المؤلفون: Hong Li, David Smith, Thomas E. Boyd, Paul M. Barr, Cindy Yu, Anne Sophie Carret, Steven I. Park, Robert T. Chen, Kathryn S. Kolibaba, Saurabh Chhabra, Tycel Phillips, Edwin C. Kingsley, Paolo Caimi, Elaina M. Gartner

المصدر: Investigational New Drugs

مصطلحات موضوعية: 0301 basic medicine, Male, Immunoconjugates, CD70 antigen, Lymphoma, Mantle-Cell, Gastroenterology, Benzodiazepines, 0302 clinical medicine, hemic and lymphatic diseases, Phase I Studies, Grade 3b Follicular Lymphoma, Pyrrolobenzodiazepine dimer (PBD), Pharmacology (medical), Tissue Distribution, Aged, 80 and over, Antibodies, Monoclonal, Diffuse, large B cell, lymphoma (DLBCL), Middle Aged, Prognosis, Gene Expression Regulation, Neoplastic, Mantle-cell lymphoma, Oncology, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, medicine.symptom, Adult, medicine.medical_specialty, Lymphoma, B-Cell, Maximum Tolerated Dose, Anemia, Nausea, 03 medical and health sciences, Refractory, Internal medicine, medicine, Biomarkers, Tumor, Humans, Pyrroles, Adverse effect, Antibody-drug conjugate, Aged, Pharmacology, Salvage Therapy, business.industry, medicine.disease, Grade 3 follicular lymphoma, Lymphoma, 030104 developmental biology, Drug Resistance, Neoplasm, Mantle cell lymphoma, Neoplasm Recurrence, Local, business, Diffuse large B-cell lymphoma, CD27 Ligand, Follow-Up Studies

الوصف: Summary Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure. Electronic supplementary material The online version of this article (10.1007/s10637-018-0655-0) contains supplementary material, which is available to authorized users.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b4e977ba1b77526f3582de9b9ef2df5cTest
http://europepmc.org/articles/PMC6440937Test

المؤلفون: Amy Kellerman, Eric Laille, Edwin C. Kingsley, Carlos Becerra, Michael R. Savona, Barry S. Skikne, Stacey M. Ukrainskyj, Qian Dong, Paul Conkling, Kathryn S. Kolibaba, Robert M. Rifkin, John C. Morris

المصدر: American Journal of Hematology

مصطلحات موضوعية: Male, medicine.medical_specialty, Antimetabolites, Antineoplastic, Myeloid, Anemia, Gastrointestinal Diseases, Azacitidine, Chronic myelomonocytic leukemia, Administration, Oral, Neutropenia, Gene mutation, Gastroenterology, Drug Administration Schedule, 03 medical and health sciences, Food-Drug Interactions, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Drug Interactions, Fatigue, Research Articles, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, business.industry, Myelodysplastic syndromes, Leukemia, Myelomonocytic, Chronic, Proton Pump Inhibitors, Hematology, Gastric Acidity Determination, DNA Methylation, Middle Aged, medicine.disease, Hematologic Diseases, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Tolerability, Food, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Female, business, 030215 immunology, medicine.drug, Research Article

الوصف: CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS The safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::954945bda5af4f30afbbce27ec2e3ed2Test
https://pubmed.ncbi.nlm.nih.gov/30016552Test