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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Idarubicin + Cytarabine + DLI | Experimental | Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Idarubicin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | up to 8 weeks after last cell infusion |
| Measure | Description | Time Frame |
|---|---|---|
| Disease Free Survival | 1 year disease free survival rate following adoptive transfer | one year following adoptive transfer |
| Overall Survival | Number of participants alive 2 years after completing adoptive transfer therapy. |
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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:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Anthony Sung, MD | Duke University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
1 subject was a screen failure and 1 subject withdrew prior to starting study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Idarubicin + Cytarabine + DLI | Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI) Idarubicin: 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. Cytarabine: 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 |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Overall Number of Baseline Participants represents the number of participants who were Enrolled.
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| ID | Title | Description |
|---|---|---|
| BG000 | Idarubicin + Cytarabine + DLI | Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI) Idarubicin: 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. Cytarabine: 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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) | Posted | Count of Participants | Participants | up to 8 weeks after last cell infusion |
|
All serious adverse events (SAEs) that occur up to 30 days after the last Donor Lymphocyte Infusion (DLI) will be reported.
After 30 days, SAEs will be reported if thought related to treatment for the duration of the study. Non-treatment related SAEs were not collected past 30 days after the last DLI.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Idarubicin + Cytarabine + DLI | Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI) Idarubicin: 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. Cytarabine: 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Anthony Sung, MD | Duke University | 919-668-1002 | anthony.sung@duke.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 10, 2017 | Jun 11, 2018 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 4, 2018 | Jun 11, 2018 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D009190 | Myelodysplastic Syndromes |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D015255 | Idarubicin |
| D003561 | Cytarabine |
| ID | Term |
|---|---|
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
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|
| Cytarabine | Drug | 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. |
|
| DLI | Biological | 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. |
|
| 2 years after completing 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 | 8 weeks after last cell infusion |
| 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 | 8 weeks after the last cell infusion |
| 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). | 2 years after completing therapy |
| 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 | up to 2 years after completing therapy |
| 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. | 2 years after completion of therapy |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
|
|
| Secondary | Disease Free Survival | 1 year disease free survival rate following adoptive transfer | Data not collected on one subject. | Posted | Count of Participants | Participants | one year following adoptive transfer |
|
|
|
| Secondary | Overall Survival | Number of participants alive 2 years after completing adoptive transfer therapy. | Seventeen patients were enrolled between 2014 and 2017 with a median follow-up time of 299 days among all patients. One enrolled patient who developed sepsis during induction chemotherapy did not receive MST, and was excluded from final analysis of safety and efficacy. | Posted | Number | participants | 2 years after completing therapy |
|
|
|
| Secondary | 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 | Posted | Number | percentage of participants | 8 weeks after last cell infusion |
|
|
|
| Secondary | 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 | Posted | Number | percentage of participants | 8 weeks after the last cell infusion |
|
|
|
| Secondary | 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). | Data not collected on one subject. | Posted | Count of Participants | Participants | 2 years after completing therapy |
|
|
|
| Secondary | 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 | Data not collected on one subject. | Posted | Count of Participants | Participants | up to 2 years after completing therapy |
|
|
|
| Secondary | 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. | Data not collected on one subject. | Posted | Median | Full Range | days | 2 years after completion of therapy |
|
|
|
| 12 |
| 17 |
| 8 |
| 17 |
| 17 |
| 17 |
| Atrial fibrillation | Cardiac disorders | Systematic Assessment |
|
| Ileus | Gastrointestinal disorders | Systematic Assessment |
|
| Mucositis oral | Gastrointestinal disorders | Systematic Assessment |
|
| Multi-organ failure | General disorders | Systematic Assessment |
|
| Hepatic failure | Hepatobiliary disorders | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Treatment related secondary malignancy | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Delirium | Psychiatric disorders | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Blood and lymphatic system disorders other | Blood and lymphatic system disorders | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | Systematic Assessment |
|
| cardiac disorders other | Cardiac disorders | Systematic Assessment |
|
| Hearing impaired | Ear and labyrinth disorders | Systematic Assessment |
|
| eye disorders other | Eye disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Mucositis oral | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Fever | Infections and infestations | Systematic Assessment |
|
| general disorders and administration site conditions | Infections and infestations | Systematic Assessment |
|
| Infections and infestations other | Infections and infestations | Systematic Assessment |
|
| Lung infection | Infections and infestations | Systematic Assessment |
|
| Penile infection | Infections and infestations | Systematic Assessment |
|
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Splenic infection | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | Systematic Assessment |
|
| Creatinine increased | Investigations | Systematic Assessment |
|
| ECG QT corrected interval prolonged | Investigations | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | Systematic Assessment |
|
| Platelet count decreased | Investigations | Systematic Assessment |
|
| White blood cell decreased | Investigations | Systematic Assessment |
|
| Acidosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Alkalosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Tumor lysis syndrome | Metabolism and nutrition disorders | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| treatment related secondary malignancy | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| peripheral sensory neuropathy | Nervous system disorders | Systematic Assessment |
|
| Syncope | Nervous system disorders | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| Hematuria | Renal and urinary disorders | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary edema | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders other | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hypertension | Vascular disorders | Systematic Assessment |
|
| Hypotension | Vascular disorders | Systematic Assessment |
|
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| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D001855 | Bone Marrow Diseases |
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |