Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory Acute Myeloid Leukemia

A Phase 1 Trial of the CD123 X CD3 DART Molecule Flotetuzumab (NSC#808294) in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia

This phase I trial studies the side effects and best dose of flotetuzumab and how well it works in treating patients with acute myeloid leukemia that has come back (recurrent) or has not responded to treatment (refractory). Immunotherapy with flotetuzumab may induce changes in the body's immune system and may interfere with the ability of leukemia cells to grow and spread. Giving flotetuzumab may stop the leukemia from growing or shrink for a period of time, as well as possibly lessening symptoms, such as pain, that are caused by the leukemia.

PRIMARY OBJECTIVES: I. To assess the safety and tolerability of flotetuzumab administered by continuous intravenous (IV) infusion to pediatric patients < 21 years of age with relapsed or refractory acute myeloid leukemia (AML). II. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of flotetuzumab administered by continuous IV infusion to pediatric patients < 21 years of age with relapsed or refractory AML. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics of flotetuzumab in pediatric patients with relapsed or refractory AML. II. To define preliminarily the anti-tumor activity of flotetuzumab within the confines of a phase 1 study and correlate potential activity with baseline disease burden at study entry. III. To monitor anti-drug antibody (ADA) production and characterize the immunogenicity of flotetuzumab. EXPLORATORY OBJECTIVES: I. To evaluate changes in T-lymphocyte population numbers before and after flotetuzumab treatment. II. To evaluate the tumor microenvironment and cytokine production by immune effector cells before and after flotetuzumab treatment. III. To quantify CD123 surface expression on AML cells at baseline and evaluate expression as a potential biomarker of flotetuzumab response. OUTLINE: This is a dose-escalation study of flotetuzumab. Patients receive cytarabine intrathecally (IT) on days -6 to 0 prior to cycle 1. Patients may receive additional doses of cytarabine on day 1 of subsequent cycles per physician discretion. Patients also receive flotetuzumab IV continuously for 28 days. Treatment repeats every 29 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 30 days.

Patients receive cytarabine IT on days -6 to 0 prior to cycle 1. Patients may receive additional doses of cytarabine on day 1 of subsequent cycles per physician discretion. Patients also receive flotetuzumab IV continuously for 28 days. Treatment repeats every 29 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

CD123 x CD3 DART Bi-Specific Antibody MGD006, CD123 x CD3 Dual Affinity Re-Targeting Bi-Specific Antibody MGD006, MGD006, RES234, S80880

Frequency and proportion of patients experiencing dose limiting toxicities during cycle 1 that are possibly, probably, or definitely due to flotetuzumab by dose level and study part.

A descriptive analysis of the area under the plasma concentration curve versus time at steady state of flotetuzumab including median, minimum and maximum by dose level.

ADA production will be summarized by medians with minimum and maximum values stratified by patient response (responder vs. non-responder).

Changes in T cell number will be described and exploratory analysis will be conducted to assess their correlation with clinical features including occurrence of infections and response. Disease response will be assessed according to the revised acute myeloid leukemia (AML) International Working Group (IWG) criteria and will be reported descriptively. Analyses will be descriptive and exploratory and hypothesis-generating in nature.

CD123 expression will be analyzed in an exploratory fashion, both using a binary scale and using a continuous scale to evaluate whether there are correlations between CD123 expression and anti-leukemia effects. Analyses will be descriptive and exploratory and hypothesis-generating in nature.

