Duvelisib and Nivolumab for the Treatment of Stage IIB-IVB Mycosis Fungoides and Sezary Syndrome

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed MF or SS, stages IIB toIVB with measurable disease and/or detectable blood involvement based on the GlobalCutaneous Lymphoma Response Criteria

• Patients must have had at least one line of prior systemic therapy

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

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

• Absolute neutrophil count >= 1000/mcL

• Platelets > 75,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) or =< 5 xinstitutional ULN if with history of Gilbert's syndrome

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

• Creatinine =< 2.0 x institutional ULN

• 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 known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• The effects of nivolumab and duvelisib on the developing human fetus are unknown.For this reason and because other therapeutic agents used in this trial are known tobe teratogenic, women of child-bearing potential (WOCBP) and men must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry and for the duration of study participation. WOCBP should usean adequate method to avoid pregnancy for 5 months after the last dose of nivolumaband duvelisib. WOCBP must have a negative serum or urine pregnancy test (minimumsensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])within 7 days prior to the start of nivolumab and duvelisib. Women must not bebreastfeeding. Men who are sexually active with WOCBP must use any contraceptivemethod with a failure rate of less than 1% per year. Men receiving nivolumab andduvelisib and who are sexually active with WOCBP will be instructed to adhere tocontraception for a period of 7 months after the last dose of investigationalproduct. Women who are not of childbearing potential (i.e., who are postmenopausalor surgically sterile as well as azoospermic men) do not require contraception.WOCBP is defined as any female who has experienced menarche and who has notundergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who isnot postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in awoman over 45 in the absence of other biological or physiological causes. Inaddition, women under the age of 55 must have a documented serum folliclestimulating hormone (FSH) level less than 40 mIU/mL

• Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of study participation,and 7 months after completion of administration of investigational agents on thisstudy

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

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

Exclusion Criteria:

• Prior therapy with a PI3K inhibitor

• Prior therapy with nivolumab or other agents targeting T-cell co-stimulation orcheckpoint pathways

• 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,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 are permitted to enroll if they have vitiligo, type I diabetes mellitus,residual hypothyroidism due to autoimmune condition only requiring hormonereplacement, psoriasis not requiring systemic treatment, or conditions not expectedto recur in the absence of an external trigger (precipitating event)

• Patients should be excluded if they have a condition requiring systemic treatmentwith either corticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 7 days of study drug administration. Inhaled ortopical steroids, steroids for physiologic or adrenal replacement doses =< 10 mgdaily prednisone equivalents are permitted in the absence of active autoimmunedisease. Patients are permitted to use topical, ocular, intra-articular, intranasal,and inhalational corticosteroids (with minimal systemic absorption). A brief courseof corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment ofnon-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused bycontact allergen) is permitted

• History of tuberculosis treatment within the 2 years prior to enrollment

• Ongoing treatment with other immunosuppressive agent including, but not limited to,methotrexate, azathioprine, anti-tumor necrosis factor (TNF) agents, etc. with theexception of steroids

• Administration of a live or live attenuated vaccine within 6 weeks of initiation ofstudy therapy

• Ongoing treatment with systemic steroids at dose equivalent to greater thanprednisone 10 mg daily or other immunosuppressive medication within 7 days ofinitiation of study therapy

• Inhaled steroids will be permitted

• Topical steroids for cutaneous manifestations of MF/SS will be permitted below:

• Continued use of select concomitant topical steroids is permitted if thepatient has remained clinically stable for at least 4 weeks.

• Patients who are on low or moderate potency topical corticosteroids mayparticipate if they are on a stable dose for at least 4 weeks beforeenrollment. Local injections of corticosteroids are acceptable; allcorticosteroids will be reported as concomitant medications.

• Patients prescribed prednisone 10 mg PO daily or less (or equivalent) will notbe excluded

• Concomitant use of another systemic therapy for MF/SS. Patients must have thefollowing minimum wash-out from previous treatments:

• At least 8 weeks for low-dose (12 Gy or less) total skin electron beam therapy (TSEBT)

• At least 4 weeks for systemic cytotoxic anticancer agents or fortumor-targeting monoclonal antibodies (mAbs), with the exception ofalemtuzumab, for which the washout is at least 16 weeks

• At least 2 weeks or 5 half-lives for systemic retinoids, interferons,vorinostat, romidepsin, and denileukin diftitox, or anticancer investigationalagents that are not defined as immunotherapy

• At least 2 weeks for local radiation therapy

• At least 1 week for topical retinoids, nitrogen mustard, or imiquimod

• Concomitant malignancy requiring active systemic therapy, excluding adjuvantendocrine therapy with the following exceptions:

• Patients with non-melanoma skin cancer or carcinoma in situ of the cervix willnot be excluded

• Adjuvant or maintenance therapy to reduce the risk of recurrence of anothermalignancy (excluding cutaneous T-cell lymphoma) is permissible afterdiscussion with the Washington University principal investigator

• Subjects with previous malignancies are eligible if disease-free for > 2 years

• History of solid organ transplantation or allogeneic bone marrow transplantation

• Uncontrolled infection requiring systemic antimicrobials: Patients on antibacterial,antifungal, and antiviral prophylaxis will not be excluded if all other exclusion /inclusion criteria are met

• Patients with active cytomegalovirus (CMV) (positive serology for anti-CMV IgMantibody and negative for anti-CMV IgG antibody or positive CMV PCR with clinicalmanifestations consistent with active CMV infection) and requiring therapy will beexcluded from participation in the study. Carriers will be monitored perinstitutional guidelines

• Patients should be excluded if they have known active hepatitis B (e.g. hepatitis Bvirus [HBV] surface antigen [HBsAg] reactive) or hepatitis C (e.g. hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Patients with chronic HBV or HCV are defined as patients with positivehepatitis B serology: Patients with a negative HBsAg and a positive hepatitis Bcore antibody (HBcAb) require an undetectable/negative hepatitis Bdeoxyribonucleic acid (DNA) test (e.g. polymerase chain reaction [PCR] test) tobe enrolled, and will require prophylactic antiviral treatment initiated priorto the first dose of study drug, and continued until approximately 6 to 12months after completion of study drug(s)

• 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 andneuropathy

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to duvelisib or nivolumab

• Patients receiving any medications or substances that are strong inhibitors orinducers of CYP3A4 are ineligible to start study therapy. Patients who are on stronginhibitors or inducers of CYP3A4 may start study therapy if discontinued 5 halflives before start of study therapy. Because the lists of these agents areconstantly changing, it is important to regularly consult a frequently-updatedmedical reference. As part of the enrollment/informed consent procedures, thepatient will be counseled on the risk of interactions with other agents, and what todo if new medications need to be prescribed or if the patient is considering a newover-the-counter medicine or herbal product

• Patients with uncontrolled intercurrent illness including, but not limited to,ongoing or active infection, interstitial lung disease or active, non-infectiouspneumonitis, congestive heart failure New York Heart Association (NYHA) grade >= 3,unstable angina pectoris, and cardiac arrhythmia

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Baseline QT interval corrected with Fridericia's method (QTcF) > 500 ms

• Note: Criteria does not apply to subjects with a right or left bundle branchblock

• Pregnant women are excluded from this study because nivolumab and duvelisib have thepotential for teratogenic or abortifacient effects. Because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with nivolumab and duvelisib, breastfeeding should be discontinued if themother is treated with nivolumab and duvelisib. These potential risks may also applyto other agents used in this study

• 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