A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2577-2577
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Bo Gao ◽  
Kate Wilkinson
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Gastroesophageal Junction Cancer ◽  
Anti Cancer ◽  
Ongoing Phase

2577 Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
Jermaine Coward ◽  
Afaf Abed ◽  
Adnan Nagrial ◽  
Ben Markman
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Febrile Episodes ◽  
Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

scholarly journals A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000530 ◽  
Author(s):  
Aung Naing ◽  
Justin F Gainor ◽  
Hans Gelderblom ◽  
Patrick M Forde ◽  
Marcus O Butler ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Wide Range ◽  
Tumor Types ◽  
Tumor Biopsies

BackgroundSpartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration numberNCT02404441.

Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2617-2617
Author(s):  
Todd Michael Bauer ◽  
Jeffrey R. Infante ◽  
Ramesh K. Ramanathan ◽  
Glen Weiss ◽  
Jasgit C. Sachdev ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Hsp90 Inhibitor ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Two Phase ◽  
Blurry Vision

2617 Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX-2112 and SNX-5422. Methods: Two phase 1, open-label, 3 + 3 dose-escalation studies evaluated SNX-5422 when given daily (QD) or every-other-day (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.

A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumors.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2574-2574
Author(s):  
Jordan Berlin ◽  
Ramesh K. Ramanathan ◽  
John H. Strickler ◽  
Deepa Suresh Subramaniam ◽  
Herbert Hurwitz ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study
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