Τίτλος:
Phosphatidylinositol 3-kinase inhibition by Copanlisib in relapsed or refractory indolent lymphoma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-a and -d isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods: In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results: Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade $3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion: PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma. © 2017 by American Society of Clinical Oncology.
Συγγραφείς:
Dreyling, M.
Santoro, A.
Mollica, L.
Leppä, S.
Follows, G.A.
Lenz, G.
Kim, W.S.
Nagler, A.
Panayiotidis, P.
Demeter, J.
Öcan, M.
Kosinova, M.
Bouabdallah, K.
Morschhauser, F.
Stevens, D.A.
Trevarthen, D.
Giurescu, M.
Cupit, L.
Liu, L.
Köchert, K.
Seidel, H.
Peña, C.
Yin, S.
Hiemeyer, F.
Garcia-Vargas, J.
Childs, B.H.
Zinzani, P.L.
Περιοδικό:
Journal of Clinical Oncology
Εκδότης:
American Society of Clinical Oncology
Λέξεις-κλειδιά:
alanine aminotransferase; alkylating agent; aspartate aminotransferase; B lymphocyte receptor; copanlisib; phosphatidylinositol 3 kinase; rituximab; 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide; isoenzyme; phosphatidylinositol 3 kinase; protein kinase inhibitor; pyrimidine derivative; quinazoline derivative; transcriptome, abnormal laboratory result; adult; aged; Akt signaling; alanine aminotransferase blood level; anemia; anorexia; Article; aspartate aminotransferase blood level; B cell lymphoma; blood toxicity; bronchitis; cancer combination chemotherapy; cancer patient; cancer recurrence; cancer survival; colitis; constipation; coughing; diarrhea; diffuse large B cell lymphoma; drug dose reduction; drug efficacy; drug safety; enzyme inhibition; fatigue; female; fever; flu like syndrome; follicular lymphoma; gene expression; human; hyperglycemia; hypertension; lung infection; lymphocytic lymphoma; lymphoplasmacytoid lymphoma; lymphoplasmacytoid lymphoma; maculopapular rash; major clinical study; male; marginal zone lymphoma; molecularly targeted therapy; multiple cycle treatment; nausea; neutropenia; neutrophil count; nodal marginal zone lymphoma; nonhodgkin lymphoma; occlusive cerebrovascular disease; open study; oral mucositis; overall survival; phase 2 clinical trial; pneumonia; priority journal; progression free survival; recurrent disease; refractory indolent nonhodgkin lymphoma; refractory indolent nonhodgkin lymphoma; relapsed indolent nonhodgkin lymphoma; relapsed indolent nonhodgkin lymphoma; respiratory failure; side effect; skin infection; splenic marginal zone lymphoma; thrombocyte count; treatment response; upper respiratory tract infection; Waldenstroem macroglobulinemia; antagonists and inhibitors; clinical trial; enzymology; genetics; middle aged; multicenter study; very elderly, Adult; Aged; Aged, 80 and over; Female; Humans; Isoenzymes; Lymphoma, B-Cell; Male; Middle Aged; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Transcriptome
DOI:
10.1200/JCO.2017.75.4648
