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Adoptive Transfer of Haplo-identical DLI for AML and MDS

Primary Purpose

Acute Myeloid Leukemia, Myelodysplastic Syndrome

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Idarubicin

Cytarabine

DLI

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subjects must have their diagnosis of high-risk AML or high-risk MDS confirmed by pathologic review of bone marrow biopsy according to WHO guidelines
Patients will be defined as high risk AML and thus eligible if they meet one or more of the following criteria:
1. Secondary AML (from underlying MDS or therapy related)
2. Presence of complex cytogenetic abnormalities (3 or more cytogenetic abnormalities), all monosomies, del 5q, del 7q, inv3, t(3;3), t(6;9), t(9;22), abn 11q23 (excluding t(9;11))
3. Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation positive
4. Age ≥ 65 years given poor outcomes even with favorable cytogenetics
Patients will be defined as high risk MDS and thus eligible if they have a MD Anderson Comprehensive Cancer MDS Risk Score ≥9
Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status of 0,1,or 2; if ECOG 2, they must also have a Charlson comorbidity index of ≤5.
Subjects must be 55 years of age or older
Subjects should have a 3-5/6 HLA-matched related haploidentical donor who is evaluated and deemed able to provide DLI.
Patient should be able to provide informed consent
Subjects must have a multigated acquisition (MUGA) and /or ECHO or cardiac magnetic resonance imaging (MRI). The required minimum standards include MUGA or ECHO or cardiac MR showing an ejection fraction( EF) of 40%. Those with an EF 40-49% must also have a cardiologist consult and assist with management.
Pulmonary function tests (PFTs) with diffusing capacity of lung for carbon monoxide (DLCO) are conditional for subjects at the discretion of the physician. The required minimum standards for those who have PFTs include DLCO of 40%. Those with DLCO of 40-49% must have a pulmonologist consult and assist with management.
Subjects of all genders and races are eligible

Exclusion Criteria:

Pregnant or lactating women.
Patients with other major medical or psychiatric illnesses which the treating physician feels could seriously compromise tolerance to this protocol
Patients with known active central nervous system (CNS) disease
Patients with acute promyelocytic leukemia (FAB M3)

Sites / Locations

Duke University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Idarubicin + Cytarabine + DLI

Arm Description

Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)

Outcomes

Primary Outcome Measures

Number of Subjects With Unacceptable Toxicity

Unacceptable toxicity is defined as: i. Grade III or IV acute GVHD (aGVHD) of the gut or liver or Grade IV aGVHD of the skin lasting > 7 days; ii. Grade IV Common Terminology Criteria for Adverse Events (CTCAE) toxicity attributable to DLI (e.g. infusion reaction, as opposed to Grade IV CTCAE toxicity from chemotherapy) and lasting >7 days iii. Treatment-related mortality (TRM)

Secondary Outcome Measures

Disease Free Survival

1 year disease free survival rate following adoptive transfer

Overall Survival

Number of participants alive 2 years after completing adoptive transfer therapy.

Percentage of Subjects With Acute GVHD

Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting > 7 days

Percentage of Subjects With Unacceptable Toxicity

Grade IV CTCAE toxicity attributable to DLI (e.g. infusion reaction, as opposed to Grade IV CTCAE toxicity from chemotherapy) and lasting >7 days, Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting > 7 days, or death

Rate of Efficacy

Efficacy as measured by the number of subjects with a complete remission. Responses were evaluated according to standard criteria defined by the National Comprehensive Cancer Network Guidelines for AML (www.nccn.org).

Number of Participants With Immune Recovery

Immune recovery determined by measurements of cytokine profiles, lymphocyte and natural killer (NK) enumeration and flow-based assays, measured prior to induction, prior to each round of consolidation, 8 weeks after the last cycle of consolidation, and every 3 months after treatment for up to 2 years

Number of Days to Hematopoietic Recovery

Hematopoietic recovery as measured by the date of the first of three consecutive laboratory values where the absolute neutrophil count (ANC) ≥ 500/μl , the date of the first of three consecutive laboratory values obtained on different days where the platelet count was > 20,000/μl without transfusion.

Full Information

NCT ID

NCT02046122

First Posted

January 23, 2014

Last Updated

December 1, 2020

Sponsor

Duke University

1. Study Identification

Unique Protocol Identification Number

NCT02046122

Brief Title

Adoptive Transfer of Haplo-identical DLI for AML and MDS

Official Title

Safety and Efficacy of Chemotherapy Combined With Adoptive Transfer of Human Leukocyte Antigen (HLA)-Haploidentical Donor Lymphocyte Infusion (DLI) in Older Patients With Righ-Risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2020

Overall Recruitment Status

Completed

Study Start Date

July 2014 (undefined)

Primary Completion Date

June 15, 2017 (Actual)

