CG. Intermediate-dose posttransplantation cyclophosphamide for myeloablative HLA-haploidentical bone marrow transplantation. Blood Adv. 2025 May 27;9(10):2553-2569. doi: 10.1182/bloodadvances.2024014879.

  PMID: 39908565 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Graft vs Host Disease; Hematologic Neoplasms

Interventions

Busulfan; fludarabine; Cyclophosphamide; Mycophenolic Acid; Sirolimus

Condition Hierarchy (Ancestors)

Immune System Diseases; Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones

Study Officials

• Christopher G Kanakry, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: June 8, 2019
• First Posted: June 12, 2019
• Study Start: July 9, 2019
• Primary Completion: November 25, 2025
• Study Completion (Estimated): October 26, 2026
• Last Updated: December 26, 2025

Record last verified: 2025-12-23

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: Data from this study may be requested by contacting the PI.@@@@@@@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)