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Dose Limiting Toxicities
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In this study the investigators are proposing to treat patients with steroid-refractory Graft-versus-host Disease (GVHD) stabilization using IL-2 and azacitidine
High-dose cyclophosphamide and sirolimus have been successfully used for the prevention of Graft-versus-host Disease (GVHD) and have shown to enhance the Tregs subpopulation. The addition of low dose IL-2 and a demethylating agent such as azacitidine will also be studied in an attempt to promote and stabilize the FoxP3 expression of Tregs.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cyclophosphamide and Sirolimus | Experimental | cyclophosphamide and sirolimus combo |
|
| Lowdose IL-2, Cytoxan + Sirolimus | Experimental | Low dose IL-2 with Cytoxan + Sirolimus Patients in treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus. |
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| Lowdose IL-2, Vidaza, cyclophosphamide & Sirolimus | Experimental | Lowdose IL-2, Vidaza, cyclophosphamide (Cytoxan) & Sirolimus Patients in treatment arm C will be receiving low-dose azacitidine (Vidaza). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cyclophosphamide and Sirolimus | Drug | On the first day of treatment, cyclophosphamide will be administered at a dose of 4g/m2 IV x 1 dose. Patients who are >40% above ideal weight will be dosed based on adjusted weight and adjusted BSA. One day after the administration of cyclophosphamide, patients will receive sirolimus 6 mg PO x 1 and on the following day will start sirolimus at a dose of 2 mg PO daily. |
| Measure | Description | Time Frame |
|---|---|---|
| Response Rate of Patients With Steroid-refractory Graft-versus-host Disease (GVHD) Using Cyclophospahmide and Sirolimus Combined With 3 Variations of Low-dose IL 2 and Low-dose Vidaza. | The primary objective of this study is to determine the response rate of patients treated steroid-refractory graft-versus-host disease (GVHD) using cyclophospahmide and sirolimus combined with 3 variations of low-dose IL 2 and low-dose Vidaza with an outcome goal of promoting CD4+CD25+FoxP3+ Tregs. | 28 days to 100 days post transplant |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michele Donato, MD | Hackensack Meridian Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| John Theurer Cancer Center at Hackensack University Medical Center | Hackensack | New Jersey | 07601 | United States |
Pts.must have a documented clinical diagnosis of grade II-IV acute graft-versus- host disease defined as GVHD (graft versus host disease) within 100 days p transplantation.
Patients must be steroid-refractory defined as progression after 3 days of corticosteroid therapy or no response after 5 days of same. see study details.
4/11/2011 - 5/1/2013 - recruitment at Hackensack University Medical Center
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| ID | Title | Description |
|---|---|---|
| FG000 | Cyclophosphamide and Sirolimus Only | Cyclophosphamide = 4g/m2 IV Sirolimus = 6 mg PO x 1; 2 mg PO No patients were enrolled in the Cyclophosphamide, Sirolimus, IL-2 arm or the Cyclophosphamide, Sirolimus, IL-2, azacitidine arm |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Low dose IL-2 with Cytoxan + Sirolimus | Drug | Patients in treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus. IL-2 will be administered at a dose of 0.5E6 IU/m2 SQ daily x 8 weeks followed by 4 weeks off, starting 14 days after the cyclophosphamide. |
|
|
| Low dose IL-2, low dose Vidaza, cyclophosphamide & Sirolimus | Drug | Patients in treatment arm C will be receiving low-dose azacitidine (Vidaza). The Vidaza will be initiated between day 27 and 32 following the cyclophosphamide. The dose administered will be 10 mg SQ daily for 5 days followed by 3 weeks off. |
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| Cyclophosphamide and Sirolimus | Drug | Day 1: Cyclophosphamide Day 2: Sirolimus |
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|
| Low dose IL-2 with Cytoxan + Sirolimus | Drug | treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus |
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| Low dose IL-2, Vidaza, Cytoxan & Sirolimus | Drug | Vidaza will be initiated between day 27 and 32 following the cyclophosphamide. |
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| COMPLETED |
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| NOT COMPLETED |
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Three subjects started the study - all three had limiting toxicities and died. Study was terminated
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| ID | Title | Description |
|---|---|---|
| BG000 | Cyclophosphamide and Sirolimus | Patients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | number of subjects in age categories | Count of Participants | Participants |
| |||||||||||||||||||
| Sex: Female, Male | Gender | Count of Participants | Participants |
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| 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 | Response Rate of Patients With Steroid-refractory Graft-versus-host Disease (GVHD) Using Cyclophospahmide and Sirolimus Combined With 3 Variations of Low-dose IL 2 and Low-dose Vidaza. | The primary objective of this study is to determine the response rate of patients treated steroid-refractory graft-versus-host disease (GVHD) using cyclophospahmide and sirolimus combined with 3 variations of low-dose IL 2 and low-dose Vidaza with an outcome goal of promoting CD4+CD25+FoxP3+ Tregs. | No patients were enrolled in the Low dose IL-2 with Cytoxan + Sirolimus or Low dose IL-2, Vidaza, Cytoxan & Sirolimus arms | Posted | Number | Participants | 28 days to 100 days post transplant |
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SAE data was collected over a period of 6 months for the three patients enrolled in the study
Please see SAE # 5045 and 5063 SAE # 5633 and 5878 and SAE 5055 for h/o DVT, CMV+ -dated 10-18-11 SAE 5247 for diarrhea and fever - dated 12-13-11 SAE 5379 for severe anemia dated 1-10-12 SAE 5899 for new brain masses vs abscess dated 4-6-12 SAE 5917 for confusion,malaise weakness dated 4-23-12
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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 | Cyclophosphamide and Sirolimus | Cyclophosphamide and Sirolimus - Patients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only | 3 | 3 | 0 | 3 | ||
| EG001 | Low Dose IL-2 With Cytoxan + Sirolimus | Low dose IL-2 with Cyclophosphamide + Sirolimus - In cohort B, the next 5 patients will additionally receive cyclophosphamide and sirolimus & low-dose IL-2 Low dose IL-2, low dose Vidaza, Cyclophosphamide & Sirolimus | 0 | 0 | 0 | 0 | ||
| EG002 | Low Dose IL-2, Vidaza, Cytoxan & Sirolimus | Low dose IL-2, Vidaza, Cytoxan & Sirolimus - In cohort C the next 5 enrolled patients will additionally receive cyclophosphamide and Sirolimus, low-dose IL-2 and low-dose Vidaza | 0 | 0 | 0 | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| SAE 5379 - Anemia | Blood and lymphatic system disorders | SAE 5379 | Systematic Assessment | 5379-1/10-2012- Blood test revealed anemia, rated as category 3 severe, affecting subject 1, possibly treatment related |
|
| SAE 5917-neurological | Nervous system disorders | SAE 5917 | Systematic Assessment | 5917 - 4/23/2012 - Upon examination using scans based on symptoms, pt 1 was found to have neurological symptoms related to transplant hospitalized, and categorized as serious - rated 3 |
|
| SAE 6031- Post-transplant lymphoproliferative disorder (PTLD) | Immune system disorders | SAE 6031 | Systematic Assessment | 6031- 5/22/2012 - Pt developed post transplant lymphoproliferative disorder due to GVHD reseulting in death, rated as severe |
|
| SAE 5063 - C. difficile Infection | Infections and infestations | SAE 5063 | Systematic Assessment | 5063- 10-22-2011 - Pt 2 experienced severe refractory GVHD and c diff infection resulting in death on 10-22-2011, listed as severe - category 5, and possibley related to treatment |
|
| SAE 5878- Graft Versus Host Disease (GVHD) | Hepatobiliary disorders | SAE 5878 | Systematic Assessment | 5878 - 4/15/2012 - Pt 3 experienced severe grade 4 GVHD of liver resulting in death, rated as severe, category 5 and possibly related to condition/treatment |
|
| SAE 5856-brain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | SAE 5856 | Systematic Assessment | 5856- 4/6/2012 - Pt 1 experienced new brain masses found on cat scan and erythema around rt eye, rated as category 3, Serious and listed as a known possible side effect of treatment |
|
| SAE 5055- Deep vein thrombosis (DVT) | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | SAE 5055 | Systematic Assessment | 5055- 10-13-2011 - Pt 1 admitted to hospital for treatment of new brain tumor or abcess, rated as category 2, and category 3, and listed as known side effect of transplant chemo |
|
| Deep Vein Thrombosis, Cytomegalovirus infection and Graft Versus Host Disease Complications | Infections and infestations | SAE 5985 - DVT CMV | Systematic Assessment | Pt 1 was admitted for treatment of left upper extremity DVT, CMV infection and GVHD complications - categorized as serious level 3 and listed as possible treatment related |
|
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3 patients enrolled - all 3 had grade 4 (possibly treatment related) limiting toxicities. All three patients have since passed away. Study was closed after being on hold as per stopping rules.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Michele Donato, MD | Hackensack University Medical Center | 551-996-2000 | 3524 | MDonato@hackensackumc.org |
| ID | Term |
|---|---|
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D003520 | Cyclophosphamide |
| D020123 | Sirolimus |
| D007376 | Interleukin-2 |
| D001374 | Azacitidine |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D018942 | Macrolides |
| D007783 | Lactones |
| D007378 | Interleukins |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008222 | Lymphokines |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D001372 | Aza Compounds |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
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