Study Completion Date

July 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Duke University

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The primary hypothesis is that chemotherapy followed by donor lymphocyte infusion (DLI) from HLA-haploidentical donors is a safe procedure that will not cause Graft versus Host Disease (GVHD) or increased treatment-related mortality. The Investigator further believes that this will improve outcomes of elderly patients with high-risk AML or MDS compared to chemotherapy alone, and that that this benefit will be even greater in donor-recipient pairs that share maternal-fetal microchimerism or non-inherited maternal antigen (NIMA) mismatch. A large part of this trial will include immune function assays as well as assessments of efficacy, toxicity, and GVHD. Because this therapy may be a tolerable alternative to allogeneic hematopoietic stem cell transplantation (alloHSCT) for elderly patients, the Investigator will validate functional measurements (e.g. Comprehensive Geriatric Assessment (CGA)) with biologic correlates (cytokine and genomic profiles) and clinical outcomes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia, Myelodysplastic Syndrome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

19 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Idarubicin + Cytarabine + DLI

Arm Type

Experimental

Arm Description

Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)

Intervention Type

Drug

Intervention Name(s)

Idarubicin

Intervention Description

Eligible subjects will receive induction chemotherapy with idarubicin (12 mg/m2 intravenously for 3 days) and cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5. Subjects who experience no remission or partial remission will receive a second course of the identical induction chemotherapy.

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Intervention Description

Cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5. Subjects who achieve a complete remission (CR) will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after the second consolidation.

Intervention Type

Biological

Intervention Name(s)

DLI

Intervention Description

HLA-mismatched DLI will be administered Day 9, approximately 24-48 hours following completion of chemotherapy at a dose of 1x10^8 cluster of differentiation 3 (CD3+) cells; however, due to logistics of planning infusions with staffing, donor availability, weekends/holidays, etc., it may be necessary to postpone cell infusion up to 96 hours. Given the time constraints presented by the need to start induction chemotherapy as soon as possible, in some cases, it may not be logistically possible to administer cells with induction. In these cases, patients would just receive standard induction chemotherapy and cells would be administered after consolidation 1 in addition to consolidation 2 Subjects who achieve a CR will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after the second consolidation.

Primary Outcome Measure Information:

Title

Number of Subjects With Unacceptable Toxicity

Description

Time Frame

up to 8 weeks after last cell infusion

Secondary Outcome Measure Information:

Title

Disease Free Survival

Description

1 year disease free survival rate following adoptive transfer

Time Frame

one year following adoptive transfer

Title

Overall Survival

Description

Number of participants alive 2 years after completing adoptive transfer therapy.

Time Frame

2 years after completing therapy

Title

Percentage of Subjects With Acute GVHD

Description

Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting > 7 days

Time Frame

8 weeks after last cell infusion

Title

Percentage of Subjects With Unacceptable Toxicity

Description

Time Frame

8 weeks after the last cell infusion

Title

Rate of Efficacy

Description

Time Frame

2 years after completing therapy

Title

Number of Participants With Immune Recovery

Description

Time Frame

up to 2 years after completing therapy

Title

Number of Days to Hematopoietic Recovery

Description

Time Frame

2 years after completion of therapy

10. Eligibility

Sex

All

Minimum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subjects must have their diagnosis of high-risk AML or high-risk MDS confirmed by pathologic review of bone marrow biopsy according to WHO guidelines Patients will be defined as high risk AML and thus eligible if they meet one or more of the following criteria: Secondary AML (from underlying MDS or therapy related) Presence of complex cytogenetic abnormalities (3 or more cytogenetic abnormalities), all monosomies, del 5q, del 7q, inv3, t(3;3), t(6;9), t(9;22), abn 11q23 (excluding t(9;11)) Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation positive Age ≥ 65 years given poor outcomes even with favorable cytogenetics Patients will be defined as high risk MDS and thus eligible if they have a MD Anderson Comprehensive Cancer MDS Risk Score ≥9 Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status of 0,1,or 2; if ECOG 2, they must also have a Charlson comorbidity index of ≤5. Subjects must be 55 years of age or older Subjects should have a 3-5/6 HLA-matched related haploidentical donor who is evaluated and deemed able to provide DLI. Patient should be able to provide informed consent Subjects must have a multigated acquisition (MUGA) and /or ECHO or cardiac magnetic resonance imaging (MRI). The required minimum standards include MUGA or ECHO or cardiac MR showing an ejection fraction( EF) of 40%. Those with an EF 40-49% must also have a cardiologist consult and assist with management. Pulmonary function tests (PFTs) with diffusing capacity of lung for carbon monoxide (DLCO) are conditional for subjects at the discretion of the physician. The required minimum standards for those who have PFTs include DLCO of 40%. Those with DLCO of 40-49% must have a pulmonologist consult and assist with management. Subjects of all genders and races are eligible Exclusion Criteria: Pregnant or lactating women. Patients with other major medical or psychiatric illnesses which the treating physician feels could seriously compromise tolerance to this protocol Patients with known active central nervous system (CNS) disease Patients with acute promyelocytic leukemia (FAB M3)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Anthony Sung, MD

Organizational Affiliation

Duke University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

12. IPD Sharing Statement

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Adoptive Transfer of Haplo-identical DLI for AML and MDS

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