A Phase 1 Multiple Dose Study to Evaluate the Safety and Tolerability of XmAb®14045 in Patients with CD123-Expressing Hematologic Malignancies
The goal of this clinical research study is to learn about the safety of giving XmAb14045 to patients that have blood or bone marrow cancer. Researchers also want to learn the highest tolerable dose of XmAb14045 that can be given. This is the first study using XmAb14045 in humans.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: XmAb14045
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Xencor, Inc
Primary Objectives To determine the safety and tolerability profile of weekly IV dosing of XmAb14045 To identify the first dose Maximum Tolerated Dose/Recommended Dose At first dose Maximum Tolerated Dose/Recommended Dose, to then identify the second (and subsequent) infusion Maximum Tolerated Dose/Recommended Dose Secondary Objectives To characterize the pharmacokinetics (PK) and immunogenicity of XmAb14045, as well as the pharmacodynamics (PD) of the CD123- expressing cellular compartment (including tumor cells, leukemia stem cells, and basophils) in blood and marrow. To preliminarily assess antitumor activity of XmAb14045 by response rates, duration of response, progression-free survival(Progression Free Survival), and overall survival Exploratory Objectives To assess changes induced by XmAb14045 in lymphocyte subsets and the hematopoietic stem cell population in peripheral blood and bone marrow by flow cytometry To measure changes in T-cell activation after XmAb14045 administration by flow cytometric assessment of activation markers on T-lymphocytes To evaluate changes in programmed cell death protein-1 (PD-1) expression on lymphocytes in response to treatment with XmAb14045.
IRB Review and Approval Date: 08/16/2016
Recruitment Status: Open
Projected Accrual: 66
1) Adult (age >/= 18 years)
2) Diagnosis of 1 of the following diseases: a. Primary or secondary AML (including erythroleukemia and eosinophilic leukemia, but excluding acute promyelocytic leukemia) b. B-cell ALL c. BPDCN d. CML in blast phase, resistant or intolerant to tyrosine kinase inhibitor therapy
3) Patients with relapsed or refractory disease with no available standard therapy. For AML, this includes patients with: a. newly diagnosed leukemia refractory to >/=2 induction attempts, b. leukemia in first relapse with initial CR duration of < 6 months c. leukemia in first relapse following >/=1 unsuccessful salvage attempts, or d. leukemia in second or higher relapse or e. patients who are not candidates for aggressive induction therapies (i.e. "7+3" or similar regimens) who have relapsed after initial treatment.
4) ECOG performance status 0-2
5) Not a candidate for, or refusing treatment with HSCT
6) Female patients of childbearing potential must agree to use a highly effective method of birth control during and for 4 weeks after completion of study. Women are considered to be of childbearing potential unless it is documented that they are over the age of 60 OR postmenopausal by history with no menses for 1 year and confirmed by FSH (using local reference ranges) OR have a history of hysterectomy and/or bilateral oophorectomy OR have a history of bilateral tubal ligation. Highly effective methods of birth control include hormonal birth control (oral, intravaginal, transdermal, implantable, or intrauterine), IUDs, vasectomy, or any double-barrier methods (combination of male condom and spermicide with either cap, diaphragm, or sponge).
7) Able and willing to complete the entire study according to the study schedule.
8) Patients must give written informed consent. A copy of the signed informed consent form (ICF) will be retained in the patient’s chart.
1) Systemic antineoplastic therapy (including cytotoxic chemotherapy and
toxin immunoconjugates, but excluding hydroxyurea), unconjugated
antibody therapy, or radiotherapy within 2 weeks of the first dose of
study treatment, or small molecule kinase inhibitors within 6
elimination half-lives of the first dose of study treatment.
2) Prior therapy with CD123- or IL-3R-directed immunotherapies, including monospecific and bsAbs, immunoconjugates, or chimeric antigen receptor-modified T-cell (CAR-T) therapy
3) Failure to recover from Grade 3 or 4 toxicity from previous treatment (unrelated to malignant bone marrow involvement)
4) Known uncontrolled CNS involvement by malignant disease
5) Absolute blast count >/=10,000/mm3 or symptoms of leukostasis (hydroxyurea or other therapies may be used to control leukocytosis through the first month of study therapy)
6) Diagnosis of promyelocytic leukemia (FAB M3)
7) AST or ALT at screening > 3.0 x upper limit of normal (ULN) unless considered due to leukemic organ involvement.
8) Bilirubin > 1.5 x ULN, unless prior diagnosis and documentation of leukemic organ involvement, ongoing hemolysis, or Gilbert's syndrome has been made.
9) Serum creatinine > 2.0 x ULN OR estimated creatinine clearance < 40 mL/min calculated by either the Cockroft Gault or Modification of Diet in Renal Disease (MDRD)55 formula at screening.
10) History or evidence of a clinically unstable/uncontrolled disorder, condition or disease (including but not limited to cardiopulmonary, renal, metabolic, hematologic or neurologic) other than their primary malignancy, that in the opinion of the Investigator would pose a risk to patient safety or interfere with the study evaluation, procedures or completion.
11) Evidence of any active, uncontrolled bacterial, viral, parasitic or systemic fungal infections within 1 week of first dose of study drug.
12) Positive test for human immunodeficiency virus (HIV) -I or -II antibodies, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody (unless HCV viral load test by PCR is negative). HBcAb positivity will be allowed if one or more of the following is true: a) HBsAb is present; or b) hepatitis B DNA testing is negative and the patient is receiving hepatitis B reactivation prophylaxis with entecavir, tenofovir, or lamivudine.
13) Patient is pregnant or breast feeding, or planning to become pregnant while enrolled in the study, up to End of Study (EOS) visit.
14) Positive urine pregnancy test (i.e., urine human chorionic gonadotropin [Beta-hCG]) at screening.
15) Patients with substance abuse or other medical or psychiatric conditions that, in the opinion of the investigator, would confound study interpretation or affect the patient’s ability to tolerate or complete the study.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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