Duvelisib and Venetoclax in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)

Inclusion Criteria:

• Phase I: Histologically confirmed relapsed/refractory PTCL, except the followinglymphoma subtypes: cutaneous T-cell lymphoma (CTCL) and T-cell-prolymphocyticleukemia (TPLL).

• Phase II: same as phase I

• Disease that has progressed during or relapsed after at least two previoustherapies.

• ECOG performance status ≤ 2

• Adequate hepatic function defined as: o Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upperlimit of normal (ULN), bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due toGilbert's syndrome or of non-hepatic origin

• Adequate renal function as defined by: o Creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula ormeasured by 24 hours urine collection

• Patients must meet the following hematologic criteria at screening, unless they havesignificant bone marrow involvement confirmed on biopsy:

• Absolute neutrophil count ≥ 1500 cells/mm3 (1.5 x 109/L) or ≥ 1000 cells/mm3 (1.5 x 109/L) with bone marrow involvement. Growth factor use is allowed inorder to achieve this

• Platelet count ≥ 50,000 cells/mm3 (50 x 109/L) independent of transfusionwithin 7 days of screening

• Hemoglobin ≥8 g/dL (without transfusion support.)

Exclusion Criteria:

• Phase I and Phase II:

• Patients eligible for Hematopoietic stem cell transplantation (HSCT)

• Cutaneous T-cell lymphoma (CTCL) and T-cell-prolymphocytic leukemia (TPLL)

• Suspected and confirmed central nervous system involvement

• Previous treatment with venetoclax or a PI3K inhibitor.

• Active malignancy other than NHL requiring ongoing therapy, with the exceptionof hormonal therapy (i.e. castration-sensitive prostate cancer stable ontestosterone blockade)

• Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,immunotherapy, biologic therapy, surgery) within 2 weeks of Cycle 1/Day 1 withthe following exceptions:

• For patients on targeted therapies, a washout of least five half-lives isrequired

• Patients who experience clinical deterioration may start therapy after ashorter washout period with prior approval by the PI

• Corticosteroid therapy (prednisone or equivalent <20 mg daily) is allowed

• Patients with multiple basal cell carcinomas that undergo sequential Moh'sexcisions with interim observation

• Allogeneic hematologic stem cell transplant within 6 months of starting studytreatment or active graft vs. host disease (GVHD) requiring treatment orprophylaxiso Patients with a history of an allogeneic stem cell transplant > 6 monthsprior to starting study treatment should be stable, off of immunosuppressionfor at least 2 months.

• Any active systemic infection requiring systemic antibiotics or otheruncontrolled, active infections

• Positive Human immunodeficiency virus (HIV), hepatitis C virus (HCV), orhepatitis B virus (HBV) antibody testo For HCV and HBV, patients with evidence of prior infection also excluded

• Evidence of other clinically significant uncontrolled condition(s) including,but not limited to:

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal)

• Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.Note: subjects with serologic evidence of prior vaccination to HBV (i.e.hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positiveand anti-hepatitis B core (HBc) antibody negative) or positive anti-HBcantibody from intravenous immunoglobulins (IVIG) may participate

• Uncontrolled, not disease-related autoimmune hemolytic anemia or ITP

• History of stroke or intracranial hemorrhage

• History of severe bleeding disorder (hemophilia A or B, von Willebrand disease (VWD)), history of spontaneous bleeding requiring blood transfusions or othermedical intervention, history of life-threatening hemorrhage within 3 months offirst dose.

• Currently active gastrointestinal disease, including colitis, inflammatorybowel disease and diarrhea requiring therapy

• Currently active, clinically significant cardiovascular disease, such asuncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined bythe New York Heart Association Functional Classification; or a history ofmyocardial infarction, unstable angina, or acute coronary syndrome within 6months prior to enrollment

• Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% orchronic stable angina

• Use of Coumadin for anticoagulation (other anticoagulants permitted)

• Lactating or pregnant

• Unable to swallow capsules or malabsorption syndrome, disease significantlyaffecting gastrointestinal function, or resection of the stomach or smallbowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partialor complete bowel obstruction resulting in malabsorption or chronic diarrhea

• Concurrent administration of medications or foods that are strong inhibitors orinducers of CYP3A (see Appendix D)

• Treatment with any of the following within 7 days prior to the first dose ofstudy drug:

• Steroid therapy for anti-neoplastic intent (defined as prednisone or equivalent >20 mg daily)

• Moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see Appendix D forexamples)

• Moderate or strong CYP3A inducers (see Appendix D for examples)

• Administration or consumption of any of the following within 7 days prior tothe first dose of study drug:

• Grapefruit or grapefruit products

• Seville oranges (including marmalade containing Seville oranges)

• Star fruit