Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Myelofibrosis, Myeloproliferative Neoplasms
Conditions
Keywords
Myelofibrosis, Chronic Myelomonocytic Leukemia, Myeloproliferative Neoplasms, Myelodysplastic Syndromes, Acute Myeloid Leukemia
Brief summary
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.
Interventions
DRUGIpilimumab
Ipilimumab is an antibody that acts against CTLA-4
BIOLOGICALCD25hi Treg depleted DLI
Donor lymphocyte product
Sponsors
National Cancer Institute (NCI)
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) for DLI | Day 43 (6 weeks) | 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. |
| Maximum Tolerated Dose (MTD) for Ipilimumab | Day 43 (6 weeks) | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Day 92 and Week 60 | Duration of time from start of treatment to time of death. |
| Incidence of Acute GVHD Rates | Day 92 | 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. |
| Response Rate as Determined by Complete Remission (CR) and CR With Incomplete Count Recovery (CRi) | Day 43 (6 weeks) | 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. |
| Severity of Acute GVHD Rates | Day 92 | Severity 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 per Harris et al, 2016 GVHD Target Organ Staging, where 0 is no GVHD and 4 is severe. For the data table below: Grade I-IV reports any incidence of aGVHD, Grade II-IV reports the number of subjects who developed grade II, III, and IV aGVHD and Grade III-IV reports the number of subjects who developed Grade III and IV aGHVD. Grade 0: No stage 1-4 of any organ. Grade I: Stage 1-2 skin without liver, upper GI, or lower GI involvement. Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. Grade III: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. Grade IV: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. |
| Severity of Chronic GVHD Rates | Day 92 | Provider will assess study subject for severity of cGVHD per 2014 NIH consensus criteria at day 92. |
| Incidence of Chronic GVHD Rates | Day 92 | Provider will assess study subject for severity of cGVHD per 2014 NIH consensus criteria at day 92. |
| Progression Free Survival | Day 92 and Week 60 | 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.). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level: 0 1 mg/kg of Ipilimumab will be administered intravenously over 90 ± 10 minutes after the DLI product observation period is completed, and dosing will continue in 3-week intervals for 4 cycles, unless unacceptable toxicity or symptomatic disease progression occurs. | 18 |
| Dose Level: 1 3 mg/kg of Ipilimumab will be administered intravenously over 90 ± 10 minutes after the DLI product observation period is completed, and dosing will continue in 3-week intervals for 4 cycles, unless unacceptable toxicity or symptomatic disease progression occurs. | 6 |
| Dose Level: 2 10 mg/kg of Ipilimumab will be administered intravenously over 90 ± 10 minutes after the DLI product observation period is completed, and dosing will continue in 3-week intervals for 4 cycles, unless unacceptable toxicity or symptomatic disease progression occurs. | 1 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse reaction to Ipilimumab | 2 | 0 | 1 |
| Overall Study | Progression/Relapse | 7 | 3 | 0 |
| Overall Study | Prohibited concomitant treatments | 3 | 1 | 0 |
| Overall Study | Prolonged treatment delays | 3 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Level: 0 | Dose Level: 1 | Dose Level: 2 | Total |
|---|---|---|---|---|
| Age, Continuous | 65 years | 57.5 years | 68 years | 65 years |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black/African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown/Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 15 Participants | 6 Participants | 1 Participants | 22 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 0 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 2 Participants | 1 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 18 | 2 / 6 | 1 / 1 |
| other Total, other adverse events | 18 / 18 | 6 / 6 | 1 / 1 |
| serious Total, serious adverse events | 4 / 18 | 2 / 6 | 1 / 1 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) for DLI
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.
Time frame: Day 43 (6 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CD25/Treg-depleted DLI | Maximum Tolerated Dose (MTD) for DLI | 30000000 cells/kg |
Primary
Maximum Tolerated Dose (MTD) for Ipilimumab
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.
Time frame: Day 43 (6 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CD25/Treg-depleted DLI | Maximum Tolerated Dose (MTD) for Ipilimumab | 1 mg/kg |
Secondary
Incidence 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.
Time frame: Day 92
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD25/Treg-depleted DLI | Incidence of Acute GVHD Rates | 2 Participants |
| Dose Level: 1 | Incidence of Acute GVHD Rates | 2 Participants |
| Dose Level: 2 | Incidence of Acute GVHD Rates | 1 Participants |
Secondary
Incidence of Chronic GVHD Rates
Provider will assess study subject for severity of cGVHD per 2014 NIH consensus criteria at day 92.
Time frame: Day 92
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD25/Treg-depleted DLI | Incidence of Chronic GVHD Rates | 7 Participants |
| Dose Level: 1 | Incidence of Chronic GVHD Rates | 1 Participants |
| Dose Level: 2 | Incidence of Chronic GVHD Rates | 0 Participants |
Secondary
Overall Survival
Duration of time from start of treatment to time of death.
