Duvelisib and Venetoclax for the Treatment of Relapsed or Refractory Peripheral T-cell Lymphoma

Inclusion Criteria

• Signed informed consent form
• Age ≥ 18 years
• Histologically confirmed relapsed/refractory PTCL, except the following lymphoma subtypes: cutaneous T-cell lymphoma (CTCL), and T-cell-prolymphocytic leukemia (TPLL). The following histologies are permitted: * Extranodal NK-/T-cell lymphoma, nasal type * Enteropathy-associated T-cell lymphoma * Hepatosplenic T-cell lymphoma * Peripheral T-cell lymphoma, NOS * Angioimmunoblastic T-cell lymphoma * Follicular T-cell lymphoma * Nodal peripheral T-cell lymphoma with TFH phenotype * Anaplastic large-cell lymphoma, ALK+ * Anaplastic large-cell lymphoma, ALK−
• Disease that has progressed during or relapsed after at least two previous systemic therapies
• A measurable node must have a largest diameter (LDi) greater than 1.5 cm. Measurable extranodal disease (e.g. hepatic nodules) may be included. A measurable extranodal lesion should have a LDi greater than 1.0 cm
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Female subjects of childbearing potential must have negative serum pregnancy test result within 14 days prior to initiation of study treatment
• Absolute neutrophil count ≥ 1500 cells/mm^3 (1.5 x 10^9/L) or ≥ 1000 cells/mm^3 (1.5 x 10^9/L) with bone marrow involvement. Growth factor is allowed in order to achieve this (within 14 days prior to initiation of study treatment, unless they have significant bone marrow involvement confirmed on biopsy)
• Platelet count ≥ 50,000 cells/mm^3 (50 x 10^9/L) independent of transfusion within 7 days of screening (within 14 days prior to initiation of study treatment, unless they have significant bone marrow involvement confirmed on biopsy)
• Hemoglobin ≥ 8 g/dL without transfusion support (within 14 days prior to initiation of study treatment, unless they have significant bone marrow involvement confirmed on biopsy)
• Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN) (within 14 days prior to initiation of study treatment)
• Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin) (within 14 days prior to initiation of study treatment)
• Creatinine clearance ≥ 30 mL/min calculated by the Cockcroft Gault formula or measured by 24 hours urine collection (within 14 days prior to initiation of study treatment)
• Women of child-bearing potential must use effective contraception for at least a month after last dose of either drug. Men must use effective contraception for at least 1 month after last dose of duvelisib

Exclusion Criteria

• Patients eligible for hematopoietic stem cell transplantation (HSCT)
• Cutaneous T-cell lymphoma (CTCL) and T-cell-prolymphocytic leukemia (TPLL)
• Suspected or confirmed central nervous system involvement
• Previous treatment with venetoclax or a PI3K inhibitor
• Concurrent active malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix * NOTE: Subjects with previous malignancies are eligible if disease-free for > 2 years
• Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, surgery) within 2 weeks of cycle 1 day 1 with the following exceptions: * For patients on targeted small-molecule therapies, a washout of least five half-lives is required * Patients who experience clinical deterioration may start therapy after a shorter washout period with prior approval by the Data and Safety Monitoring Board (DSMB) and Institutional Review Board (IRB) * Corticosteroid therapy (prednisone or equivalent ≤ 20 mg daily) is allowed
• Prior history of drug-induced colitis or drug-induced pneumonitis
• Unresolved toxicity from prior therapy, except for alopecia and grade ≤ 2 peripheral neuropathy
• Major surgery within 4 weeks prior to screening
• Allogeneic hematologic stem cell transplant within 6 months of starting study treatment or active graft versus (vs.) host disease (GVHD) requiring treatment or prophylaxis * Patients with a history of an allogeneic stem cell transplant > 6 months prior to starting study treatment should be stable, off of immunosuppression for at least 2 months
• Any active systemic infection requiring intravenous (IV) antibiotics or other uncontrolled, active infections
• Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications
• Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV) at screening
• Positive human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) antibody test * 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 positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
• Uncontrolled, not disease-related autoimmune hemolytic anemia or thrombocytopenia (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 other medical intervention, history of life-threatening hemorrhage within 3 months of first dose
• History of tuberculosis treatment within the 2 years prior to start of study treatment
• Administration of a live or live attenuated vaccine within 6 weeks prior to start of study treatment
• Currently active gastrointestinal disease, including colitis, inflammatory bowel disease and diarrhea requiring therapy
• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
• Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina
• Baseline QT interval corrected with Fridericia’s method (QTcF) > 500 ms * NOTE: criterion does not apply to subjects with a right or left bundle branch block (BBB)
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety
• Use of Coumadin for anticoagulation (other anticoagulants permitted)
• Active abuse of alcohol and/or illicit drugs
• Lactating or pregnant
• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction resulting in malabsorption or chronic diarrhea
• Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A
• Treatment with any of the following within 7 days prior to the first dose of study drug: * Steroid therapy for anti-neoplastic intent * Moderate or strong cytochrome P450 3A (CYP3A) inhibitors * Moderate or strong CYP3A inducers
• Administration or consumption of any of the following within 7 days prior to the first dose of study drug: * Grapefruit or grapefruit products * Seville oranges (including marmalade containing Seville oranges) * Star fruit * Preparations containing St John's Wort