Blinatumomab After TCR Alpha Beta/CD19 Depleted HCT

B-cell Acute Lymphoblastic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04746209
• Other study ID #: Blina Part 2
• Status: Recruiting
• Phase: Phase 2
• Start date: February 1, 2021
• Est. completion date: December 31, 2029

Study information

• Verified date: September 2021
• Source: Medical College of Wisconsin
• Contact: Meredith Beversdorf, RN
• Phone: 414-266-5891
• Email: mbeversdorf[@]chw.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: December 31, 2029
• Est. primary completion date: February 28, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• B-cell Acute Lymphoblastic Leukemia
• B-Cell ALL, Childhood
• B-cell Childhood Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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

Locations

Country	Name	City	State
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin

Sponsors (3)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Amgen, University of Wisconsin, Madison

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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-?, IL-10, IL-12p70, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IL-1a, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1ß, TARC, TNF-a, TNF-ß, 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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Engraftment	Defined as the number of patients who achieve ANC > 500/uL for 3 consecutive days	Day +100 and +1 year post-HCT
Secondary	Primary Graft Failure	is defined as failure to achieve ANC > 500/uL by Day +28	Day +28 and + 1 year post-HCT
Secondary	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
Secondary	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
Secondary	Acute & Chronic GVHD	Incidences of Grades 2-4 and Grades 3-4 acute GVHD	Day +100, +180 and 1 year post-HCT
Secondary	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
Secondary	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
Secondary	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
Secondary	Relapse	Cumulative incidence of relapse in all patients	Day of HCT to day +180 and 1 year post-HCT