Donor Lymphocyte Infusion After Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

NCT05327023 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10000489000489-C
• Study Type: interventional
• Target: 430
• Locations: 1 country
• Sites: 1

Brief Summary

Background: People with blood cancers often receive blood or bone marrow transplants. But even with these treatments, the risk of relapse is high. Researchers want to see if giving the transplant recipient an infusion of lymphocytes (a type of white blood cell) from their transplant donor early after the transplant can reduce that risk. Objective: To learn if giving donor lymphocytes early after a transplant will help reduce the risk of relapse for people with certain blood cancers. Eligibility: Adults aged 18-65 with high-risk leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma that does not respond well to standard treatments and/or has a high risk of relapse. Healthy potential bone marrow and lymphocyte donor relatives aged 12 and older are also needed. Design: Participants will be screened with: Physical exam Blood and urine tests Spinal tap Eye exam Dental exam Heart and lung tests Imaging scans. A radioactive substance may be injected in their arm if a PET scan is needed. Bone marrow aspiration and biopsy Some screening tests will be repeated during the study. Participants will stay at the NIH hospital for about 4 weeks. They will receive a central venous catheter. They will get chemotherapy and other drugs starting 6 days before transplant. Then they will have their transplant. They will receive donor white blood cells 7 days later. They will give blood, bone marrow, urine, and stool samples for research. They must stay near NIH for at least 100 days after transplant. Participants will have periodic follow-up visits for 5 years. Healthy donors will have 2-3 visits. They will give blood, bone marrow, white blood cells, and stool samples for research. Participation will last for 5 years....

Conditions

Hematologic Neoplasms

Keywords

Prophylactic Donor Lymphocyte Infusions; Chronic Graft-Versus-Host Disease; Immunotherapeutic Strategies; myeloablative conditioning; Steroid-Refractory Grade

Outcome Measures

Primary Outcomes (1)

• determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT

  fraction of evaluable patients who experience steroid-refractory 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 (7)

• determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of Steroid-refractory Grades II-IV and Grades III-IV aGVHD at days +100 and +200 for HLA-matched-related and HLA-haploidentical

  Day 100 and 200

• determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of chronic GVHD at 1 year for HLA-matched-related and HLA-haploidentical

  1 year

• determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of Grades II-IV and Grades III-IV aGVHD at days +100 and +200 for HLA-matched-related and HLA-haploidentical

  Day 100 and 200

• determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of non-relapse mortality at 100 days and 1 year for HLA-matched-related and HLA-haploidentical

  Day 100 and 1 year

• determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of relapse at 1 year for HLA-matched-related and HLA-haploidentical

  1 year

Study Arms (5)

Donor Arm

NO INTERVENTION

Donors for Recipients in Arms 1-4

Phase I Dose Escalation, Cohort 1 (matched)

EXPERIMENTAL

DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)

Procedure: donor lymphocyte infusion; Drug: Cyclophosphamide; Drug: Busulfan; Drug: Mycophenolate mofetil; Drug: Fludarabine; Drug: Sirolimus

Phase I Dose Escalation, Cohort 2 (haploidentical)

EXPERIMENTAL

DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)

Procedure: donor lymphocyte infusion; Drug: Cyclophosphamide; Drug: Busulfan; Drug: Mycophenolate mofetil; Drug: Fludarabine; Drug: Sirolimus

Phase II Efficacy, Cohort 1 (matched)

EXPERIMENTAL

DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)

Procedure: donor lymphocyte infusion; Drug: Cyclophosphamide; Drug: Busulfan; Drug: Mycophenolate mofetil; Drug: Fludarabine; Drug: Sirolimus

Phase II Efficacy, Cohort 2 (haploidentical)

EXPERIMENTAL

DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)

Procedure: donor lymphocyte infusion; Drug: Cyclophosphamide; Drug: Busulfan; Drug: Mycophenolate mofetil; Drug: Fludarabine; Drug: Sirolimus

Interventions

donor lymphocyte infusion PROCEDURE

The DLI will be given on Day +7 (Day +21 for dose level -1). If a recipient participant is deemed too critically ill/unstable to receive DLI on the protocol specified day, the DLI will be delayed up to 4 days at the discretion of the PI and given within this time frame once the recipient participant s clinical status has stabilized or improved. If the DLI cannot be given during this time frame, the recipient participant will be taken off study and not considered evaluable for DLT, outcomes, or adverse events since the experimental intervention will not have been given.

Phase I Dose Escalation, Cohort 1 (matched); Phase I Dose Escalation, Cohort 2 (haploidentical); Phase II Efficacy, Cohort 1 (matched); Phase II Efficacy, Cohort 2 (haploidentical)

Cyclophosphamide DRUG

HLA-matched: 50 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. HLA haploidentical: 25 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight.

