The OPAL Study: AVM0703 for Treatment of Lymphoid Malignancies

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 acuteleukemia161 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, acuteleukemia/lymphoma, acute leukemias of ambiguous lineage, or NK cell lymphoblasticleukemia/lymphoma;

3. Patients must have relapsed or refractory (R/R) disease with prior therapiesdefined below:

• DLBCL and high-grade B-cell lymphoma: e) R/R after autologous hematopoietic cell transplant (HCT); or f) R/R afterchimeric antigen receptor T-cell (CAR T) therapy; or g) Patients not eligible forautologous HCT or CAR T therapy; or h) R/R after ≥2 lines of therapy includinganti-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 musthave 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, orlenalidomide; or for whom no standard therapy is available;
• Primary mediastinal large B-cell lymphoma: R/R after ≥1 line of therapy and arenot eligible for or have recurred after autologous HCT or CAR T cell therapy, orfor 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 recurredafter autologous HCT or CAR T cell therapy, or for whom no standard therapy isavailable;
• Burkitt or Burkitt-like lymphoma/leukemia: R/R after ≥1 line of therapy includingmethotrexate (unless intolerant to methotrexate) and are not eligible for or haverecurred after autologous HCT or CAR T cell therapy, or for whom no standardtherapy is available;
• CLL/SLL: patients who have active disease requiring treatment and who are deemedat high-risk for disease progression by the investigator or have high riskfeatures per the iwCLL criteria, such as primary resistance to first-linechemo(immune)therapy, or progression of disease <3 years after fludarabine-basedchemo(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 BTKinhibitor, venetoclax, idelalisib, or duvelisib, or for whom no standard therapyis 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 followingdisease specific specifications:
• B-cell lymphoblastic leukemia/lymphoma: ≥2 lines of therapy including approvedCAR T cell therapies, inotuzumab ozogamicin, or blinatumomab, or for whom nostandard 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 isavailable;
• All other diagnoses: R/R after autologous or allogeneic HCT; or R/R after atleast 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 dueto the disease;
• Total bilirubin <1.5 × ULN (if secondary to Gilbert's syndrome, <3 × ULN ispermitted), unless due to the disease; and
• Glomerular filtration rate ≥30 mL/min ; except for patients on metformin atbaseline GFR must be ≥45 mL/min; GFR can be calculated by the Cockcroft-Gaultformula Appendix C);

6. Minimum level of pulmonary reserve defined as <Grade 2 dyspnea and pulseoximetry ≥92% on room air;
7. Females of childbearing potential must have a negative serum pregnancy test atscreening. Females of childbearing potential and nonsterile males must agree touse medically effective methods of contraception from the time of informedconsent/assent through 1 month after study drug infusion, which must, at aminimum, include a barrier method; and
8. The ability to understand and willingness to sign a written informed consentform (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 orregulation) must be willing and able to provide written assent and have aparent(s) or guardian(s) willing and able to provide written, signed informedconsent after the nature of the study has been explained and prior to performanceof any study-related procedure.

Exclusion Criteria:

• Patients who meet any of the following criteria will be excluded from participation inthe 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 withlow-grade prostate cancer, on active surveillance, and not expected toclinically progress over 2 years are allowed;

2. Significant cardiovascular disease (e.g., myocardial infarction, arterialthromboembolism, cerebrovascular thromboembolism) within 3 months prior to thestart of AVM0703 administration, angina requiring therapy, symptomatic peripheralvascular disease, New York Heart Association Class III or IV congestive heartfailure, left ventricular ejection fraction <30%, left ventricular fractionalshortening <20%, or uncontrolled ≥Grade 3 hypertension (diastolic blood pressure >100 mmHg or systolic blood pressure >150 mmHg) despite antihypertensive therapyfor patients ≥18 years of age, or uncontrolled stage 2 hypertension (diastolicblood pressure >90 mmHg or systolic blood pressure >140 mmHg) despiteantihypertensive therapy for patients ≥12 years of age;
3. Significant screening electrocardiogram (ECG) abnormalities, including unstablecardiac arrhythmia requiring medication, atrial fibrillation/flutter, seconddegree atrioventricular (AV) block type 2, third-degree AV block, ≥Grade 2bradycardia, or heart rate corrected QT interval using Fridericia's formula >480msec;
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 upperrespiratory tract infections) at the start of AVM0703 administration, includingthe following:

• Positive hepatitis B surface antigen and/or hepatitis B core antibody testplus a positive hepatitis B polymerase chain reaction (PCR) assay. Patientswith a negative PCR assay are permitted with appropriate antiviralprophylaxis;
• Positive hepatitis C virus antibody (HCV Ab) test. Patients with a positiveHCV Ab test are eligible if they are negative for hepatitis C virus by PCR;
• Positive human immunodeficiency virus (HIV) antibody test with detectableHIV load by PCR, or the patient is not able to tolerate antiretroviraltherapy; or
• Positive tuberculosis test during screening; test must be positive and notindeterminate due to anergy; if the result is indeterminate due to anergythe patient must not have a history of recent exposure to tuberculosis.Patients in Phase 2 repeat dosing cohorts should not travel to anydestination where they might be exposed to tuberculosis during their entiretreatment period with AVM0703.

8. Received live vaccination within 8 weeks of screening;
9. Pregnant or breastfeeding;
10. Concurrent participation in another therapeutic clinical study (exceptAVM0703-001); or
11. Uncontrolled bipolar disorder or schizophrenia. Patients with a diagnosis, pastor current, of bipolar disorder or schizophrenia or having a history of severedepression or substance abuse must be prophylactically treated with circadianphysiologic hydrocortisone per section 5.5.3.3 CNS prophylaxis, withoutexception.