A Phase 1 Trial of CD25/Treg-depleted DLI Plus Ipilimumab for Myeloid Disease Relapse After Matched-HCT

Study Overview
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Brief Summary
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In this research study, our main goal for the ipilimumab portion of the study is to determine the highest dose of ipilimumab that can be given safely in several courses and to determine what side effects are seen in patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), Myeloproliferative Neoplasms (MPN), Chronic Myelomonocytic Leukemia (CMML), or Myelofibrosis (MF).

Detailed Description
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This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. Investigational means that the intervention is being studied. The U.S. Food and Drug Administration (FDA) has not approved ipilimumab for this specific disease but it has been approved for other uses. This drug has been used in other research studies and is now FDA-approved for the treatment of melanoma. Many people have also received ipilimumab on research studies for possible treatment of prostate cancer, lymphoma, kidney cancer, ovarian cancer and HIV infection. Information from those other research studies suggests that ipilimumab may help to treat the participant's cancer. Ipilimumab is an antibody that acts against CTLA-4. An antibody is a common type of protein produced by the body that the immune system (a system that defends the body against potentially harmful particles) uses to find and destroy foreign molecules (particles not typically found in the body) such as bacteria and viruses.

Official Title
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A Phase 1 Trial of CD25/Treg-depleted DLI Plus Ipilimumab for Myeloid Disease Relapse After Matched-HCT

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasms, Chronic Myelomonocytic Leukemia, Myelofibrosis

Intervention / Treatment
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* Drug: Ipilimumab
* Biological: CD25hi Treg depleted DLI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed relapse of AML, MDS or MPN (CMML or myelofibrosis or MDS/MPN with ≥5% blasts in the marrow). Relapse at ≥2 months after any 8/8 or better HLA-matched HCT Available original stem cell donor. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of Ipilimumab in participants <18 years of age, children are excluded from this study. ECOG performance status ≤2 (Karnofsky performance status ≥60, see Appendix A). Recipient donor T cell chimerism ≥20% within 4 weeks prior to cell infusion. <50% bone marrow involvement within 4 weeks prior to cell infusion. No systemic corticosteroid therapy for GVHD (≤5 mg of prednisone or equivalent doses of other systemic steroids for non-GVHD, non-autoimmune indications for at least 4 weeks prior to cell infusion). No other systemic medications/treatments (e.g. ECP) for GVHD for at least 4 weeks prior to cell infusion. Ability to understand and willingness to sign written informed consents. Adequate organ function as defined below: Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then < 3 x ULN) AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN creatinine clearance: ≤1.5 x institutional ULN O2 saturation: ≥90% on room air LVEF >40% The effects of CD25/Treg-depleted DLI and Ipilimumab on the developing human fetus are unknown. For this reason and because immunomodulatory agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study or within 23 weeks after the last dose of study drug, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for at least 31 weeks after completion of Ipilimumab administration. Negative pregnancy test for females of childbearing potential only Exclusion Criteria: Extramedullary relapse involving immuno-privileged sites (e.g. CNS, testes, eyes). Other sites of extramedullary relapse (e.g. leukemia cutis, granulocytic sarcoma) are acceptable. Participants who have had anti-tumor chemotherapy or other investigational agents within 4 weeks prior to cell infusion (6 weeks for nitrosoureas or mitomycin C), or immunotherapy within 8 weeks prior, or those who have not recovered from adverse events due to agents administered more than 4 weeks prior. Use of hydroxyurea to control counts within 4 weeks prior to cell infusion is permitted. Prior history of DLI Prior history of treatment with anti-CTLA-4 or anti-PD-1 pathway therapy, or CD137 agonist therapy. Prior history of severe (grade 3 or 4) acute GVHD, or ongoing active GVHD requiring systemic treatment. Organ transplant (allograft) recipient. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Ipilimumab or other agents used in study. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients with Hashimoto's thyroiditis are eligible to go on study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because of the unknown teratogenic risk. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated on this study. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with agents used in this study. In addition, these participants are at increased risk of lethal infections when treated with marrow- suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after HCT.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD25/Treg-depleted DLI + Ipilimumab<br>Ipilimumab is administered intravenously every 12 weeks Patients will receive a defined dose of CD25hi Treg depleted DLI intravenously | Drug: Ipilimumab<br>* Ipilimumab is an antibody that acts against CTLA-4<br>* Other names: Yervoy;Biological: CD25hi Treg depleted DLI<br>* Donor lymphocyte product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The primary objective of this study is to determine the safety (MTD) of CD25/Treg-depleted donor lymphocyte infusion (DLI) plus Ipilimumab in patients with myeloid relapse after matched-HCT. Participants will be evaluated for dose limiting toxicities (DLTs) at day 43. DLTs explained within section 5.4 of the protocol. | Day 43 (6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate as determined by Complete remission (CR) and CR with incomplete count recovery (CRi) | Complete remission will be evaluated for each disease, along with duration of complete remission. AML morphological complete remission can be found in Appendix E (E.1.1.), and Relapse from CR/CRi is in E.1.3. MDS/MPN complete remission criteria is found in Appendix F (F.1.1), and criteria for relapse is found in F.1.5. | Day 43 (6 weeks) | 
| Progression Free Survival | Duration of time from start of treatment to time of objective disease progression or death, whichever comes first. AML progressive disease is defined in Appendix E (E.1.7.), and criteria for MDS/MPN is in Appendix F (F.1.4.). | Day 92 and Week 60 | 
| Overall Survival | Duration of time from start of treatment to time of death. | Day 92 and Week 60 | 
| Incidence and Severity of Acute GVHD Rates | Incidence of aGVHD will be measured at the below time point, and grading severity of aGVHD will be standardized using the chart and information in Appendix C. | Day 92 | 
| Incidence and Severity of Chronic GVHD Rates | Provider will assess study subject for severity of cGVHD per 2014 NIH consensus criteria at day 92. | Day 92 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Chronic Myelomonocytic Leukemia, Myeloproliferative Neoplasms, Myelodysplastic Syndromes, Acute Myeloid Leukemia