Inclusion Criteria:
* 1\. Age ≥12 years and weight ≥40 kg;
2\. Histologically confirmed diagnosis per 2016 World Health Organization (WHO) classification of lymphoid neoplasms160 and per the 2016 WHO classification of acute leukemia161 of the following indications:
* DLBCL, including arising from follicular lymphoma;
* High-grade B-cell lymphoma;
* MCL;
* Primary mediastinal large B-cell lymphoma;
* Primary DLBCL of the CNS;
* Burkitt or Burkitt-like lymphoma/leukemia;
* CLL/SLL; or
* B-lymphoblastic leukemia/lymphoma, T-lymphoblastic leukemia/lymphoma, acute leukemia/lymphoma, acute leukemias of ambiguous lineage, or NK cell lymphoblastic leukemia/lymphoma;
3\. Patients must have relapsed or refractory (R/R) disease with prior therapies defined below:
* DLBCL and high-grade B-cell lymphoma:
e) R/R after autologous hematopoietic cell transplant (HCT); or f) R/R after chimeric antigen receptor T-cell (CAR T) therapy; or g) Patients not eligible for autologous HCT or CAR T therapy; or h) R/R after ≥2 lines of therapy including anti-CD20 antibody and failed, intolerant or ineligible for polatuzamab vedotin, or for whom no standard therapy is available.
* MCL:
c) R/R after autologous HCT; or d) Patients not eligible for autologous HCT must have failed acalabrutinib or be R/R after ≥2 lines of therapy including at least 1 of the following: a Bruton's tyrosine kinase (BTK) inhibitor, bortezomib, or lenalidomide; or for whom no standard therapy is available;
* Primary mediastinal large B-cell lymphoma: R/R after ≥1 line of therapy and are not eligible for or have recurred after autologous HCT or CAR T cell therapy, or for whom no standard therapy is available;
* Primary DLBCL of the CNS: R/R after ≥1 line of therapy including methotrexate (unless intolerant to methotrexate) and are not eligible for or have recurred after autologous HCT or CAR T cell therapy, or for whom no standard therapy is available;
* Burkitt or Burkitt-like lymphoma/leukemia: R/R after ≥1 line of therapy including methotrexate (unless intolerant to methotrexate) and are not eligible for or have recurred after autologous HCT or CAR T cell therapy, or for whom no standard therapy is available;
* CLL/SLL: patients who have active disease requiring treatment and who are deemed at high-risk for disease progression by the investigator or have high risk features per the iwCLL criteria, such as primary resistance to first-line chemo(immune)therapy, or progression of disease \<3 years after fludarabine-based chemo(immune)therapy, or leukemia cells with del(17p)/TP53 mutation, must be:
d) R/R after autologous or allogeneic HCT; or e) Patients not eligible for HCT; or f) R/R after ≥2 lines of therapy including at least 1 of the following: a BTK inhibitor, venetoclax, idelalisib, or duvelisib, or for whom no standard therapy is available;
* Acute lymphoblastic leukemia (ALL):
c) R/R after allogeneic HCT and for whom no standard therapy is available; or d) Patients not eligible for allogeneic HCT must be R/R according to the following disease specific specifications:
* B-cell lymphoblastic leukemia/lymphoma: ≥2 lines of therapy including approved CAR T cell therapies, inotuzumab ozogamicin, or blinatumomab, or for whom no standard therapy is available;
* T-cell lymphoblastic leukemia/lymphoma: ≥2 lines of therapy including nelarabine, or for whom no standard therapy is available;
* NK cell leukemia/lymphoma: ≥1 line of therapy or for whom no standard therapy is available;
* All other diagnoses: R/R after autologous or allogeneic HCT; or R/R after at least one line of therapy, or for whom no standard therapy is available.
