Copanlisib and Gemcitabine in Relapsed/Refractory PTCL

• 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