Inclusion Criteria: Patients must weigh >/= 17 kg Weight limit is due to constraints related to the concentration of the current drug formulation. If a new formulation of flotetuzumab becomes available to allow dosing of smaller patients, the protocol will be amended Patients with recurrent or refractory AML are eligible. Patients must have histologic verification of malignancy at relapse Patients with leukemia must have >/= M2 marrow by morphology and/or flow cytometry and one of the following: Second or greater relapse Refractory after 2 or more chemotherapy cycles First relapse after primary chemotherapy-refractory disease First relapse after hematopoietic stem cell transplantation (HSCT) Central nervous system (CNS) disease: Patients must have the status of CNS1 and no clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial palsy. Patients with CNS3 or CNS2 status may receive antecedent intrathecal chemotherapy to achieve CNS1 status prior to study entry. Patients with a history of CNS chloromatous disease are required to have no radiographic evidence of disease prior to enrollment. Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life. Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =/< 16 years of age. Use appropriate score for study population. NOTE: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately. Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. >/= 14 days must have elapsed after the completion of other cytotoxic therapy with the exception of hydroxyurea. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy. NOTE: Cytoreduction with hydroxyurea is recommended to be discontinued >/= 24 hours prior to the start of protocol therapy. No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >/= 7 days after the last dose of agent. Antibodies: >/= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =/< 1. Corticosteroids: If used to modify immune adverse events related to prior therapy, >/= 14 days must have elapsed since last dose of corticosteroid. Hematopoietic growth factors: >/= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator. Interleukins, interferons and cytokines (other than hematopoietic growth factors): >/= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors). Stem cell infusions (with or without total body irradiation [TBI]): Allogeneic (non-autologous) bone marrow or stem cell transplant, or stem cell boost: >/= 84 days after infusion and no evidence of graft versus host disease (GVHD) Donor leukocyte infusion: >/= 42 days Autologous stem cell infusion including boost infusion: >/= 42 days Cellular therapy: >/= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.) Radiation therapy (XRT)/external beam irradiation including protons: >/= 14 days after local XRT; >/= 84 days after TBI, craniospinal XRT or if radiation to >/= 50% of the pelvis; >/= 42 days if other substantial bone marrow (BM) radiation Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >/= 42 days after systemically administered radiopharmaceutical therapy Patients must not have received prior exposure to flotetuzumab. Platelet count >/= 20,000/mm^3 (may receive platelet transfusions) These patients must not be known to be refractory to red cell or platelet transfusion Hemoglobin >/= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions) These patients must not be known to be refractory to red cell or platelet transfusion. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >/= 70 ml/min/1.73 m^2 or A serum creatinine based on age/gender as follows: Age: Maximum serum creatinine (mg/dL) 1 to < 2 years: male - 0.6; female - 0.6 2 to < 6 years: male - 0.8; female - 0.8 6 to < 10 years: male - 1; female - 1 10 to < 13 years: male - 1.2; female - 1.2 13 to < 16 years: male - 1.5; female - 1.4 >/= 16 years: male - 1.7; female - 1.4 Bilirubin (sum of conjugated + unconjugated) =/< 1.5 x upper limit of normal (ULN) for age regardless of baseline Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =/< 3 x ULN. For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline. Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST/< 3 x ULN. For the purpose of this study, the ULN for SGPT is 50 U/L regardless of baseline. Serum albumin >/= 2 g/dL Shortening fraction of >/= 27% by echocardiogram, or Ejection fraction of >/= 50% by gated radionuclide study Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5) resulting from prior therapy must be =/< grade 2 with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible. All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. Permanent central access should be established with a central line. A central line that contains 2 lumens is preferred Exclusion Criteria: Pregnant or breast-feeding women will not be entered on this study because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy and for 12 weeks after flotetuzumab discontinuation. Patients must be off steroids (unless physiologic replacement dosing) for at least 7 days prior to enrollment. If used to modify immune adverse events related to prior therapy, >/= 14 days must have elapsed since last dose of corticosteroid. Patients who are currently receiving another investigational drug are not eligible. Patients who are currently receiving other anti-cancer agents are not eligible (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy). Patients who are receiving cyclosporine, tacrolimus or other agents to treat graft-versus-host disease post bone marrow transplant are not eligible for this trial. Patient has French-American-British classification (FAB) type M3 leukemia (acute promyelocytic leukemia) or identification of t(15;17). Patient has isolated CNS involvement or isolated extramedullary relapse. Patient with known human immunodeficiency virus (HIV) infection are eligible if he or she has a negative HIV serology and an undetectable viral load. Patient known to have one of the following concomitant genetic syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome ARE eligible for the study. Patients must not weigh < 17 kg. Patients must not have received prior therapy with a CD123 directed antibody or CD123 directed chimeric antigen receptor (CAR) T cells. Patients who have an uncontrolled infection are not eligible. Patients who have received a prior solid organ transplantation are not eligible. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. Known hypersensitivity to murine, yeast, or recombinant proteins; polysorbate 80; recombinant human serum albumin; benzyl alcohol; or any excipient contained in the flotetuzumab drug formulation. Additionally, those patients who have had a hypersensitivity reaction to etoposide that is considered likely related to polysorbate 80 are not eligible. Patients must refrain from driving a motor vehicle or operating heavy machinery while receiving flotetuzumab and for 30 days from the date of last study drug administration