Phase I Dose Escalation, Cohort 1 (matched); Phase I Dose Escalation, Cohort 2 (haploidentical); Phase II Efficacy, Cohort 1 (matched); Phase II Efficacy, Cohort 2 (haploidentical)

Busulfan DRUG

AUC targeted dose based on busulfan test dose, with a default dose of 130 mg/m2/day, given as IV infusion over 3 hours each day for 4 days Transplant days -6 through day -3

Phase I Dose Escalation, Cohort 1 (matched); Phase I Dose Escalation, Cohort 2 (haploidentical); Phase II Efficacy, Cohort 1 (matched); Phase II Efficacy, Cohort 2 (haploidentical)

Mycophenolate mofetil 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 Escalation, Cohort 1 (matched); Phase I Dose Escalation, Cohort 2 (haploidentical); Phase II Efficacy, Cohort 1 (matched); Phase II Efficacy, Cohort 2 (haploidentical)

Fludarabine DRUG

40 mg/m2 IV infusion over 30-60 minutes once daily for 4 days Transplant days -6 through -3

Phase I Dose Escalation, Cohort 1 (matched); Phase I Dose Escalation, Cohort 2 (haploidentical); Phase II Efficacy, Cohort 1 (matched); Phase II Efficacy, Cohort 2 (haploidentical)

Sirolimus DRUG

Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, maximum 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 +70 with no taper. Doses should be modified as appropriate for drug interactions.

Phase I Dose Escalation, Cohort 1 (matched); Phase I Dose Escalation, Cohort 2 (haploidentical); Phase II Efficacy, Cohort 1 (matched); Phase II Efficacy, Cohort 2 (haploidentical)

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:

• Histologically or cytologically confirmed hematologic malignancy classified as high or very high disease risk by the Refined Disease Risk Index for HCT including one of the following:
• Acute myeloid leukemia (AML) with favorable cytogenetics (t(8;21), inv(16), t(15,17)) with induction failure (persistent disease without first achieving remission of any type) or active relapse
• AML with intermediate cytogenetics (not classified as favorable or adverse) with induction failure or active relapse (AML with intermediate cytogenetics in morphologic complete remission \[CR\] with minimal residual disease detectable by any modality also will be eligible)
• AML with adverse cytogenetics (complex karyotype with \>= 4 abnormalities) regardless of remission status
• Low risk myelodysplastic syndrome (MDS) (\<= 5% blasts, including chronic myelomonocytic leukemia) with adverse cytogenetics (abnormal chromosome 7 or \>= 4 abnormalities) with induction failure or active relapse
• High risk MDS (RAEB-1 or RAEB-2) with intermediate-risk cytogenetics (no abnormal chromosome 7 or \< 4 abnormalities) with induction failure or active relapse
• High risk MDS (RAEB-1 or RAEB-2) with adverse cytogenetics (abnormal chromosome 7 or \>= 4 abnormalities) regardless of remission status
• Acute lymphoblastic leukemia (ALL) in CR \>= 2 or with induction failure or active relapse (ALL in CR1 with minimal residual disease detected also will be eligible)
• Chronic myelocytic leukemia (CML) in blast crisis phase
• Hodgkin lymphoma with stable or progressive disease
• Mantle cell lymphoma with stable or progressive disease
• Relapsed Burkitt lymphoma in CR or partial remission (PR)
• Aggressive B-cell Non-Hodgkin Lymphoma (NHL) (e.g., diffuse large B-cell lymphoma, transformed indolent B-cell lymphoma) with stable or progressive disease
• T-cell NHL with stable or progressive disease
• Multiple myeloma (MM) with induction failure as defined by failure to achieve minimal response (CR, Very Good Partial Response \[VGPR\], or PR) or the development of progressive disease on primary therapy, or MM with active relapse as defined by previously treated myeloma that achieved a molecular response or better that then progressed

You may not qualify if:

• Subjects who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 3 weeks prior to the date of beginning conditioning.
• Prior myeloablative conditioning for autologous or allogeneic HCT.
• Active breastfeeding.
• Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is metastatic, relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment. This excludes non-melanoma skin cancers.
• Uncontrolled intercurrent illness (e.g. severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance, active hepatitis, uncontrolled dental infection) that in the opinion of the PI would make it unsafe to proceed with transplantation.
• None.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

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; Bronchiolitis Obliterans Syndrome

Interventions

Cyclophosphamide; Busulfan; Mycophenolic Acid; fludarabine; Sirolimus

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)

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

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: April 7, 2022
• First Posted: April 14, 2022
• Study Start: May 23, 2022
• Primary Completion (Estimated): July 3, 2028
• Study Completion (Estimated): July 2, 2029
• Last Updated: April 28, 2026

Record last verified: 2026-04-24

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 (1)