Duvelisib in Combination With BMS-986345 in Lymphoid Malignancy

Inclusion Criteria:

• Patients must have histologically proven diagnosis of lymphoid malignancy accordingto World health organization (WHO) defined as: a. Mature T cell lymphoma: (i) Peripheral T-Cell lymphoma not otherwise specified (PTCL, NOS) (ii) Anaplastic large T cell lymphoma, ALK +ve (ALCL ALK+) (iii)Anaplastic large T cell lymphoma, ALK +ve (ALCL ALK-) (iv) Angioimmunobastic T celllymphoma (AITL) (v) Enteropathy associated T-cell lymphoma ((EATL) (vi) EstranodalNK T cell lymphoma (ENKTL) b. T-cell Prolymphocytic leukemia c. Aggressive NK-cellleukemia d. Adult T-cell leukemia/lymphoma e. Hepatosplenic T-cell lymphoma f.Primary cutaneous T cell lymphoma: (i) Mycosis fungoides (ii) Primary cutaneousCD30+ve T cell lymphoproliferative disorder (iii) Primary cutaneous peripheral Tcell lymphoma, NOS (iv) Subcutaneous panniculitis-like T-cell lymphoma (v) Primarycutaneous gamma/delta T cell lymphoma (vi) Primary cutaneous CD8+ aggressiveepidermotropic cytotoxic T-cell lymphoma g. Mantle cell lymphoma h. Diffuse large Bcell lymphoma, NOS i. Primary mediastinal large B cell lymphoma j. High grade B celllymphoma, NOS k. High grade B cell lymphoma with myc and bcl2 and/or bcl6rearrangements

• Disease specific eligibility:

1. Mature T cell lymphoma, T cell prolymphocytic leukemia, aggressive NK-cellleukemia, adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma,subcutaneous panniculitis-like T cell lymphoma, primary cutaneous gamma/delta Tcell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxicT-cell lymphoma: Patient must have progressed after one line of therapy andineligible for hematopoietic stem cell transplantation ,or progressed on twolines of therapy with no available curative options per investigatordiscretion.

2. Mantle cell lymphoma: Patients must have progressed after at least two line oftherapy with no available options that would provide clinical benefit perinvestigator discretion. Patients with prior Chimeric Antigen Receptor T cell (CART cells) therapy are allowed .

3. Diffuse large B cell lymphoma NOS, primary mediastinal large B cell lymphoma,high grade B cell lymphoma NOS, high grade B cell lymphoma with myc, bcl2and/or bcl6 rearrangements: Patients must have progressed on at least two linesof therapy with no available options that would provide clinical benefit perinvestigator discretion. Patients with prior Chimeric Antigen Receptor T cell (CART cells) therapy are allowed.

• Patients must have measurable disease with a lymph node or tumor mass > 1.5 cm in atleast one dimension as assessed by computed tomography (CT)

• Patients must be ≥ 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (correspondsto Karnofsky Performance Status [KPS] ≥ 80%).

• Patients must have adequate organ and marrow function as defined in protocol.

• Willingness to avoid pregnancy or fathering children based on the followingcriteria: a. Woman of non-childbearing potential (ie, surgically sterile with ahysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 45 years of age). b. Woman of childbearing potential who has a negative serumpregnancy test at screening and who agrees to take appropriate precautions to avoidpregnancy (with at least 99% certainty) from screening through safety follow-up.Permitted methods that are at least 99% effective in preventing pregnancy (seeAppendix A) should be communicated to the subject and their understanding confirmed. c. Man who agrees to take appropriate precautions to avoid fathering children (withat least 99% certainty) from screening through at least 93 days after the last doseof study treatment. Permitted methods that are at least 99% effective in preventingpregnancy

Exclusion Criteria:

• History of central nervous system lymphoma (either primary or metastatic).

• Allogeneic stem cell transplant within the last 6 months, or autologous stem celltransplant within the last 3 months before the date of the first dose of studytreatment.

