A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma.

Abstract

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.

• Authors: Tycel Phillips, Paul M Barr, Steven I Park, Kathryn Kolibaba, Paolo F Caimi, Saurabh Chhabra, Edwin C Kingsley, Thomas Boyd, Robert Chen, Anne-Sophie Carret, Elaina M Gartner, Hong Li, Cindy Yu, David C Smith
• Journal: Investigational new drugs (Invest New Drugs) Vol. 37 Issue 2 Pg. 297-306 (04 2019) ISSN: 1573-0646 [Electronic] United States
• PMID: 30132271 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Biomarkers, Tumor
• CD27 Ligand
• CD70 protein, human
• Immunoconjugates
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• Benzodiazepines

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Benzodiazepines (chemistry)
• Biomarkers, Tumor (metabolism)
• CD27 Ligand (antagonists & inhibitors, immunology, metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoconjugates (pharmacokinetics, therapeutic use)
• Lymphoma, B-Cell (drug therapy, immunology, metabolism, pathology)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, immunology, metabolism, pathology)
• Lymphoma, Mantle-Cell (drug therapy, immunology, metabolism, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, immunology, metabolism, pathology)
• Prognosis
• Pyrroles (chemistry)
• Salvage Therapy
• Tissue Distribution