Blinatumomab After TCR Alpha Beta/CD19 Depleted HCT

Alpha/Beta T-cell and B-cell Depleted Allogeneic Transplantation (IDE 13641) Followed by Blinatumomab Therapy for High-Risk B-Acute Lymphoblastic Leukemia: A Pilot Study

This trial will assess the feasibility of alpha/beta T-cell and B-cell depleted allogeneic hematopoietic cell transplantation (HCT) followed by blinatumomab therapy for high-risk B cell acute lymphoblastic leukemia (ALL) as a means of reducing rates of subsequent relapse and improving survival, while also minimizing treatment-related morbidity/ mortality and late effects. The conditioning regimens will be dependent on the patient's minimal residual disease (MRD) status prior to HCT using high throughput sequencing.

Study Overview

• Status: Recruiting
• Conditions: B-cell Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-Cell ALL, Childhood
• Intervention / Treatment: Device: Alpha/Beta T-cell and B-cell depleted HCT; Drug: Blinatumomab

Detailed Description

This trial evaluates the ability of a biologically active therapy in blinatumomab, an anti-CD19/CD3 bispecific T-cell engager, to further reduce the risk of leukemia relapse following HCT to improve post-HCT outcomes. The investigators will also utilize an alpha-beta T-cell and B-cell depleted graft to reduce the risk of GVHD along with a reduced intensity conditioning regimen without the use of TBI in patients who are minimal residual disease (MRD) negative using high throughput sequencing (HTS) prior to HCT. For those patients who remain HTS-MRD positive, a myeloablative conditioning regimen will be utilized, also followed by blinatumomab. This multi-institutional pilot study will be limited to 25 (estimated 10-15 per stratum) evaluable children, adolescents and young adults with B-ALL, that have experienced a relapse or have high-risk disease.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Meredith Beversdorf, RN; Phone Number: 414-266-5891; Email: mbeversdorf@chw.org
• Study Contact Backup: Name: Emily Ruszkiewicz, BS; Phone Number: 414-266-4092; Email: eruszkiewicz@mcw.edu

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Children's Hospital of Wisconsin
      • Contact: Meredith Beversdorf, RN; Phone Number: 414-266-5891; Email: mbeversdorf@chw.org
      • Contact: Emily Ruszkiewicz, BS; Phone Number: 414-266-4092; Email: eruszkiewicz@mcw.edu
      • Principal Investigator: Rachel Phelan, MD, MPH
      • Sub-Investigator: Julie-An Talano, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of B-ALL with no evidence of minimal residual disease in the bone marrow by multi-parameter flow cytometry (FC-MRD negative, <0.01%) and meet at least one of the following:

  1. In remission after first relapse or greater (≥ CR2)
  2. Very-high risk biology ALL that is proceeding to HCT in first remission (e.g. Induction failure, Severe-hypodiploidy, Ph-like ALL)
  3. First remission with persistent disease identified as end of consolidation (EOC) MRD > 0.01%.
• Patients must have an available unrelated or haploidentical donor
• Age ≤ 25 years at time of study enrollment
• Karnofsky Performance Status ≥ 60% for patients 16 years and older and Lansky Play Score ≥ 60 for patients under 16 years of age
• Have acceptable organ function as defined within 14 days of study registration: Renal: creatinine clearance or radioisotope GFR ≥ 60 mL/min/1.73m2 Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 3 mg/dL Cardiac: left ventricular ejection fraction ≥ 40% by ECHO/MUGA Pulmonary: No evidence of dyspnea at rest. No supplemental oxygen requirement. If measured, carbon monoxide diffusion capacity (DLCO) > 50%. Central Nervous System: Based on clinical exam, no concern for/evidence of active CNS infection. Patients with fully treated prior CNS infections are eligible. Patients with seizure disorders may be enrolled if seizures are well-controlled on anticonvulsant therapy.
• Patients who have experienced their relapse after HCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are off all transplant immune suppression therapy for at least 7-days (e.g. steroids, cyclosporine, tacrolimus). Steroid therapy for non-GVHD and/or non-leukemia therapy is acceptable.
• Immunotherapy: At least 42 days after the completion of any type of immunotherapy aside from blinatumomab (e.g. tumor vaccines or CAR T-cell therapy).
• XRT: Cranial or craniospinal XRT is prohibited during protocol therapy. ≥ 90 days must have elapsed if prior TBI, cranial or craniospinal XRT
• Sexually active females of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the completion of blinatumomab therapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the completion of blinatumomab therapy.
• Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• All patients enrolled in this study must have been enrolled in the Blinatumomab Bridging Therapy (BBT) Trial

Exclusion Criteria:

