iCare 2: Personalized Genomic Mutation Informed Treatment of Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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This open-label, randomized, parallel group phase II study will investigate the efficacy of computational biology-informed treatment vs. standard of care treatment for patients with relapsed or refractory myelodysplastic syndromes (MDS).

Detailed Description
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It is hypothesized that personalized treatment informed by computational biology simulation technology will improve treatment outcomes for patients with relapsed or refractory MDS.

Official Title
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iCare 2: Personalized Genomic Mutation Informed Treatment of Patients With Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: FDA-approved drug or combination of drugs
* Drug: FLAG induction
* Drug: 7 + 3 induction
* Drug: Low-dose cytarabine
* Other: Supportive care alone
* Device: Computational biology simulations software


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent Must be at least 18 years of age Diagnosis of MDS, as defined by World Health Organization (WHO) 2008, that has relapsed after any duration of time from last best response or is refractory to induction therapy (defined as 4 cycles of treatment with a hypomethylating agent, 2 cycles of lenalidomide, 1 cycle of low intensity chemotherapy, or 1 cycle of high intensity chemotherapy) ECOG performance status of 0-2 Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) may participate, provided they meet the following conditions: Must agree to use physician-approved contraceptive methods (e.g., abstinence, intrauterine device, oral contraceptive, double barrier device) throughout the study and for 3 months following the last dose of study treatment; and Must have a negative serum or urine pregnancy test within 7 days prior to beginning treatment on this trial Males with female partners of child-bearing potential must agree to use physician approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 6 months following the last dose of study treatment. Exclusion Criteria: Must not have acute myeloid leukemia (AML), as defined by WHO 2008 Pregnant and nursing subjects are excluded because the effects of study treatments on a fetus or nursing child are unknown Must not have had treatment with any anti-cancer therapy (investigational or standard) within the previous 21 days prior to the first dose of study drug or less than full recovery (no worse than CTCAE v4.0 grade 1) from the clinically significant toxic effects of that treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Computational Biology-Informed Treatment<br>Patients randomized to this arm will receive an FDA-approved drug or combination of drugs predicted to have a therapeutic effect based on their individual MDS disease genetic profile by a computational biology simulation software program. The specific drug or combination of drugs that a patient on this arm will receive will be decided jointly by a molecular oncology board comprised of physicians, pharmacists, and nurse coordinators and the treating physician. Patients will receive a minimum of 2 months and a maximum of 4 months of treatment with the selected drug or combination of drugs. | Drug: FDA-approved drug or combination of drugs<br>* Patients assigned to this arm will receive an FDA-approved drug or combination of drugs. Dosing and treatment schedule will follow the package insert for the selected drug(s).<br>Device: Computational biology simulations software<br>* Genetic testing results for each patient randomized to this arm will be used by a computational biology simulations software program to generate a personalized map of dysregulated metabolic pathways contributing to the patient's disease. This map will then be used to digitally screen for potentially therapeutic FDA-approved drugs or drug combinations to target the dysregulated metabolic pathways.<br>|
| Active Comparator: Standard of Care Treatment<br>Patients randomized to this arm will receive either one of three standard of care treatment regimens of the treating physician's choice (low-dose cytarabine, 7 + 3 induction, or FLAG induction) or supportive care alone. Patients will receive a minimum of 2 months and a maximum of 4 months of the selected treatment regimen or of supportive care alone. | Drug: FLAG induction<br>* Patients will receive 30 mg/m2 per day intravenously of fludarabine for 5 days and 2000 mg/m2 per day intravenously of cytarabine for 5 days. 5 mg/kg per day of granulocyte colony stimulating factor (G-CSF) may be given subcutaneously beginning on Day 1 of each treatment until absolute granulocyte count > 500/ microliter for 3 days.<br>Drug: 7 + 3 induction<br>* Patients will receive 100-200 mg/m2 per day intravenously of cytarabine for 7 days, plus either 45-60 mg/m2 per day intravenously of daunorubicin or 9-12 mg/m2 per day intravenously of idarubicin for 3 days.<br>Drug: Low-dose cytarabine<br>* Patients will receive 20 mg/m2 per day subcutaneously of cytarabine for 10 days every 28 days.<br>Other: Supportive care alone<br>* Patients will receive one or more of the following: blood product transfusions, antibiotics, granulocyte colony-stimulating factor (G-CSF), erythropoietic stimulating factors, and iron chelation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in overall response, as measured by International Working Group (IWG) 2006 criteria for response in MDS | Difference in overall response (number of patients who achieve complete response, partial response, stable disease, or hematologic improvement per IWG 2006 criteria) between patients treated with computational biology-informed therapy vs. those treated with standard of care regimens | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in safety and feasibility, as measured by CTCAE v4.0 criteria | Difference in safety and feasibility, as measured by CTCAE v4.0 criteria, between patients treated with computational biology-informed treatment and those who receive a standard of care regimen | 5 months | 
| Difference in time to death between patients treated with computational biology-informed therapy and those treated with standard of care regimens |  | 3 years | 
| Difference in time to progression to acute myeloid leukemia (AML), as measured by IWG 2006 criteria for response in MDS, between patients treated with computational biology-informed therapy and those treated with standard of care regimens |  | 4 months | 
| Difference in time to disease relapse, as measured by IWG 2006 criteria for response in MDS, between patients treated with computational biology-informed therapy and those treated with standard of care regimens |  | 4 months | 
| Difference in time to best response, as measured by IWG 2006 criteria for response in MDS, between patients treated with computational biology-informed therapy and those treated with standard of care regimens |  | 4 months | 
| Difference in change in myeloblast percentage between patients treated with computational biology-informed therapy and those treated with standard of care regimens |  | 4 months | 
| Difference in blood transfusion rate between patients treated with computational biology-informed therapy and those treated with standard of care regimens |  | 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myelodysplastic syndromes, MDS, computational biology, relapsed, refractory