ALX148, Rituximab and Lenalidomide for the Treatment of Indolent and Aggressive B-cell Non-Hodgkin Lymphoma

Inclusion Criteria:

• Phase I: histologically confirmed B-cell NHL, including marginal zone lymphoma,follicular lymphoma, mantle cell lymphoma, large B-cell lymphoma (includingtransformed MZL, transformed FL, Richter Syndrome with ALC < 5,000 109/L, FL grade 3B, high grade B-cell lymphoma and primary mediastinal B-cell lymphoma), andcomposite lymphoma (concomitant indolent and aggressive B-NHL)

• Phase I: have failed at least one line of systemic therapy and not be eligible forknown standard of care curative treatment option; patients with mantle cell lymphomaand aggressive B-cell lymphoma will need to have received 2 prior lines of systemictherapy.

• Phase II: histologically confirmed follicular lymphoma, grade 1, 2, or 3a ormarginal zone lymphoma

• Phase II: have had no prior systemic treatment for lymphoma

• Phase II: high tumor burden disease, defined by meeting 1 or more of the followingGELF criteria

• Bulky disease defined as: a nodal or extranodal (except spleen) mass >7cm inits greater diameter or, involvement of at least 3 nodal or extranodal sites (each with a diameter greater than >3 cm)

• Presence of at least one of the following B symptoms: fever (>38C) of unclearetiology, night sweats, weight loss greater than 10% within the prior 6 months

• Symptomatic splenomegaly

• Impending organ compression or involvement

• Any one of the following cytopenias due to lymphoma: hemoglobin < 10 g/dL (6.25mmol/L), platelets < 100 x 10^9/L , or absolute neutrophil count (ANC) < 1.5 x 10^9 /L

• Pleural or peritoneal serous effusion (irrespective of cell content)

• Lactate dehydrogenase [LDH] > upper limit of normal (ULN) or beta 2microglobulin > ULN

• Phase II: stage III or IV disease

• Bi-dimensionally measurable disease, with at least one nodal lesion >= 1.5 cm or oneextra-nodal lesion >= 1 cm in longest diameter by computed tomography (CT), positronemission tomography (PET)/CT, and/or magnetic resonance imaging (MRI)

• Must be >= 18 years of age

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Absolute neutrophil count (ANC) >= 1,000/mm^3, independent of growth factor support (within 28 days prior to signing informed consent)

• Platelet counts >= 75,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement withlymphoma, independent of transfusion support for >= 14 days in either situation (within 28 days prior to signing informed consent)

• Hemoglobin > 8 g/dL, independent of transfusion support for >= 14 days (within 28days prior to signing informed consent)

• Serum aspartate transaminase (AST) and alanine transaminase (ALT) < 2 x upper limitof normal (ULN)

• Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula

• Total bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert's syndrome,documented liver involvement with lymphoma, or of non-hepatic origin, in which casebilirubin should not exceed 3 g/dL

• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partialthromboplastin time (PTT) < 1.5 x ULN

• Must be able to adhere to the study visit schedule and other protocol requirements

• Women of childbearing potential and men who are sexually active must be practicing ahighly effective method of birth control during and after the study (females ofchildbearing potential: must either completely abstain from heterosexual sexualconduct or must use 2 methods of reliable contraception, 1 highly effective [intrauterine device, birth control pills, hormonal patches, injections, vaginalrings, or implants] and at least 1 additional method [condom, diaphragm, cervicalcap] of birth control). Reliable contraceptive methods must be started at least 4weeks before lenalidomide, and continued for at least 4 weeks after last dose oflenalidomide. Males who are sexually active must be practicing complete abstinenceor agree to a condom during sexual contact with a pregnant female or female of childbearing potential. Men must agree to not donate sperm during the study and 28 daysafter the last dose of lenalidomide. For females, these restrictions apply at least 4 weeks before study treatment, during the period of therapy and for 120 days afterthe last dose of study drug. For males, these restrictions apply during the periodof therapy and for 28 days after the last dose of study drug

• Women of childbearing potential must have a negative serum (beta-human chorionicgonadotropin [beta-hCG]) pregnancy test at screening. Women who are pregnant orbreastfeeding are ineligible for this study.

