Clinical Trials /

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

NCT03912064

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Myelofibrosis
  • Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 19-142
  • NCT ID: NCT03912064

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasms
  • Chronic Myelomonocytic Leukemia
  • Myelofibrosis

Interventions

DrugSynonymsArms
IpilimumabYervoyCD25/Treg-depleted DLI + Ipilimumab
CD25hi Treg depleted DLICD25/Treg-depleted DLI + Ipilimumab

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
CD25/Treg-depleted DLI + IpilimumabExperimentalIpilimumab is administered intravenously every 12 weeks Patients will receive a defined dose of CD25hi Treg depleted DLI intravenoudsly
  • Ipilimumab
  • CD25hi Treg depleted DLI

Eligibility Criteria

        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 first 8/8 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:Day 43 (6 weeks)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Response rate as determined by Complete remission (CR) and CR with incomplete count recovery (CRi)
Time Frame:Day 43 (6 weeks)
Safety Issue:
Description: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.
Measure:Progression Free Survival
Time Frame:Day 92 and Week 60
Safety Issue:
Description: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.).
Measure:Overall Survival
Time Frame:Day 92 and Week 60
Safety Issue:
Description:Duration of time from start of treatment to time of death.
Measure:Incidence and Severity of Acute GVHD Rates
Time Frame:Day 92
Safety Issue:
Description: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.
Measure:Incidence and Severity of Chronic GVHD Rates
Time Frame:Day 92
Safety Issue:
Description:Provider will assess study subject for severity of cGVHD per 2014 NIH consensus criteria at day 92.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Myelofibrosis
  • Chronic Myelomonocytic Leukemia
  • Myeloproliferative Neoplasms
  • Myelodysplastic Syndromes
  • Acute Myeloid Leukemia

Last Updated

November 6, 2019