Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors.

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.

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Abstract A216: Results of a phase 1, open-label, dose-escalation study evaluating the safety and tolerability of EZN-3042, a survivin mRNA antagonist, administered with docetaxel (D) in adult patients (Pts) with advanced solid tumors.

10.1158/1535-7163.targ-11-a216 ◽

2011 ◽

Cited By ~ 1

Author(s):

Anthony W. Tolcher ◽

Amita Patnaik ◽

Kyriakos P. Papadopoulos ◽

James Agnew ◽

Francois M. Lokiec ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Adult Patients ◽

Advanced Solid Tumors ◽

Survivin Mrna ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose

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Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2519 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2519-2519 ◽

Cited By ~ 1

Author(s):

Kathleen N. Moore ◽

Johanna C. Bendell ◽

Anthony J. Olszanski ◽

Madhuri Desai ◽

Mendel Jansen ◽

...

Keyword(s):

Monoclonal Antibody ◽

Growth Factor ◽

Solid Tumors ◽

Dose Escalation ◽

Tumor Growth Inhibition ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

Anti Tumor Activity

2519 Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.

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Preliminary safety and pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15001 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15001-e15001

Author(s):

Barbara Hickingbottom ◽

Raphael Clynes ◽

John Desjarlais ◽

Caiyan Li ◽

Ying Ding

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Clinical Symptoms ◽

Standard Of Care ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Heavily Pretreated ◽

Label Dose ◽

Pretreated Patients

e15001 Background: Interim safety and PD data from an ongoing first-in-human, multi-center, open-label dose escalation study of XmAb20717 (XmAb20717-01; NCT03517488) are reported here. The primary objectives were to determine safety, tolerability, and the MTD and/or recommended doses (RDs). Secondary objectives included preliminary anti-tumor activity and PK/PD. Methods: A 3+3 dose escalation design was used to establish an MTD/RD(s) for infusions on Days 1 and 15 of each 28-day cycle. DLT evaluation was based on Cycle 1 through Day 28. Patients with selected solid tumors (in indications both with and without approved checkpoint therapy) who have exhausted standard of care are eligible. Results: As of 05FEB 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313), and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/IV, and 68% had been exposed to checkpoint therapy. XmAb20717 treatment was generally well tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycaemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible. Responses were evaluated based on RECIST 1.1 criteria, and there was 1 CR reported (melanoma, progressed on prior pembrolizumab) at 10 mg/kg (highest dose level). Dose-dependent pharmacodynamic activity consistent with dual PD-1/CTLA-4 blockade was noted, namely a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Table). Conclusions: XmAb20717 is generally safe and has demonstrated PD activity in heavily pretreated patients with selected advanced solid tumors. Dose escalation continues. Clinical trial information: NCT03517488 . [Table: see text]

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