IS-free Treg HaploHCT

• ClinicalTrials.gov Identifier: NCT04678401
• Recruitment Status: Recruiting
• First Posted: December 22, 2020
• Last Update Posted: January 5, 2024
• Sponsor: Dana-Farber Cancer Institute
• Information provided by (Responsible Party): John Koreth, MD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: December 16, 2020
• First Posted Date: December 22, 2020
• Last Update Posted Date: January 5, 2024
• Actual Study Start Date: January 12, 2021
• Estimated Primary Completion Date: October 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2020)

Dose-limiting toxicities (DLT) [ Time Frame: 30 days after hematopoietic cell transplantation (HCT) ]

Safety will be assessed by dose-limiting toxicities (DLT) summarized by patient, type and grade as defined by the CTCAE v5.0.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 16, 2020)

• Engraftment rate [ Time Frame: 30 days after hematopoietic cell transplantation (HCT) ]
  Will be summarized descriptively and estimated in the competing risks framework treating death without GVHD or without engraftment as a competing event depending on the actual enrolled and evaluable number of patients.
• secondary graft failure rate [ Time Frame: 100 days after hematopoietic cell transplantation (HCT) ]
  Will be summarized descriptively and estimated in the competing risks framework treating death without GVHD or without engraftment as a competing event depending on the actual enrolled and evaluable number of patients.
• graft vs host disease (GVHD) Rate [ Time Frame: 180 days after hematopoietic cell transplantation (HCT) ]
  Incidence of grade II-IV and III-IV acute graft vs host disease (GVHD) by day 180 after HCT
• Mortality Rate-GVHD Relapse [ Time Frame: 12 months after hematopoietic cell transplantation (HCT) ]
  Will also be summarized descriptively, estimated in the competing risks framework treating each event as a competing event. Corresponding 95% CIs will be provided.
• Mortality Rate-GVHD Non- Relapse [ Time Frame: 12 months after hematopoietic cell transplantation (HCT) ]
  Will also be summarized descriptively, estimated in the competing risks framework treating each event as a competing event. Corresponding 95% CIs will be provided.
• Survival Rate-Relapse-Free [ Time Frame: 12 months after hematopoietic cell transplantation (HCT) ]
  Estimated using Kaplan-Meier method with exact pointwise confidence intervals
• Progression Free-Survival (PFS) [ Time Frame: 12 months after hematopoietic cell transplantation (HCT) ]
  Estimated using Kaplan-Meier method with exact pointwise confidence intervals
• Survival Rate-Relapse-Free-GVHD [ Time Frame: 12 months after hematopoietic cell transplantation (HCT) ]
  Estimated using Kaplan-Meier method with exact pointwise confidence intervals
• Overall survival rate [ Time Frame: 12 months after hematopoietic cell transplantation (HCT) ]
  Estimated using Kaplan-Meier method with exact pointwise confidence intervals

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: IS-free Treg HaploHCT
• Official Title: A Pilot/Phase 1 Study of Immunosuppression-free Regulatory T-cell Graft-engineered Haploidentical Hematopoietic Cell Transplantation in Relapsed/Refractory and Ultra-High-risk AML/MDS

Brief Summary

This research study is evaluating the safety and efficacy of the IS-free Treg-cell graft-engineered haplo transplant method in people with relapsed/refractory and Ultra-high risk acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) receiving a haploidentical donor allogeneic hematopoietic stem cell transplant (HSCT).

The names of the study interventions involved in this study are:

• Radiation-Total Myeloid and Lymphoid Irradiation (TMLI
• Chemotherapy (Fludarabine, Thiotepa, Cyclophosphamide plus Mesna)
• Infusion of haplo Treg-enriched donor cells (experimental therapy)
• Infusion of unmodified haplo donor T cells (includes cancer-fighting T effector cells)
• Infusion of haplo donor CD34+ Peripheral Blood Stem Cells

Detailed Description

This study is assessing whether the IS-free Treg-cell graft-engineered haplo HSCT) approach will reduce risk of relapse while preventing usual toxicities related to stem cell transplants (e.g., graft-versus-host-disease (GVHD)). 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 host tissues. 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 research study procedures include: screening for eligibility and study treatment including evaluations and follow up visits.

Participants will receive the study intervention Treg-enriched donor cells and will then be followed for 1 year after transplantation.

It is expected that about 20 people will take part in this research study.

Dana-Farber Cancer Institute research funds along with charitable donations are supporting this research study. Regeneron Pharmaceuticals, Inc. (a pharmaceutical company) is also supporting this research study by providing funding and support for correlative laboratory tests.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Stem Cell Transplant Complications
• Graft Vs Host Disease
• Myeloid Leukemia, Acute
• Myeloid Leukemia in Relapse (Disorder)
• Myelodysplastic Syndromes

Intervention

• Radiation: Radiation
  Total Myeloid and Lymphoid Irradiation (TMLI) delivered through Radiation Oncology institutional standards
  Other Name: Radiotherapy
• Drug: Fludarabine
  Given intravenously -10 to -6 days prior to hematopoietic stem cell transplant (HSCT)
  Other Name: Fludara
• Drug: Thiotepa
  Given intravenously on day -10 and day- 9 prior to hematopoietic stem cell transplant (HSCT)
  Other Name: Tepadina
• Drug: Cyclophosphamide
  Given intravenously with Mesna on day -8 and day- 7 prior to hematopoietic stem cell transplant (HSCT)
  Other Name: cytophosphane
• Drug: Mesna
  Given intravenously with Cyclophosphamide on day -8 and day -7 prior to hematopoietic stem cell transplant (HSCT)
  Other Name: Mesnex
• Biological: Treg-enriched donor cell
  Given intravenously -4 day prior to hematopoietic stem cell transplant (HSCT)
• Biological: Unmodified donor T Cell
  Given intravenously -1 day prior to hematopoietic stem cell transplant (HSCT)
• Procedure: CD34+ Haplo Peripheral Blood Stem Cell
  CD34+ Haplo Peripheral Blood Stem Cell Transplantation

