Testing the Combination of Nivolumab and ASTX727 for Relapsed or Refractory B-Cell Lymphoma

Inclusion Criteria:

• Dose Escalation: Histologically confirmed relapsed or refractory B cell lymphoma (non-Hodgkin lymphoma [NHL] or Hodgkin lymphoma [HL])

• Dose Expansion: Patients must have histologically confirmed relapsed or refractoryDLBCL or HL

• Patients with DLBCL must have failed at least first line chemotherapy and must betransplant ineligible (either secondary to performance status or lack of adequatedisease control or patient preference). Patients may be relapsed after autologous orallogeneic stem cell transplant (SCT), or after chimeric antigen receptor (CAR)-Tcell therapy

• In dose escalation patients with HL or B cell NHL other than DLBCL must haverelapsed after at least 2 lines of therapy and have no other curative options left.HL patients must be brentuximab vedotin refractory or intolerant. In dose expansion,patients with classic HL must have relapsed after at least 2 lines of therapy, andhad autologous stem cell transplantation (ASCT), be ineligible for ASCT, or haverefused ASCT. Prior treatment with checkpoint inhibitor is allowed

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of nivolumab in combination with ASTX727 in patients < 18 years of age,children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status =< 2 (Karnofsky >= 70%)

• Leukocytes >= 1,500/mcL (unless documented bone marrow involvement in which caselower values may be allowed)

• Absolute neutrophil count >= 1,000/mcL (unless documented bone marrow involvement inwhich case lower values may be allowed)

• Platelets >= 75,000/mcL (unless documented bone marrow involvement in which caselower values may be allowed)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if usingthe Cockcroft-Gault formula)

• Patients with a requirement for steroid treatment or other immunosuppressivetreatment: Patients should be excluded if they have a condition requiring systemictreatment with either corticosteroids (> 10 mg daily prednisone equivalents) orother immunosuppressive medications within 14 days of study drug administration.Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisoneequivalents are permitted in the absence of active autoimmune disease

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Patients with a prior malignancy that has completed treatment and or in remissionfor at least 3 years, or non-melanoma skin cancer or in situ cancer are eligible forthis trial. Patients with concurrent malignancy or recent treatment for a concurrentmalignancy are not eligible

• Patients should be New York Heart Association Functional Classification of class 2Bor better

• The effects of nivolumab and ASTX727 on the developing human fetus are unknown. Forthis reason and because DNMTi agents as well as other therapeutic agents used inthis trial are known to be teratogenic, women of child-bearing potential (WOCBP) andmen must agree to use highly effective contraception (hormonal or barrier method ofbirth control; abstinence) prior to study entry and for the duration of studyparticipation. WOCBP should use a highly effective contraception method to avoidpregnancy during treatment with ASTX727 and for at least 6 months after the lastdose of investigational drug and must agree not to donate eggs (ova, oocytes) forthe purpose of reproduction for the same time period. Women of childbearingpotential must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hoursprior to the start of nivolumab. An extension up to 72 hours prior to the start ofstudy treatment is permissible in situations where results cannot be obtained withinthe standard 24-hour window. Women must not be breastfeeding. Men who are sexuallyactive with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere tohighly-effective contraceptive measures of birth control and not to father a childwhile receiving treatment and for a period of 3 months after the last dose ofinvestigational product. Women who are not of childbearing potential (i.e., who arepostmenopausal or surgically sterile as well as azoospermic men) do not requirecontraception

• Women of childbearing potential (WOCBP) is defined as any female who hasexperienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Womenwill be considered post-menopausal if they have been amenorrheic for 12 monthswithout an alternative medical cause. The following age-specific requirementsapply:

• Women < 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥ 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses > 1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).

WOCBP receiving ASTX727 will be instructed to adhere to contraception for a period of 6 months after the last dose of investigational product. Men receiving ASTX727 and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 3 months after the last dose of investigational product. WOCBP receiving nivolumab as a single agent will be instructed to adhere to contraception for a period of 5 months after the last dose. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (2 weeks forRevlimid, 6 weeks for nitrosoureas or mitomycin C) prior to entering the study.Palliative (limited-field) radiation therapy is permitted, if all of the followingcriteria are met:

• Repeat imaging demonstrates no new sites of bone metastases

• The lesion being considered for palliative radiation is not a target lesion

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who have had prior treatment with anti-PD-1/PD-L1 inhibitors or anti CTLA4antibodies and were permanently discontinued from further treatment because of anadverse event. All other prior therapies are permissible. Prior checkpoint inhibitortherapy is allowed if there was no discontinuation due to adverse event

• Patients who are receiving any other investigational agents

• Patients with known brain metastases or leptomeningeal metastases may be excludedbecause of poor prognosis and concerns regarding progressive neurologic dysfunctionthat would confound the evaluation of neurologic and other adverse events