• Females of reproductive potential must adhere to the scheduled pregnancytesting as required in the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program

• Sign (or their legally-acceptable representatives must sign) an informed consentdocument indicating that they understand the purpose of and procedures required forthe study, including biomarkers, and are willing to participate in the study

• All study participants must be registered into the mandatory Revlimid REMS program,and be willing and able to comply with the requirements of the REMS program

Exclusion Criteria:

• Known active central nervous system lymphoma or leptomeningeal disease, exceptsubjects with a history of central nervous system lymphoma treated and in remission > 6 months

• Burkitt lymphoma

• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) orlymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia

• Any prior history of other malignancy besides B-NHL, unless the patient has beenfree of disease for >= 3 years and felt to be at low risk for recurrence by thetreating physician, except:

• Adequately treated localized skin cancer without evidence of disease

• Adequately treated cervical carcinoma in situ without evidence of disease

• Any life-threatening illness, medical condition, or organ system dysfunction which,in the investigator's opinion, could compromise the subject's safety, interfere withthe absorption or metabolism of lenalidomide capsules, or put the study outcomes atundue risk

• Known history of human immunodeficiency virus (HIV), or active hepatitis C virus, oractive hepatitis B virus infection, or any uncontrolled active significantinfection, including suspected or confirmed JC virus infection and severe acuterespiratory syndrome coronavirus 2 (SARS-CoV2)

• Patients with inactive hepatitis B infection must adhere to hepatitis Breactivation prophylaxis unless contraindicated. Hepatitis B or C serologicstatus: subjects who are hepatitis B core antibody (anti-HBc) positive and whoare surface antigen negative will need to have a negative polymerase chainreaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive orhepatitis B PCR positive will be excluded. Subjects who are hepatitis Cantibody positive will need to have a negative PCR result. Those who arehepatitis C PCR positive will be excluded. Subjects with a history of hepatitisC who received antiviral treatment are eligible as long as PCR is negative

• History of immunodeficiency (with the exception of hypogammaglobulinemia) orconcurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,or chronic administration glucocorticoid equivalent of > 10 mg/day of prednisone)within 28 days of the first dose of study drug

• Known anaphylaxis or immunoglobulin (Ig)E-mediated hypersensitivity to murineproteins or to any component of ALX148, lenalidomide and/or rituximab.

• In regards to rituximab, exclusion is for known severe anaphylaxis to rituximabor any allergic reaction to rituximab that in the opinion of the PI andtreating physician contraindicate re-challenge with rituximab

• Requires chronic treatment with strong CYP3A inhibitors, for a list of strong CYP3Ainhibitors. If patients have been on a strong CYP3A inhibitor in the past, they willnot be eligible if the CYP3A inhibitor was administered within 7 days of the firstdose of study drug

• Clinically significant cardiovascular disease such as uncontrolled or symptomaticarrhythmias, congestive heart failure, or myocardial infarction within 6 months ofscreening, or any class 3 (moderate) or class 4 (severe) cardiac disease as definedby the New York Heart Association Functional Classification. Subjects withcontrolled, asymptomatic atrial fibrillation during screening can enroll on study

• Significant screening electrocardiogram (ECG) abnormalities including left bundlebranch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rddegree block

• Active bleeding or known bleeding diathesis (e.g., von Willebrand's disease) orhemophilia

• History of stroke or intracranial hemorrhage within 6 months prior to study entry

• Vaccinated with live, attenuated vaccines within 4 weeks of study entry

• Lactating or pregnant subjects

• Administration of any investigational agent within 28 days of first dose of studydrug

• Patients who have undergone major surgery within 28 days or minor surgery within 3days of first dose of study drug

• Patients taking corticosteroids during the last 4 weeks, unless administered at adose equivalent to < 10 mg/day prednisone (over these 4 weeks)

• Life expectancy < 6 months

• Neuropathy > grade 1

• Prior exposure to lenalidomide or to a CD47/SIRP alpha antagonist/inhibitor,independently from indication

• Patient who received chimeric antigen receptor (CAR) T-cell therapy within 1 month,autologous stem cell transplant within 3 months, allogeneic stem cell transplantwithin 6 months

• Patients who have difficulty with or are unable to swallow oral medication, or havedisease significantly affecting gastrointestinal function that would limitabsorption of oral medication

• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenicpurpura (ITP)

• History of hemolytic transfusion reaction secondary to allo-antibodies

• Patients who have an active autoimmune disease that has required systemic treatmentin past 2 years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment and is allowed. Agentswith limited immunosuppressive activity (ex. Hydroxychloroquine) are allowed afterdiscussion with the study PI ).

• Patients who have a history of (non-infectious) pneumonitis that required steroidsor has current pneumonitis

• Known history of symptomatic deep vein thrombosis or pulmonary embolism

• Known history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)or drug rash with eosinophilia and systemic symptoms (DRESS)