Study Arms

• Experimental: IS-FREE TREG CRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2

  After meeting eligibility criteria and being enrolled, patients will receive:

  Day -15 to -6 prior to hematopoietic stem cell transplant (HSCT), preparatory regimen of radiation and chemotherapy: Total Myeloid and Lymphoid Irradiation (TMLI): Days -15 to -11 prior to HSCT; - Chemotherapy (infusion): Day -10 to day -6 prior to HSCT: Fludarabine (all days), Thiotepa (days -10 and -9) and Cyclophosphamide and Mesna (days -8 and -7)

  Day -4 prior to (HSCT), a Treg-enriched donor cell infusion and graft vs host disease (GVHD) assessment

  Day -1 prior to (HSCT), a unmodified donor T Cell infusion and (GVHD) assessment

  Day of (day 0) (HSCT), CD34+ Haplo Peripheral Blood Stem Cell Infusion/Transplant and (GVHD) assessment

  Days 30, 60,100, 180, 365 post hematopoietic stem cell transplant (HSCT), participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD)

  Interventions:

  • Radiation: Radiation
  • Drug: Fludarabine
  • Drug: Thiotepa
  • Drug: Cyclophosphamide
  • Drug: Mesna
  • Biological: Treg-enriched donor cell
  • Biological: Unmodified donor T Cell
  • Procedure: CD34+ Haplo Peripheral Blood Stem Cell
• Experimental: IS-FREE TREG CRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53

  After meeting eligibility criteria and being enrolled, patients will receive:

  Day -15 to -6 prior to hematopoietic stem cell transplant (HSCT), preparatory regimen of radiation and chemotherapy: Total Myeloid and Lymphoid Irradiation (TMLI): Days -15 to -11 prior to HSCT; - Chemotherapy (infusion): Day -10 to day -6 prior to HSCT: Fludarabine (all days), Thiotepa (days -10 and -9) and Cyclophosphamide and Mesna (days -8 and -7)

  Day -4 prior to (HSCT), a Treg-enriched donor cell infusion and graft vs host disease (GVHD) assessment

  Day -1 prior to (HSCT), a unmodified donor T Cell infusion and (GVHD) assessment

  Day of (day 0) (HSCT), CD34+ Haplo Peripheral Blood Stem Cell Infusion/Transplant and (GVHD) assessment

  Days 30, 60,100, 180, 365 post hematopoietic stem cell transplant (HSCT), participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD)

  Interventions:

  • Radiation: Radiation
  • Drug: Fludarabine
  • Drug: Thiotepa
  • Drug: Cyclophosphamide
  • Drug: Mesna
  • Biological: Treg-enriched donor cell
  • Biological: Unmodified donor T Cell
  • Procedure: CD34+ Haplo Peripheral Blood Stem Cell

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 26, 2023): 20
• Original Estimated Enrollment (submitted: December 16, 2020): 10
• Estimated Study Completion Date: October 31, 2027
• Estimated Primary Completion Date: October 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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, HMA therapy): Rel/ref AML (de novo or secondary) with ≥5% blasts in BM (or extramedullary sites); MDS EB-2 (BM ≥10% blasts, 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 Classification1 (Appendix L) regardless of response
• Available haploidentical HLA-matched (-A, -B, -C, -DRB1) related donor aged 18-65 years.
• Age ≥18 to 65 years. Older patients are not candidates for myeloablative HCT. Because no dosing or adverse event data are currently available on the use of IS-free haploHCT in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status ≤2 (Karnofsky ≥60, see Appendix A).

• Adequate organ and marrow function as defined below:

  • Pulmonary Function: FEV1, FVC and DLCO ≥ 60% of predicted (corrected for hemoglobin)
  • Cardiac Ejection Fraction ≥ 45%, and no evidence of pulmonary hypertension
  • Hepatic: Total bilirubin within normal institutional limits (exception permitted in Gilbert's Syndrome after discussion with study PI, on a case by case basis); and AST (SGOT)/ALT (SGPT) <2x institutional upper limit of normal
  • Renal: Serum Creatinine within normal institutional limits or creatinine clearance > 50 mL/min/1.73 m2 (see Appendix B) 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 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 halflives) prior to study entry, whichever is longer, unless cleared by the study PI.
• Participants with extramedullary disease at immune privileged sites (e.g., 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 DVT/ PE within 1 year prior to enrollment. 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 (see Section 5.5) during day - 10 through day -5. It is acceptable 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, or solid organ transplantation.
• Prior radiation exposure or other medical condition (e.g., Fanconi syndrome) that precludes use of myeloablative radiation (TMLI).
• 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 and 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: John Koreth, MBBS, DPhil; (617) 632-2949; john_koreth@dfci.harvard.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04678401
• Other Study ID Numbers: 20-336
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Current Responsible Party: John Koreth, MD, Dana-Farber Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: John Koreth, MBBS, DPhil; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: January 2024