A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3106-TPS3106 ◽  
Author(s):  
Naiyer A. Rizvi ◽  
Jeffrey R. Infante ◽  
Geoffrey Thomas Gibney ◽  
Erin Marie Bertino ◽  
Sarah A. Cooley ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Adaptive Immunity ◽  
Phase I Study ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Innate And Adaptive Immunity

TPS3106 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.

A phase I dose-escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) administered in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3110-TPS3110 ◽  
Author(s):  
Rachel E. Sanborn ◽  
William Howard Sharfman ◽  
Neil Howard Segal ◽  
F. Stephen Hodi ◽  
Jedd D. Wolchok ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Adaptive Immunity ◽  
Dose Escalation ◽  
Killer Cell ◽  
Primary Study ◽  
Clinical Activity ◽  
Cell Lung Carcinoma ◽  
Innate And Adaptive Immunity

TPS3110 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptor (KIR) and programmed death-1 (PD-1) are immune receptors that down-regulate NK and T cell activity, respectively. Lirilumab, an anti-KIR antibody that potentiates innate immunity, has demonstrated modest side effects in a phase I monotherapy trial. Nivolumab, a PD-1 receptor blocking antibody that potentiates adaptive immunity, has shown clinical activity with various solid tumors in phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity with anti-KIR and anti-PD-1 antibodies could achieve more favorable biologic and clinical activity than either agent alone. Here, we describe a phase I study of lirilumab plus nivolumab in pts with advanced solid tumors, the first collaborative clinical trial being conducted by the International Immuno-Oncology Network (II-ON). Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with any solid tumor, except primary central nervous system tumors, will be enrolled. During cohort expansion, pts (N=16/cohort) with non-small cell lung carcinoma – squamous and non-squamous histology, renal cell carcinoma, melanoma, colorectal carcinoma, or ovarian carcinoma will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity in all pts, and pharmacodynamic effect on tumor infiltrating lymphocyte subsets from melanoma pts. Exploratory objectives include a thorough assessment of innate and adaptive immunity modulation by this combination in peripheral blood and/or tumor specimens, as well as preliminary associations with clinical outcome. As of Feb 1, 2013, three pts have started therapy. Clinical trial registration number: NCT01714739. Clinical trial information: NCT01714739.

A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
Devalingam Mahalingam ◽  
Montaser F. Shaheen ◽  
John Sarantopoulos ◽  
Steven Weitman ◽  
Beppino C. Giovanella ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Poor Correlation ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.

scholarly journals A First-in-Human Phase I Study of MORAb-004, a Monoclonal Antibody to Endosialin in Patients with Advanced Solid Tumors

2014 ◽  
Vol 21 (6) ◽  
pp. 1281-1288 ◽  
Author(s):  
Luis A. Diaz ◽  
Christina M. Coughlin ◽  
Susan C. Weil ◽  
Jean Fishel ◽  
Mrinal M. Gounder ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Advanced Solid Tumors
Sign in / Sign up

Export Citation Format

Share Document