XmAb18968 (CD3-CD38) in Relapsed or Refractory Acute Leukemia and T Cell Lymphoblastic Leukemia

Inclusion Criteria

• Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care.
• Male or female subjects 18 years or older.
• Morphologically documented T-ALL, AML (including undifferentiated leukemia and bi-phenotypic leukemia, or T-LBL in relapsed/refractory status (at least one line of prior therapy). Subjects with measurable residual disease by flow cytometry, molecular testing or cytogenetics will be eligible for the trial.
• CD38 expression ≥ 20% by flow cytometry or immunohistochemistry at time of relapse.
• Adequate organ system function as outlined below:
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN. If total bilirubin > 1.5 × ULN then check direct bilirubin. Subject will be eligible if direct bilirubin is < 1.5 × ULN.
• Calculated creatinine clearance ≥ 40 mL/min (calculated by Cockcroft-Gault formula) for subjects with creatinine levels above institutional normal.
• Ejection > 40% by echocardiogram or multiple-gated acquisition (MUGA) scan.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Female subjects who:
• Are postmenopausal for at least one year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential: i. Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through four months after the last dose of study drug (female and male condoms should not be used together), OR ii. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).
• Male subjects, even if surgically sterilized (i.e., status postvasectomy), who:
• Agree to practice effective barrier contraception during the entire study drug treatment period from the time of signing the informed consent through four months after the last dose of study drug (female and male condoms should not be used together), OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

Exclusion Criteria

• Acute promyelocytic leukemia.
• Treatment with systemic antineoplastic therapy within 5 half-lives from the last dose before cycle one day one of therapy. Radiation within 7 days before C1D1 of therapy. The use of hydroxyurea, steroids, or vincristine for leukoreduction is permitted.
• Prior treatment with an anti-CD38 antibody in last 6 months.
• Hematopoietic stem cell transplantation within 6 months of enrollment, or evidence of veno-occlusive disease at any time post-transplant, or active graft-versus-host disease requiring immunosuppressive therapy.
• Any serious medical or psychiatric illness that could, in the Investigator's opinion, potentially interfere with the completion of study procedures.
• Active, significant, uncontrolled infection. Subjects with infections that are controlled by antibiotics, antiviral or antifungal therapy can be enrolled in the study.
• Presence of another active malignancy (requiring treatment) treated within 12 months with the exception of:
• Adequately treated non-melanoma skin cancer,
• Adequately treated melanoma Grade 2 or less,
• Cervical intraepithelial neoplasia,
• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast,
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin,
• Adequately treated prostate cancer.
• Life-threatening illness with life expectancy < 6 months unrelated to cancer.
• Subjects with active central nervous system (CNS) disease. Subjects with adequately treated CNS disease may enroll on the study.
• Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection. Note: Subjects who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Subjects who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
• Known cardiopulmonary disease defined as:
• Unstable angina,
• Congestive heart failure (New York Heart Association [NYHA] Class III or IV;
• Myocardial infarction (MI) within six months prior to enrollment (subjects who had ischemic heart disease such as acute coronary syndrome, MI, and/or revascularization > 6 months before Screening and who are without cardiac symptoms may enroll),
• Clinically significant pulmonary hypertension requiring pharmacologic therapy,
• Clinically significant arrhythmia: i. History of polymorphic ventricular fibrillation or torsade de pointes, ii. Uncontrolled permanent atrial fibrillation (A-Fib), defined as continuous A-Fib for ≥ 6 months and not well controlled with adequate A-Fib therapy, iii. Uncontrolled persistent A-Fib, defined as sustained A-Fib lasting > 7 days and/or requiring cardioversion in the four weeks before Screening and not well controlled with A-Fib therapy, iv. Grade 3 A-Fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation, and v. Subjects with paroxysmal A-Fib or < Grade 3 A-Fib for a period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen.
• Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, gastrointestinal or any other medical condition that in the opinion of the Investigator would adversely affect his/her participating in this study.
• Uncontrolled high blood pressure as determined by the treating physician (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 100 mm Hg).
• Subjects with uncontrolled coagulopathy or bleeding disorder.
• Known moderate-to-severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis.
• Major surgery within 14 days before the enrollment or a prescheduled major surgery during study period.
• Female subjects who are both lactating and breastfeeding or of childbearing potential who have a positive serum or urine test during Screening.
• Female subjects who intend to donate eggs (ova) during the course of this study or four months after receiving their last dose of study drug(s).
• Male subjects who intend to donate sperm during the course of this study or four months after receiving their last dose of study drug(s).