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ASTX727 or nivolumab, including severe hypersensitivityreaction to any monoclonal antibody

• Patients with uncontrolled intercurrent illness

• Patients with cognitive or other impairment that would prevent compliance with studyrequirements

• Pregnant women are excluded from this study because ASTX727 is a DNMTi agent andnivolumab is a PD-L1 inhibitor with the potential for teratogenic or abortifacienteffects. Because there is an unknown but potential risk for adverse events intreatments and if they have luteinizing hormone and follicle-stimulating&#xd;hormone levels in the post-menopausal range for the institution or underwent&#xd;surgical sterilization (bilateral oophorectomy or hysterectomy).&#xd; &#xd;

• Women ≥ 50 years of age would be considered post-menopausal if they have been&#xd;amenorrheic for 12 months or more following cessation of all exogenous hormonal&#xd;treatments, had radiation-induced menopause with last menses > 1 year ago, had&#xd;chemotherapy-induced menopause with last menses > 1 year ago, or underwent&#xd;surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or&#xd;hysterectomy).&#xd; &#xd; WOCBP receiving ASTX727 will be instructed to adhere to contraception for a period of 6&#xd; months after the last dose of investigational product. Men receiving ASTX727 and who are&#xd; sexually active with WOCBP will be instructed to adhere to contraception for a period of&#xd; 3 months after the last dose of investigational product. WOCBP receiving nivolumab as a&#xd; single agent will be instructed to adhere to contraception for a period of 5 months after&#xd; the last dose. These durations have been calculated using the upper limit of the&#xd; half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP&#xd; use contraception for 5 half-lives plus 30 days Should a woman become pregnant or suspect&#xd; she is pregnant while she or her partner is participating in this study, she (or the&#xd; participating partner) should inform the treating physician immediately&#xd; &#xd;

• Ability to understand and the willingness to sign a written informed consent&#xd;document. Participants with impaired decision-making capacity who have a&#xd;legally-authorized representative (LAR) and/or family member available will also be&#xd;eligible&#xd; &#xd; Exclusion Criteria:&#xd; &#xd;

• Patients who have had chemotherapy or radiotherapy within 4 weeks (2 weeks for&#xd;Revlimid, 6 weeks for nitrosoureas or mitomycin C) prior to entering the study.&#xd;Palliative (limited-field) radiation therapy is permitted, if all of the following&#xd;criteria are met:&#xd; &#xd;

• Repeat imaging demonstrates no new sites of bone metastases&#xd; &#xd;

• The lesion being considered for palliative radiation is not a target lesion&#xd; &#xd;

• Patients who have not recovered from adverse events due to prior anti-cancer therapy&#xd; (i.e., have residual toxicities > grade 1) with the exception of alopecia&#xd; &#xd;

• Patients who have had prior treatment with anti-PD-1/PD-L1 inhibitors or anti CTLA4&#xd;antibodies and were permanently discontinued from further treatment because of an&#xd;adverse event. All other prior therapies are permissible. Prior checkpoint inhibitor&#xd;therapy is allowed if there was no discontinuation due to adverse event&#xd; &#xd;

• Patients who are receiving any other investigational agents&#xd; &#xd;

• Patients with known brain metastases or leptomeningeal metastases may be excluded&#xd;because of poor prognosis and concerns regarding progressive neurologic dysfunction&#xd;that would confound the evaluation of neurologic and other adverse events&#xd; &#xd;

• History of allergic reactions attributed to compounds of similar chemical or&#xd;biologic composition to ASTX727 or nivolumab, including severe hypersensitivity&#xd;reaction to any monoclonal antibody&#xd; &#xd;

• Patients with uncontrolled intercurrent illness&#xd; &#xd;

• Patients with cognitive or other impairment that would prevent compliance with study&#xd;requirements&#xd; &#xd;

• Pregnant women are excluded from this study because ASTX727 is a DNMTi agent and&#xd;nivolumab is a PD-L1 inhibitor with the potential for teratogenic or abortifacient&#xd;effects. Because there is an unknown but potential risk for adverse events in&#xd;nursing infants secondary to treatment of the mother with ASTX727 and nivolumab,breastfeeding should be discontinued if the mother is treated with ASTX727 andnivolumab

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, should be excluded. These include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome (GBS),myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxicepidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded because of the risk of recurrence or exacerbation of disease.Patients with vitiligo, endocrine deficiencies including thyroiditis managed withreplacement hormones including physiologic corticosteroids are eligible. Patientswith rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasiscontrolled with topical medication and patients with positive serology, such asantinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for thepresence of target organ involvement and potential need for systemic treatment butshould otherwise be eligible

• Patients who have had evidence of active or acute diverticulitis, intra-abdominalabscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which areknown risk factors for bowel perforation should be evaluated for the potential needfor additional treatment before coming on study