Copanlisib and Gemcitabine in Relapsed/Refractory PTCL

Inclusion criteria

• Histologically confirmed relapsed or refractory PTCL or NK/T-cell lymphomas, excluding primary cutaneous T-cell lymphoma, and Sezary syndrome based on WHO classification,
• Age ≥ 19
• ECOG performance status ≤ 2
• at least one bi-dimensional measurable lesion
• Laboratory values

• Serum Cr < 1.5 mg/dL or CrCl > 50 mL/min
• Transaminase (AST/ALT) < 2.5 x ULN (or < 5 x ULN in the presence of lymphoma involvement of the liver)
• Bilirubin < 1.5 x UNL ( or < 3 x ULN in the presence of lymphoma involvement of the liver or Gilbert syndrome)
• PT (INR) ≤ 1.5 x ULN and aPTT ≤ 1.5 x ULN
• Lipase ≤ 1.5 x ULN
• Hematologic functions: absolute neutrophil count (ANC) ≥ 1,500/µL and platelet count ≥ 75,000/µL, hemoglobin ≥ 8 g/dL
• Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal for the institution
• Women of childbearing potential and men must agree to use adequate contraception when sexually active
• Written informed consent

Exclusion criteria

• B-cell NHL, or primary cutaneous T-cell lymphoma and Sezary syndrome
• Patients who had previous history of lymphoma involvement of the CNS.
• History of previous gemcitabine therapy
• Type I or II diabetes mellitus with HbA1c > 8.5% at screening
• History of chronic hepatitis B; subjects positive for HBsAg will be excluded from this study. However, subjects with HBcAb will be eligible if they are negative for HBV DNA quantification
• History of chronic hepatitis C; subjects positive for HCV IgG will be eligible if they are negative for HCV-RNA quantification
• Known history of human immunodeficiency virus (HIV) infection
• History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
• Any other malignancies within the past 3 years except curatively treated basal cell carcinoma of the skin, carcinoma in situ of the uterine cervix, or papillary carcinoma of the thyroid
• Other serious illness or medical conditions

• Congestive heart failure > NYHA class 2 (Appendix III)
• Unstable angina or new-onset angina within the last 3 months; Myocardial infarction within 6 months prior to study entry
• History of significant neurological or psychiatric disorders including dementia or seizure
• Uncontrolled hypertension despite optimal medical management (per investigator's opinion)
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of study treatment
• Non-healing wound, ulcer, or bone fracture
• Active uncontrolled infection (viral, bacterial, or fungal infection)
• Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ grade 3 within 4 weeks of start of study medication
• Proteinuria estimated by urine protein/creatinine ratio > 3.5 on a random urine sample
• Concurrent diagnosis of pheochromocytoma
• Other previous or concurrent treatments

• Ongoing immunosuppressive therapy
• Radiotherapy or immune-/chemotherapy less than 4 weeks before start of treatment
• Radioimmunotherapy or autologous transplant less than 3 months before start of treatment
• Myeloid growth factors within 14 days prior to treatment start
• Blood or platelet transfusion within 7 days prior to treatment start
• Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent
• History of having received an allogeneic bone marrow or organ transplant
• Major surgical procedure or significant trauma injury within 28 days before start of study medication, open biopsy within 7 days before start of study treatment
• Anti-arrhythmic therapy (beta-blockers or digoxin are permitted)
• Use of CYP3A4 inhibitor or inducer
• Pregnant or lactating women, women of childbearing potential not employing adequate contraception
• Concomitant administration of any other experimental drugs under investigation