4\. Lansky (12 to 15 years of age) (Appendix G) or Karnofsky (≥16 years of age) (Appendix H) performance status ≥50;
5\. Screening laboratory values that meet all of the following criteria:
* Absolute neutrophil count ≥0.05 × 109/L;
* Platelet count ≥25 × 109/L;
* Hemoglobin ≥6.5 g/dL;
* • Aspartate aminotransferase or alanine aminotransferase ≥2.5 × ULN, unless due to the disease;
* Total bilirubin \<1.5 × ULN (if secondary to Gilbert's syndrome, \<3 × ULN is permitted), unless due to the disease; and
* Glomerular filtration rate ≥30 mL/min ; except for patients on metformin at baseline GFR must be ≥45 mL/min; GFR can be calculated by the Cockcroft-Gault formula Appendix C);
6\. Minimum level of pulmonary reserve defined as \<Grade 2 dyspnea and pulse oximetry ≥92% on room air;
7\. Females of childbearing potential must have a negative serum pregnancy test at screening. Females of childbearing potential and nonsterile males must agree to use medically effective methods of contraception from the time of informed consent/assent through 1 month after study drug infusion, which must, at a minimum, include a barrier method; and
8\. The ability to understand and willingness to sign a written informed consent form (ICF) and the ability to adhere to the study schedule and prohibitions. Patients under the age of 18 years (or other age as defined by regional law or regulation) must be willing and able to provide written assent and have a parent(s) or guardian(s) willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any study-related procedure.
Exclusion Criteria:
* Patients who meet any of the following criteria will be excluded from participation in the study for Phase 2:
1. History of another malignancy, except for the following:
* Adequately treated local basal cell or squamous cell carcinoma of the skin;
* Adequately treated carcinoma in situ without evidence of disease;
* Adequately treated papillary, noninvasive bladder cancer; or
* Other cancer that has been in complete remission for ≥2 years. Patients with low-grade prostate cancer, on active surveillance, and not expected to clinically progress over 2 years are allowed;
2. Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to the start of AVM0703 administration, angina requiring therapy, symptomatic peripheral vascular disease, New York Heart Association Class III or IV congestive heart failure, left ventricular ejection fraction \<30%, left ventricular fractional shortening \<20%, or uncontrolled ≥Grade 3 hypertension (diastolic blood pressure \>100 mmHg or systolic blood pressure \>150 mmHg) despite antihypertensive therapy for patients ≥18 years of age, or uncontrolled stage 2 hypertension (diastolic blood pressure \>90 mmHg or systolic blood pressure \>140 mmHg) despite antihypertensive therapy for patients ≥12 years of age;
3. Significant screening electrocardiogram (ECG) abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation/flutter, second degree atrioventricular (AV) block type 2, third-degree AV block, ≥Grade 2 bradycardia, or heart rate corrected QT interval using Fridericia's formula \>480 msec;
4. Known gastric or duodenal ulcer;
5. Uncontrolled type 1 or type 2 diabetes;
6. Known hypersensitivity or allergy to the study drug or any of its excipients;
7. Untreated ongoing bacterial, fungal, or viral infection (including upper respiratory tract infections) at the start of AVM0703 administration, including the following:
* Positive hepatitis B surface antigen and/or hepatitis B core antibody test plus a positive hepatitis B polymerase chain reaction (PCR) assay. Patients with a negative PCR assay are permitted with appropriate antiviral prophylaxis;
* Positive hepatitis C virus antibody (HCV Ab) test. Patients with a positive HCV Ab test are eligible if they are negative for hepatitis C virus by PCR;
* Positive human immunodeficiency virus (HIV) antibody test with detectable HIV load by PCR, or the patient is not able to tolerate antiretroviral therapy; or
* Positive tuberculosis test during screening; test must be positive and not indeterminate due to anergy; if the result is indeterminate due to anergy the patient must not have a history of recent exposure to tuberculosis. Patients in Phase 2 repeat dosing cohorts should not travel to any destination where they might be exposed to tuberculosis during their entire treatment period with AVM0703.
8. Received live vaccination within 8 weeks of screening;
9. Pregnant or breastfeeding;
10. Concurrent participation in another therapeutic clinical study (except AVM0703-001); or
11. Uncontrolled bipolar disorder or schizophrenia. Patients with a diagnosis, past or current, of bipolar disorder or schizophrenia or having a history of severe depression or substance abuse must be prophylactically treated with circadian physiologic hydrocortisone per section 5.5.3.3 CNS prophylaxis, without exception.