• Active extramedullary disease or presence of chloromatous disease.
• Receiving concomitant chemotherapy, radiation therapy; immunotherapy or other anti-cancer therapy for treatment of disease other than is specified in the protocol.
• Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). Patients with possible fungal infections must have had at least 2 weeks of appropriate anti-fungal antibiotics and be asymptomatic.
• Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 7 days prior to registration to rule out pregnancy.
• Known allergy to any chemotherapies or targeted agents included in this protocol.
• Participating in a concomitant Phase 1 or 2 study involving treatment of disease.
• Active malignancy other than B-ALL.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alpha/beta T-cell and B-cell Depleted, Myeloablative HCT; Patients who are MRD Negative by Flow cytometry but are MRD Positive by High Throughput Sequencing, will receive a myeloablative conditioning regimen which includes total body irradiation (TBI) followed by an alpha/beta T-cell and B-cell depleted transplant. They will also receive a 28 day continuous infusion of blinatumomab starting on Day 100 post-transplant in the absence of significant ongoing GVHD.	Device: Alpha/Beta T-cell and B-cell depleted HCT; Device: Alpha/Beta T-cell and B-cell depletion; Drug: Blinatumomab; 28 day continuous infusion given on Day 100 post-HCT if no significant ongoing GVHD; Other Names: Blincyto
Experimental: Alpha/beta T-cell and B-cell Depleted, Reduced Intensity HCT; Patients who are MRD Negative by Flow cytometry and are MRD Negative by High Throughput Sequencing, will receive a reduced intensity conditioning regimen followed by an alpha/beta T-cell and B-cell depleted transplant. They will also receive a 28 day continuous infusion of blinatumomab starting on Day 100 post-transplant in the absence of significant ongoing GVHD.	Device: Alpha/Beta T-cell and B-cell depleted HCT; Device: Alpha/Beta T-cell and B-cell depletion; Drug: Blinatumomab; 28 day continuous infusion given on Day 100 post-HCT if no significant ongoing GVHD; Other Names: Blincyto

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients who are able to receive the blinatumomab infusion [Feasibility]	Percentage of patients who are able to receive the blinatumomab infusion at day +100 post-HCT and complete a minimum of 14/28 planned days	Day +100 post-HCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of treatment-related adverse events [Tolerability]	As defined by cumulative incidence of treatment-related adverse events of blinatumomab post-HCT	Day of HCT to Day +180 post-HCT
Overall Survival	Defined as the time interval from the date of transplant to death or last follow up	Day of HCT to 1 year post-HCT
Disease Free Survival	Defined as the time interval from the date of transplant to death or last follow up or disease relapse	Day of HCT to 1 year post-HCT
Engraftment	Defined as the number of patients who achieve ANC > 500/uL for 3 consecutive days	Day +100 and +1 year post-HCT
Primary Graft Failure	is defined as failure to achieve ANC > 500/uL by Day +28	Day +28 and + 1 year post-HCT
Secondary Graft Failure	Patients who initially achieve neutrophil engraftment followed by a decline in ANC < 500/uL that is unresponsive to growth factor therapy	Day +28 and +1 year post-HCT
Treatment Related Mortality	Defined as death occurring in a patient from causes other than disease relapse or progression	Day of HCT to Day +100 and 1 year post-HCT
Acute & Chronic GVHD	Incidences of Grades 2-4 and Grades 3-4 acute GVHD	Day +100, +180 and 1 year post-HCT
Patient Reported Outcomes	PROMIS Pediatric/Parent Proxy Profile 25 (either pediatric self-report if age 8-17 or parent proxy if age 5-8, or both if feasible) or PROMIS-29 Profile if age 18 or older	Baseline, Day +100, +180, +1 year post-HCT
Length of Stay	Define by the total number of days a patient spends in the hospital	Number of days between the day of transplantation, Day 0, and Day +180 post-HCT
Persistence of Minimal Residual Disease (MRD) Negativity	Number of patients remaining MRD negative by flow cytometry and/or high throughput sequencing	Days +28, +100, +180 and +1 year post-HCT
Relapse	Cumulative incidence of relapse in all patients	Day of HCT to day +180 and 1 year post-HCT

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of immune cell phenotyping	Reconstitution of T, B, and NK cell subsets in the peripheral blood will be analyzed by immune cell phenotyping using flow cytometry.	Days +19, +91, +135 and +180 post-HCT
Functional assessment of lymphocyte subsets	To assess lymphocyte function, peripheral blood mononuclear cells will be co-cultured with stimulator cells in the presence or absence of blinatumomab.	Days +19, +91, +135 and +180 post-HCT
Serum cytokine analysis	Plasma cytokines will be measured to examine pro and anti-inflammatory cytokines, chemokines and growth factors produced by donor cells during immune reconstitution and GVHD. The plasma cytokines Eotaxin, Eotaxin-3, GM-CSF, IFN-γ, IL-10, IL-12p70, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-α, TNF-β, VEGF-A, and IL-8 will be measured using a multiplex cytokine analyzer where 10 antibodies specific for the above cytokines are attached to a single well providing cytokine capture and immune specificity.	Days +19, +91, +135 and +180 post-HCT

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: University of Wisconsin, Madison; Amgen
• Investigators: Principal Investigator: Rachel Phelan, MD, MPH, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Anticipated): February 28, 2024
• Study Completion (Anticipated): December 31, 2029

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: February 8, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Actual): September 17, 2021
• Last Update Submitted That Met QC Criteria: September 12, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Antineoplastic Agents; Blinatumomab
• Other Study ID Numbers: Blina Part 2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes