Daratumumab for Chemotherapy-Refractory Minimal Residual Disease in T Cell ALL

Study Overview
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Brief Summary
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In this study, the investigators are hypothesizing that daratumumab-hyaluronidase will effectively treat T-ALL in patients who have persistent or recurrent MRD following treatment with chemotherapy.

Detailed Description
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The primary hypothesis is that daratumumab-hyaluronidase will effectively eliminate chemotherapy refractory and relapsed MRD in T-ALL. The secondary hypotheses include; daratumumab-hyaluronidase will improve hematologic relapse free survival (RFS),daratumumab-hyaluronidase will improve overall survival (OS), patients that achieve complete MRD response with daratumumab will have improved survival outcomes, and daratumumab-hyaluronidase will be well tolerated in T-ALL after allogenic stem cell transplant. The primary objective of this study is to evaluate the rate of complete MRD response by flow cytometry after 4 weekly doses of daratumumab-hyaluronidase (Day 29) among patients with MRD positive T-ALL in hematologic morphologic complete remission or complete remission with incomplete hematologic recovery. The secondary objectives include; evaluation of morphologic relapse free survival (RFS), evaluation of overall survival (OS), assessment of the the survival outcomes in patients that undergo allogeneic stem cell transplant after complete MRD response with daratumumab-hyaluronidase, assessment of adverse effects and tolerability of daratumumab-hyaluronidase in T-ALL, and assessment of flow cytometry based MRD status on Day 64 of treatment or upon count recovery for patients that receive chemotherapy in addition to daratumumab-hyaluronidase during Course 1A.

Official Title
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A Phase II Study of Daratumumab-Hyaluronidase for Chemotherapy-Relapsed/Refractory Minimal Residual Disease (MRD) in T Cell Acute Lymphoblastic Leukemia (T-ALL

