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Despite good progress during the last decade, hemophagocytic lymphohistiocytosis (HLH) remains difficult to treat. Two different treatment regimens have been used successfully. The first one, a treatment regimen based on two drugs called etoposide and dexamethasone, has been used worldwide. The second regimen, based on two drugs called Anti-thymocyte globulin (ATG) and prednisone, has been used mostly at one hospital in Paris, for over 15 years. With either regimen, about three quarters of treated children survive the most difficult time, the first two months after diagnosis. These two different regimens appear to work somewhat differently, and we suspect that combining them may give better results than either regimen alone. We are conducting this clinical trial to test the combination of ATG, dexamethasone, and etoposide for the treatment of HLH.
The purpose of this research study is to find out what effects (good and bad) this drug combination has on you and your HLH.
Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder first recognized almost 70 years ago.(1) Genetic and animal studies have indicated that the familial form of HLH is clearly due to a deficiency of cytotoxic killing. Patients with HLH present with a potentially fatal syndrome of 'hyperimmunity.' These patients have severe inflammation, associated with cytopenias and variably severe bone marrow, liver, or CNS damage. Tissue damage and mortality appear to be due to hypercytokinemia related to persistent immune hyperactivation. An animal model of HLH and correlative human studies all suggest that excessive and abnormal activation of T cells drives the pathophysiology of this disorder, and that suppressing this excessive activation is critical for successful therapy of HLH. It is believed a combination of the two proven induction regimens for hemophagocytic lymphohistiocytosis (HLH) (anti-thymocyte globulin (ATG)- and etoposide-based) will result in response rates and overall survival rates at eight weeks which are comparable or better than the current standard of care (induction therapy per the HLH-94 protocol).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Induction Therapy | Experimental | ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg, on day 7, 14, 21 and 42 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ATG, rabbit | Drug | ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours). |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival | To determine the overall survival of patients with hemophagocytic lymphohistiocytosis at 8 weeks after an ATG/etoposide-based induction regimen and to determine the feasibility of this approach in the context of a multicenter clinical trial. | 8 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Response | To determine the median time to complete response during 8 weeks of therapy | 8 Weeks |
| Overall Survival | To determine overall survival prior to the initiation of BMT (bone marrow transplant) preparative regimen (or day 180, if BMT preparative regimen not yet begun) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Jordan, MD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Phoenix Children's Hospital | Phoenix | Arizona | 85254 | United States | ||
| University of California, San Francisco Department of Pediatrics |
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| ID | Title | Description |
|---|---|---|
| FG000 | Induction Therapy | ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg, on day 7, 14, 21 and 42 ATG, rabbit: ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours). Etoposide: Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses. Methotrexate: Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Treatment Period |
|
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| Etoposide | Drug | Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses. |
|
|
| Methotrexate | Drug | Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42. |
|
| hydrocortisone | Drug | Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42. |
|
| Dexamethasone | Drug | will be started with the ATG. It will be divided BID, given IV for at least 1 week before switching to PO. Dosing: 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days. |
|
| up to day 180 |
| Number of Participants Who Experienced Reactivation | To determine the frequency of disease reactivation prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun) | up to 180 days |
| Overall Survival to Day +100 | To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry | up to day 280 |
| Disease Status at BMT | To determine the rate of complete response at the time of BMT preparative regimen initiation | up to day 180 |
| San Francisco |
| California |
| 94143 |
| United States |
| Stanford University | Stanford | California | 94305 | United States |
| University of Colorado | Aurora | Colorado | 80045 | United States |
| Nemours | Wilmington | Delaware | 19803 | United States |
| Children's National Medical Center | Washington D.C. | District of Columbia | 20010 | United States |
| Nemours | Jacksonville | Florida | 32827 | United States |
| Florida All Children's Hospital | St. Petersburg | Florida | 33701 | United States |
| Tulane University Medical Center | New Orleans | Louisiana | 70118 | United States |
| Children's Hospital Boston | Boston | Massachusetts | 02115 | United States |
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| Oregon Health and Science University | Portland | Oregon | 21703 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19145 | United States |
