Immunosuppression-Free Regulatory T Cell Graft-Engineered Haploidentical Donor Stem Cell Transplant for the Treatment of Relapsed/Refractory or Ultra High Risk Acute Myeloid Leukemia or Myelodysplastic Syndrome
This phase Ib trial is to find out the best dose, possible benefits and/or side effects of immunosuppression-free regulatory T cell graft-engineered haploidentical (haplo or half-matched) donor stem cell transplant in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed), does not respond to treatment (refractory), or is ultra high risk. Patients who receive an allogeneic (using another person as the donor) hematopoietic stem cell transplant (HSCT) may develop graft-versus-host disease (GVHD) toxicity and are also at risk of disease relapse. The word “graft” refers to the donor blood cells that a patient receives during a transplant. The word “host” refers to the person receiving the cells. GVHD is a complication of transplantation where the T cells (a type of white blood cell that helps protect the body from relapse by killing cancer cells) in the donor graft attack and damage some of the tissues - either skin, stomach and intestines, or liver early after - or other organs in a chronic fashion later after transplant. The immunosuppression-free regulatory T cell graft-engineered haplo donor stem cell transplant method may reduce risk of relapse while preventing usual toxicities related to stem cell transplants (e.g., GVHD).
Inclusion Criteria
- Cohort A: Histologically-confirmed disease in the prior 4 weeks, despite at least 1 prior line of therapy (e.g., 3+7 chemotherapy, hypomethylating agent [HMA] therapy): * Relapsed (Rel)/refractory (ref) acute myeloid leukemia (AML) (de novo or secondary) with >= 5% blasts in bone marrow (BM) (or extramedullary sites); myelodysplastic syndrome (MDS) excess blast (EB)-2 (BM >= 10% blasts, peripheral blood [PB] 5-19% blasts)
- Cohort B: Ultra high-risk AML or MDS that meets definition of ‘Myeloid Neoplasms with mutated TP53’ per 2022 International Consensus Classification regardless of response
- COHORT C: Ultra high-risk AML or MDS that meets definition of ‘Myeloid Neoplasms with multi-hit or complex karyotype (CK+) mutated TP53’ per 2022 International Consensus Classification with response: AML (de novo or secondary) with < 5% blasts in BM; MDS with < 10% blasts in BM or PB
- Available haploidentical HLA-matched (-A, -B, -C, -DRB1) related donor aged 18-65 years
- Age >= 18 to 65 years for Cohort A and B. Age ≥ 18 to 75 years for Cohort C. Because no dosing or adverse event data are currently available on the use of immunosuppression (IS)-free haploidentical (haplo)HCT in participants < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60)
- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and carbon monoxide diffusing capability (DLCO) >= 60% of predicted (Cohort A, B) or ≥ 50% of predicted (Cohort C) (corrected for hemoglobin)
- Cardiac ejection fraction >= 45% (Cohort A, B) or ≥ 40% (Cohort C), and no evidence of pulmonary hypertension
- Total bilirubin within normal institutional limits (exception permitted in Gilbert’s syndrome after discussion with study principal investigator [PI], on a case by case basis)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 x institutional upper limit of normal
- Serum creatinine within normal institutional limits or creatinine clearance >= 50 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
- The effects of IS-free haploHCT on the developing human fetus are unknown. For this reason and because radiation and chemotherapeutic 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 she or her partner is participating in this study, 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 a minimum of 4 months after completion of study
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Participants who have had cytotoxic chemotherapy or radiotherapy within 2 weeks (4 weeks for nitrosoureas or mitomycin C) prior to entering the study. Use of hydroxyurea, HMA, e.g., azacytidine, decitabine) and/or Food and Drug Administration (FDA)-approved novel targeted agents (e.g., venetoclax, FLT-3 inhibitors, IDH 1/2 inhibitors) are permitted up to day prior to start of HCT conditioning
- Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual non-hematologic toxicities > grade 1) with exception of alopecia, unless cleared by study PI
- Participants who received Mylotarg or other therapies associated with increased risk of hepatic veno-occlusive disease (VOD) or have known prior or active VOD. All novel therapies will be reviewed with PI
- Participants who are receiving any other investigational agents within 21 days (or 5 half-lives) prior to study entry, whichever is longer, unless cleared by the study PI
- Participants with extramedullary disease at immune privileged sites (e.g., central nervous system [CNS], testes, eye) are excluded, as these sites are less susceptible to the curative graft vs. leukemia effect of HCT
- Myocardial infarction within 2 years prior to enrollment
- Venous thromboembolic event (VTE) of deep vein thrombosis (DVT)/pulmonary embolism (PE) within 1 year prior to enrollment, unless approved by study PI. Patients with line-associated DVT within the past year may be enrolled if they have completed anticoagulation therapy
- Stroke or transient ischemic attack (TIA) within 1 year prior to enrollment