Time frame: Day 92 and Week 60
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CD25/Treg-depleted DLI | Overall Survival | Day 92 | 89 percentage of participants |
| CD25/Treg-depleted DLI | Overall Survival | Week 60 | 61 percentage of participants |
| Dose Level: 1 | Overall Survival | Day 92 | 100 percentage of participants |
| Dose Level: 1 | Overall Survival | Week 60 | 67 percentage of participants |
| Dose Level: 2 | Overall Survival | Week 60 | NA percentage of participants |
| Dose Level: 2 | Overall Survival | Day 92 | NA percentage of participants |
Secondary
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.).
Time frame: Day 92 and Week 60
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CD25/Treg-depleted DLI | Progression Free Survival | Day 92 | 50 percentage of participants |
| CD25/Treg-depleted DLI | Progression Free Survival | Week 60 | 33 percentage of participants |
| Dose Level: 1 | Progression Free Survival | Day 92 | 83 percentage of participants |
| Dose Level: 1 | Progression Free Survival | Week 60 | 17 percentage of participants |
| Dose Level: 2 | Progression Free Survival | Day 92 | NA percentage of participants |
| Dose Level: 2 | Progression Free Survival | Week 60 | NA percentage of participants |
Secondary
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.
Time frame: Day 43 (6 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD25/Treg-depleted DLI | Response Rate as Determined by Complete Remission (CR) and CR With Incomplete Count Recovery (CRi) | 8 Participants |
| Dose Level: 1 | Response Rate as Determined by Complete Remission (CR) and CR With Incomplete Count Recovery (CRi) | 4 Participants |
| Dose Level: 2 | Response Rate as Determined by Complete Remission (CR) and CR With Incomplete Count Recovery (CRi) | 0 Participants |
Secondary
Severity of Acute GVHD Rates
Severity 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 per Harris et al, 2016 GVHD Target Organ Staging, where 0 is no GVHD and 4 is severe. For the data table below: Grade I-IV reports any incidence of aGVHD, Grade II-IV reports the number of subjects who developed grade II, III, and IV aGVHD and Grade III-IV reports the number of subjects who developed Grade III and IV aGHVD. Grade 0: No stage 1-4 of any organ. Grade I: Stage 1-2 skin without liver, upper GI, or lower GI involvement. Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. Grade III: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. Grade IV: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI.
Time frame: Day 92
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CD25/Treg-depleted DLI | Severity of Acute GVHD Rates | Grade II-IV aGVHD | 0 Participants |
| CD25/Treg-depleted DLI | Severity of Acute GVHD Rates | Grade I-IV aGVHD | 2 Participants |
| CD25/Treg-depleted DLI | Severity of Acute GVHD Rates | Grade III-IV aGVHD | 2 Participants |
| Dose Level: 1 | Severity of Acute GVHD Rates | Grade II-IV aGVHD | 1 Participants |
| Dose Level: 1 | Severity of Acute GVHD Rates | Grade I-IV aGVHD | 2 Participants |
| Dose Level: 1 | Severity of Acute GVHD Rates | Grade III-IV aGVHD | 1 Participants |
| Dose Level: 2 | Severity of Acute GVHD Rates | Grade I-IV aGVHD | 1 Participants |
| Dose Level: 2 | Severity of Acute GVHD Rates | Grade III-IV aGVHD | 1 Participants |
| Dose Level: 2 | Severity of Acute GVHD Rates | Grade II-IV aGVHD | 0 Participants |
Secondary
Severity of Chronic GVHD Rates
Provider will assess study subject for severity of cGVHD per 2014 NIH consensus criteria at day 92.
Time frame: Day 92
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CD25/Treg-depleted DLI | Severity of Chronic GVHD Rates | Moderate cGVHD | 3 Participants |
| CD25/Treg-depleted DLI | Severity of Chronic GVHD Rates | Mild cGVHD | 2 Participants |
| CD25/Treg-depleted DLI | Severity of Chronic GVHD Rates | Severe cGVHD | 2 Participants |
| Dose Level: 1 | Severity of Chronic GVHD Rates | Moderate cGVHD | 0 Participants |
| Dose Level: 1 | Severity of Chronic GVHD Rates | Mild cGVHD | 1 Participants |
| Dose Level: 1 | Severity of Chronic GVHD Rates | Severe cGVHD | 0 Participants |
| Dose Level: 2 | Severity of Chronic GVHD Rates | Mild cGVHD | 0 Participants |
| Dose Level: 2 | Severity of Chronic GVHD Rates | Severe cGVHD | 0 Participants |
| Dose Level: 2 | Severity of Chronic GVHD Rates | Moderate cGVHD | 0 Participants |