| Texas Children's Cancer Center/Baylor College of Medicine | Houston | Texas | 77030 | United States |
| The Hospital for Sick Children | Toronto | Ontario | Canada |
| COMPLETED |
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| NOT COMPLETED |
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| Follow up Until BMT OR 6 Months |
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| Follow up Until Day 100 Post BMT |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Induction Therapy | ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg, on day 7, 14, 21 and 42 ATG, rabbit: ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours). Etoposide: Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses. Methotrexate: Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| |||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| |||||||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| 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 | Overall Survival | To determine the overall survival of patients with hemophagocytic lymphohistiocytosis at 8 weeks after an ATG/etoposide-based induction regimen and to determine the feasibility of this approach in the context of a multicenter clinical trial. | Posted | Count of Participants | Participants | 8 Weeks |
|
|
| |||||||||||||||||||||||||||
| Secondary | Time to Response | To determine the median time to complete response during 8 weeks of therapy | Patients assessed for disease features and classified each week per definition of complete response in order to determine the time at which they achieved complete response. | Posted | Median | Full Range | weeks | 8 Weeks |
|
| ||||||||||||||||||||||||||
| Secondary | Overall Survival | To determine overall survival prior to the initiation of BMT (bone marrow transplant) preparative regimen (or day 180, if BMT preparative regimen not yet begun) | Posted | Count of Participants | Participants | up to day 180 |
|
| ||||||||||||||||||||||||||||
| Secondary | Number of Participants Who Experienced Reactivation | To determine the frequency of disease reactivation prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun) | all patients surviving to BMT or day 180 and achieving complete or partial response | Posted | Count of Participants | Participants | up to 180 days |
|
| |||||||||||||||||||||||||||
| Secondary | Overall Survival to Day +100 | To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry | Posted | Count of Participants | Participants | up to day 280 |
|
| ||||||||||||||||||||||||||||
| Secondary | Disease Status at BMT | To determine the rate of complete response at the time of BMT preparative regimen initiation | Posted | Count of Participants | Participants | up to day 180 |
|
|
Adverse event data were collected over the 8 weeks of the treatment period. All cause mortality was assessed up to day +100 after BMT, if participant proceeded to BMT by day 180. If participant did not proceed to BMT by day 180, all cause mortality was only assessed until day 180.
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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 | Induction Therapy | ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg, on day 7, 14, 21 and 42 ATG, rabbit: ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours). Etoposide: Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses. Methotrexate: Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients | 11 | 31 | 22 | 31 | 31 | 31 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| hospitalization | Blood and lymphatic system disorders | Non-systematic Assessment |
| ||
| respiratory failure | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
| ||
| acute kidney injury | Renal and urinary disorders | Non-systematic Assessment |
| ||
| status epilepticus | Nervous system disorders | Non-systematic Assessment |
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| multiple organ failure | Vascular disorders | Non-systematic Assessment |
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| herpetic keratitis | Eye disorders | Non-systematic Assessment |
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| hypotension | Vascular disorders | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| fever | Immune system disorders | Non-systematic Assessment |
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| anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| hemorrhage | Blood and lymphatic system disorders | Non-systematic Assessment |
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| hypertension | Vascular disorders | Non-systematic Assessment |
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| thrombosis | Blood and lymphatic system disorders | Non-systematic Assessment |
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This is a single arm study.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michael Jordan, MD | Cincinnati Children's Hospital Medical Center | 513-803-9063 | Michael.Jordan@cchmc.org |
| ID | Term |
|---|---|
| D051359 | Lymphohistiocytosis, Hemophagocytic |
| ID | Term |
|---|---|
| D015616 | Histiocytosis, Non-Langerhans-Cell |
| D015614 | Histiocytosis |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C512542 | thymoglobulin |
| D005047 | Etoposide |
| C061400 | etoposide phosphate |
| D008727 | Methotrexate |
| D006854 | Hydrocortisone |
| D003907 | Dexamethasone |
| ID | Term |
|---|---|
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D005960 | Glucosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D013259 | Steroids, Fluorinated |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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