Copanlisib and Gemcitabine in Relapsed/Refractory PTCL

NCT ID: NCT03052933

Last Updated: 2022-06-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-01
• Study Completion Date: 2021-07-01

Brief Summary

COPGEM (Copanlisib and Gemcitabine)chemotherapy regimen is proposed as the salvage treatment for relapsed or refractory peripheral T-cell or NK/T-cell lymphomas in this study protocol, which would be expected to be feasible and effective in this group of patients.

Copanlisib (BAY 80-6946), a highly selective and potent class-1 PI3K inhibitor with sub-nanomolar IC50s against PI3Kα and PI3Kδ, has demonstrated activity in relapsed/refractory, aggressive NHLs, suggesting an ORR of 50% for T-cell lymphomas.

Gemcitabine has demonstrated clinical antitumor activity against PTCLs including NK/T-cell lymphomas both as single-agent (ORR 30-50%) and in combination therapy, with limited extramedullary toxicities.

Considering the evidence of activity for both agents against PTCLs, the investigators propose that targeted therapy with copanlisib in combination with gemcitabine will exhibit early elimination of rapidly growing tumor cells and be a rational therapeutic modality for use in relapsed or refractory PTCLs, if the overlapping toxicities can be managed.

Conditions

Mature T-Cell and NK-Cell Neoplasm

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Copanlisib/gemcitabine

Group Type: EXPERIMENTAL

Copanlisib

Intervention Type: DRUG

For phase I study, participants will receive copanlisib (in combination with gemcitabine) IV infusion at a dose of 45 mg or 60 mg on Days 1, 8, and 15 of each 28-day treatment cycle. During phase I study, participants will be treated at the level of 45 mg/dose (level+0), or 60 mg/dose (level+1) of copanlisib. Maximal tolerated dose will be determined by modified 3+3 design including level-1 dose de-escalation.

For phase II study, copanlisib dose level, determined during phase I study, will be administered on Days 1, 8, and 15.

Maximum 6 cycles of gemcitabine and copanlisib combination and subsequent copanlisib monotherapy in participants with ≥ SD to copanlisib and gemcitabine until maximum 12 cycles will be given for this study.

Gemcitabine

Intervention Type: DRUG

For phase I/II study, participants will receive gemcitabine (in combination with copanlisib) IV infusion at fixed dose of 1,000 mg/m2 on Days 1 and 8 of each 28-day treatment cycle until maximum 6 cycles.

Interventions

Copanlisib

For phase I study, participants will receive copanlisib (in combination with gemcitabine) IV infusion at a dose of 45 mg or 60 mg on Days 1, 8, and 15 of each 28-day treatment cycle. During phase I study, participants will be treated at the level of 45 mg/dose (level+0), or 60 mg/dose (level+1) of copanlisib. Maximal tolerated dose will be determined by modified 3+3 design including level-1 dose de-escalation.

For phase II study, copanlisib dose level, determined during phase I study, will be administered on Days 1, 8, and 15.

Maximum 6 cycles of gemcitabine and copanlisib combination and subsequent copanlisib monotherapy in participants with ≥ SD to copanlisib and gemcitabine until maximum 12 cycles will be given for this study.

Intervention Type: DRUG

Gemcitabine

For phase I/II study, participants will receive gemcitabine (in combination with copanlisib) IV infusion at fixed dose of 1,000 mg/m2 on Days 1 and 8 of each 28-day treatment cycle until maximum 6 cycles.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

Consortium for Improving Survival of Lymphoma

OTHER

Sponsor Role: collaborator

Chonnam National University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Deok-Hwan Yang

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Chonnam National University Hwasun Hospital

Hwasun-gun, Jeollanam-do, South Korea

Countries

South Korea

Other Identifiers

COPGEM

Identifier Type: -

Identifier Source: org_study_id