- History of bleeding peptic ulcer disease, erosive gastritis, intestinal perforation or clinically significant gastrointestinal (GI) hemorrhage or hemoptysis within the prior 6 months
- Patients with a history of thrombotic microangiopathy (TMA) or hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP)
- History of life-threatening reactions to iron infusions or murine antibody-containing products
- Known donor-specific antibodies (DSA) in the recipient of clinical significance (e.g., requiring DSA depletion with plasmapheresis, rituximab) are excluded
- Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes involved in cyclophosphamide and/or thiotepa metabolism during day -10 through day -5. It is acceptable to use alternative non-interacting medications during this period, and then restart prior medications
- Participants with uncontrolled bacterial, viral or fungal infections (i.e., currently taking medications with progression of clinical symptoms or signs)
- Recipients of prior allogeneic or autologous hematopoietic cell transplantation (prior autologous HCT allowed for Cohort C), or solid organ transplantation
- Prior radiation exposure or other medical condition (e.g., Fanconi syndrome) that precludes use of radiation at doses specified (TMLI or TBI)
- Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the multiple agents used routinely in myeloablative allogeneic stem cell transplantation. In addition, these individuals 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
- Participants seropositive for hepatitis B or C infection are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after myeloablative HCT
- Participants with psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because radiation and conditioning chemotherapy has the potential for teratogenic or abortifacient effects. A negative pregnancy test is required for females of childbearing potential. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IS-free haploHCT breastfeeding should be discontinued if the mother is treated with IS-free haploHCT
- Participants with a history of another non-hematologic malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years or are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
Additional locations may be listed on ClinicalTrials.gov for NCT04678401.
Locations matching your search criteria
United States
Massachusetts
Boston
PRIMARY OBJECTIVE:
I. Safety will be assessed by dose-limiting toxicities (DLT) by day 30 after hematopoietic cell transplantation (HCT).
SECONDARY OBJECTIVES:
I. Engraftment rate by day 30 after HCT (and secondary graft failure by day 100).
II. Incidence of grade II-IV and III-IV acute graft vs host disease (GVHD) by day 180 after HCT.
III. Incidence of chronic GVHD, relapse, and non-relapse mortality (NRM) by 12 months after HCT.
IV. Rate of relapse-free, GVHD/relapse-free and overall survival (RFS, GRFS, OS) by 12 months after HCT.
EXPLORATORY OBJECTIVES:
I. Changes in circulating regulatory T cell (Treg), T effector (Teff) and other immune cells and their functional status.
II. Changes in cytokine and chemokine levels.
III. Persistence of adoptively transferred Treg and Teff cells determined by T cell receptor (TCR) sequencing.
IV. Tumor infiltration by Treg and activated Teff, natural killer (NK) and other effector cells, while assessing tumor mutation profile (including disparate HLA loss), blast phenotype and tumor microenvironment.
V. Donor-recipient human leukocyte antigen (HLA):killer cell immunoglobulin receptor (KIR) interactions, tumor genomic/transcriptomic changes predictive of response, biomarkers of GVHD in responders versus (vs.) non-responders.
OUTLINE: Patients in cohorts A and B are assigned to the myeloablative regimen, patients in cohort C are assigned to the reduced intensity regimen.
MYELOABLATIVE REGIMEN: Patients undergo total myeloid and lymphoid irradiation (TMLI) on days -15 to -11 or total body irradiation (TBI) on days -13 to -11. Patients receive fludarabine intravenously (IV) over 30 minutes on days -10 to -6, thiotepa IV over 4 hours on days -10 and -9, and cyclophosphamide IV over 1 hour on days -8 and -7. Patients then receive Treg-enriched cells on day -4, unmodified Teff cells on day -1, and CD34+ selected stem cells IV on day 0. Patients also undergo collection of blood samples at baseline and day -10, -5, -4 (after cells), -2, -1, 0, 1, 2, 3, 4, 7, 14, 30, 60, 100, 180, 270, and 365, and undergo bone marrow aspiration at baseline and days 30, 60, 100, 180, 270, and 365.
REDUCED INTENSITY REGIMEN: Patients receive thiotepa IV, over 4 hours, twice daily (BID) on day -11, fludarabine, IV, over 30 minutes on days -10 to -7 and melphalan IV, over 30 minutes, on day -6. Patients also undergo TBI on day -5. Patients then receive Treg-enriched cells on day -4, unmodified Teff cells on day -1, and CD34+ selected stem cells IV on day 0. Patients also undergo collection of blood samples at baseline and day -10, -5, -4 (after cells), -2, -1, 0, 1, 2, 3, 4, 7, 14, 30, 60, 100, 180, 270, and 365, and undergo bone marrow aspiration at baseline and days 30, 60, 100, 180, 270, and 365.
After completion of study treatment, patients are followed yearly for 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorJohn Koreth
- Primary ID20-336
- Secondary IDsNCI-2021-00578
- ClinicalTrials.gov IDNCT04678401