• Active graft-versus-host disease

• Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemicsteroids >20 mg of prednisone (or equivalent) once daily (QD)

• Receipt of anticancer medications or investigational drugs within the followingintervals before the first dose of study treatment:a. < 6 weeks for mitomycin-C ornitrosoureas.b. < 4 weeks for immunotherapy.c. < 3 weeks for radiotherapy. d. < 2weeks for any investigational agent or other anticancer medications or equal to 5half lives of the investigational drug, whichever is longer.

• Prior CART cells therapy within 90 days of enrollment or if they have not recoveredfrom CART cells therapy toxicity to grade 1 or less.

• Inadequate recovery from toxicity and/or complications from a major surgery beforethe date of the first dose of study treatment.

• Prior treatment-related toxicities have not resolved to NCI CTCAE v5 ≤ Grade 1before the date of the first dose of study treatment except for stable chronictoxicities (Grade ≤ 2) not expected to resolve (eg, stable Grade 2 peripheralneurotoxicity).

• Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery,immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumorembolization).

• Use or expected use during the study of any prohibited medications, including potentCYP3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is longer)before the date of study treatment administration (see appendix 11.1) in addition toexcluding patients on CYP3A inducers.

• Significant concurrent, uncontrolled medical condition, including, but not limitedto, renal, hepatic, hematological, GI, endocrine, pulmonary, neurological, cerebral,or psychiatric disease.

• Current or previous other malignancy within 3 years of study entry, except curedbasal or squamous cell skin cancer, superficial bladder cancer, prostateintraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive orindolent malignancy without PI approval.

• History of stroke or intracranial hemorrhage within 6 months of the date of studytreatment administration.

• Chronic or current active infectious disease requiring systemic antibiotics,antifungal, or antiviral treatment or exposure to a live vaccine within 30 days ofstudy treatment.

• Known HIV infection or positivity on immunoassay.

• Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjectswith detectable viral load). Positive CMV or EBV result is acceptable withconfirmation of no active infection.

• Hepatitis B (HBV) or hepatitis C (HCV) infection: Subjects with a positive hepatitisB surface antigen [HBsAg] or hepatitis C antibody [HCV Ab] will be excluded.Subjects with a positive hepatitis B core antibody (HBcAb) must have negativehepatitis B virus (HBV) deoxyribonucleic acid (DNA) to be eligible, must receiveprophylaxis with entecavir (or equivalent) concomitant with duvelisib treatment, andmust be periodically monitored for HBV reactivation by institutional guidelines.Investigators who strongly believe that a positive HBcAb is false due to passiveimmunization from previous immunoglobulin infusion therapy should consider therisk-benefit for the patient given the potential for reactivation

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

• Clinically significant cardiac disease, including unstable angina, acute myocardialinfarction, and/or cardiac conduction issues within 6 months of the date of studytreatment administration.

• Current New York Heart Association Class II to IV congestive heart failure oruncontrolled arrhythmia.

• Presence of an abnormal ECG that is clinically meaningful. Screening QTc interval 450 milliseconds is excluded (corrected by Fridericia). In the event that a singleQTc is > 450 milliseconds, the subject may enroll if the average QTc for 3 ECGs is < 450 milliseconds.

• Unable to swallow and retain oral medication, malabsorption syndrome, diseasesignificantly affecting GI function, total resection of the stomach or small bowel,ulcerative colitis, symptomatic inflammatory bowel disease, or partial or completebowel obstruction.

• Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV) at screening

• Known hypersensitivity or severe reaction to duvelisib or BMS-986345 or itsexcipients (refer to the IB).

• History of serious allergic reactions including anaphylaxis and toxic epidermalnecrolysis.

• Currently pregnant or breastfeeding

• Any condition that would, in the investigator's judgment, interfere with fullparticipation in the study, including administration of study treatment andattending required study visits; pose a significant risk to the subject; orinterfere with interpretation of study data.

• Inability to comprehend or unwilling to sign the informed consent form