Conditions
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T-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Daratumumab / Hyaluronidase Injection
* Drug: Daratumumab / Hyaluronidase Injection
* Drug: Daratumumab / Hyaluronidase Injection
* Drug: Daratumumab / Hyaluronidase Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have documented T cell ALL and must be in first or later hematologic CR or CRi after a minimum of 2 blocks of intensive chemotherapy. Patients in hematologic CR or CRi must have persistent or recurrent MRD ≥ 10-4. Institution must have received central MRD status test results confirming persistent or recurrent MRD ≥ 10-4 by flow cytometry. Patient may have undergone a prior allogeneic stem cell transplant, but patient may not have Grafts Versus Host Disease (GVHD) that requires ongoing immunosuppressive therapy. Patient may receive prednisone if the dose is ≤ 10 mg per day. Patient must have an ECOG performance status 0-2. All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 registration to rule out pregnancy. Patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and continue to 3 months after the last dose of protocol treatment. Patients must also agree to abstain from donating sperm, even if they have had a successful vasectomy, or donating eggs while on study treatment and for 3 months after the last dose of protocol treatment. Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible. Patient must have adequate organ and marrow function as defined below (these labs must be obtained ≤ 7 days prior to Step 1 registration). Absolute neutrophil count (ANC) ≥ 750/μL Platelets ≥ 75,000/μL Total or Direct bilirubin ≤ 2 mg/dL AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional ULN Creatinine ≤ 1.5 x institutional ULN or Creatinine Clearance > 30 ml/min Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Patients with prior CNS involvement are eligible as long as they do not have active CNS involvement at time of Step 1 registration. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Exclusion Criteria: -Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single arm study of daratumumab-hyaluronidase in T-ALL patients in morphologic CR with persistent or relapsed MRD. MRD will be assessed centrally for eligibility and response by flow cytometry. All patients will receive daratumumab-hyaluronidase once weekly for up to 4 doses during Course 1. .
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Course 1<br>Daratumumab-hyaluronidase | Drug: Daratumumab / Hyaluronidase Injection<br>* Daratumumab-hyaluronidase 1800mg/ 30,000 units once weekly for 4 doses on Days 1, 8, 15, and 22<br>Drug: Daratumumab / Hyaluronidase Injection<br>* Patients that are MRD Negative on Day 29 will receive daratumumab-hyaluronidase 1800mg/ 30,000 units once weekly for 4 doses on Days 36, 43, 50, and 57.<br>Drug: Daratumumab / Hyaluronidase Injection<br>* Patients that remain MRD positive on Day 29 will receive a combination of daratumumab-hyaluronidase 1800mg/ 30,000 units once weekly for 4 doses on Days 36, 43, 50, and 57 and chemotherapy selected from the combinations listed below: Cytarabine 3000 mg/m2, IV, Every 12 hours for 4 doses on Days 37 and 38 Methotrexate 1000 mg/m2, IV, Over 24 hours on Day 36 OR Methotrexate, Starting dose 100 mg/m2, IV, Days 36, 46, 56 Vincristine, 1.5 mg/m2 (2 mg cap), IV, Days 36, 46, 56 Pegaspargase, 2000 IU/m2 (Capped at 3750 IU), IV Days 37, 57 Methotrexate 15 mg, IT, Days 36, 56<br>Drug: Daratumumab / Hyaluronidase Injection<br>* All patients with MRD negative response after completion of previous course are eligible for daratumumab-hyaluronidase 1800mg/ 30,000 units every 2 weeks on Days 1,15, 29, 43, 57, 71, 85, and 99 for 8 doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission (CR) | Requires that all of the following be present. Peripheral Blood Counts Neutrophil count ≥ 1,000/µL. Platelet count ≥ 100,000/µL. Reduced hemoglobin concentration or hematocrit has no bearing on remission status. Leukemic blasts must not be present in the peripheral blood. Bone Marrow Aspirate and Biopsy Cellularity of bone marrow biopsy must be > 20% with maturation of all cell lines. ≤ 5% T lymphoblasts by flow cytometry. Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present. | Day 29 | 
| Complete Remission (CR) | Requires that all of the following be present. Peripheral Blood Counts Neutrophil count ≥ 1,000/µL. Platelet count ≥ 100,000/µL. Reduced hemoglobin concentration or hematocrit has no bearing on remission status. Leukemic blasts must not be present in the peripheral blood. Bone Marrow Aspirate and Biopsy Cellularity of bone marrow biopsy must be > 20% with maturation of all cell lines. ≤ 5% T lymphoblasts by flow cytometry. Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present. | Day 64 | 
| Complete Response with Partial Count Recovery (CRh) | The same as for CR except with unsupported platelets > 50,000/μL, hemoglobin > 7 g/dL, and absolute neutrophil count > 500/μL. | Day 29 | 
| Complete Response with Partial Count Recovery (CRh) | The same as for CR except with unsupported platelets > 50,000/μL, hemoglobin > 7 g/dL, and absolute neutrophil count > 500/μL. | Day 64 | 
| Complete Remission incomplete (CRi) | All the same response criteria in peripheral blood and bone marrow as CR with the exception that there is incomplete platelet recovery (platelets > 75,000/uL but < 100,000/μL independent of platelet transfusions) or incomplete neutrophil count recovery > 750/uL but < 1000/μL. | Day 29 | 
| Complete Remission incomplete (CRi) | All the same response criteria in peripheral blood and bone marrow as CR with the exception that there is incomplete platelet recovery (platelets > 75,000/uL but < 100,000/μL independent of platelet transfusions) or incomplete neutrophil count recovery > 750/uL but < 1000/μL. | Day 64 | 
| Minimal Residual Disease Negativity (MRD-) | Bone marrow lymphoblast percent < 0.01% (< 10-4) by flow cytometry in a patient that fulfills count requirements for CR/CRh/CRi.. | Day 29 | 
| Minimal Residual Disease Negativity (MRD-) | Bone marrow lymphoblast percent < 0.01% (< 10-4) by flow cytometry in a patient that fulfills count requirements for CR/CRh/CRi.. | Day 64 | 
| Morphologic Relapse | Bone Marrow Aspirate and Biopsy Presence of > 5% T lympho-blasts, not attributable to another cause (e.g., bone marrow regeneration). If there are no circulating blasts and the bone marrow contains 5% to 20% blasts, then a repeat bone marrow performed ≥ 1 week later documenting more than 5% blasts is necessary to meet the criteria for relapse. | Day 29 | 
| MRD Relapse | • Relapse following MRD negativity is defined as bone marrow T lymphoblast percent ≥ 0.01% (10-4). | Day 29 | 
| Morphologic Relapse | Bone Marrow Aspirate and Biopsy Presence of > 5% T lympho-blasts, not attributable to another cause (e.g., bone marrow regeneration). If there are no circulating blasts and the bone marrow contains 5% to 20% blasts, then a repeat bone marrow performed ≥ 1 week later documenting more than 5% blasts is necessary to meet the criteria for relapse. | Day 64 | 
| MRD Relapse | • Relapse following MRD negativity is defined as bone marrow T lymphoblast percent ≥ 0.01% (10-4). | Day 64 | 
| Refractory | Failure to achieve MRD negativity as defined by bone marrow with CR/CRh/CRi with T lymphoblast percent ≥ 0.01% (10-4). | Day 29 | 
| Refractory | Failure to achieve MRD negativity as defined by bone marrow with CR/CRh/CRi with T lymphoblast percent ≥ 0.01% (10-4). | Day 64 |