Abstract A082: A phase 1, first-in-human, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma

2019 ◽  
Author(s):  
Anthony Tolcher ◽  
Raghad Karim ◽  
Christina Rosas ◽  
Guizhong Liu ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Agonistic Antibody ◽  
Non Hodgkin Lymphoma ◽  
Human Dose

A phase I, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced solid tumors or relapsed/refractory non-Hodgkin lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3105-3105 ◽  
Author(s):  
Li Zhang ◽  
Hongyun Zhao ◽  
Yuxiang Ma ◽  
Xin Zheng ◽  
Ji Jiang ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Systemic Exposure ◽  
Pharmacokinetic Analysis ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Expansion Cohort ◽  
Dose Levels

3105 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody, targeting a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 ligand antagonism and potent cross-linking via FcgRIIb. This phase 1 study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and preliminary efficacy. Methods: Eligible patients with age 18 to 75, ECOG ≤1, measurable lesion received intravenous infusion of ADG106 every 3 weeks for a maximum of 24 months. Accelerated titration was applied in 0.1mg/kg dose level and traditional Fibonacci 3+3 method was applied in 0.5, 1.5, 3.0, 5.0 and 10.0 mg/kg dose levels. A dose-expansion cohort will be started for dose levels that have been proved tolerable and with evidence of clinical or biological activity. Results: Data cutoff at Jan 17 2020, 15 patients [5 adenoid cystic carcinoma (ACC), 5 non-small cell lung cancer (NSCLC), 3 nasopharyngeal carcinoma, 1 malignant pleural mesothelioma and 1 follicular lymphoma] were enrolled and received treatment: 0.1mg/kg (n = 1), 0.5mg/kg (n = 3), 1.5mg/kg (n = 5), 3mg/kg (n = 3), and 5mg/kg (n = 3). Of these 15 patients, 6 with ongoing treatment, 9 discontinued (8 progression disease, 1 lack of clinical benefit). Medium treatment duration was 2 cycles (range 2-8). No dose limiting toxicities were observed. Seven (47%) patients experienced treatment-related AEs (TRAEs): rash (13%), pruritus (13%), nausea (7%), pyrexia (7%), hemoptysis (7%), mouth ulceration (7%), vomiting (7%), chest discomfort (7%), LDH increased (7%). All TRAEs were grade 1, no grade ≥3 occurred. One serious adverse event (anemia, not related) was observed. Pharmacokinetic analysis of ADG106 showed a half-life ranging from 5~10 days, with dose-dependent increase of systemic exposure. Treatment induced anti-drug antibodies were developed in 3 (20%) patients. No objective response was observed among the 14 evaluated patients. Disease control rate was 57% (8 stable disease), tumor shrinkage was observed in 3 (21%) patients (2 ACC, 1 NSCLC). Conclusions: ADG106 is safe and tolerable at doses up to 5 mg/kg in solid tumors and non-Hodgkin lymphoma. The dose expansion cohorts have started at selected doses. Clinical trial information: NCT03802955 .

Anti-CD79B Antibody-Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study

2022 ◽  
pp. clincanres.3261.2021
Author(s):  
Alex F. Herrera ◽  
Manish R. Patel ◽  
John M. Burke ◽  
Ranjana Advani ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Non Hodgkin Lymphoma ◽  
Antibody Drug

Interim analysis of a phase 1, open-label, dose-escalation study of SGN-CD19A in patients with relapsed or refractory B-lineage non-Hodgkin lymphoma (NHL).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 8505-8505 ◽  
Author(s):  
Andres Forero-Torres ◽  
Craig Moskowitz ◽  
Ranjana H. Advani ◽  
Bijal D. Shah ◽  
Ana Kostic ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Interim Analysis ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Label Dose ◽  
B Lineage

scholarly journals Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study

2020 ◽  
Vol 51 (1) ◽  
pp. 70-77
Author(s):  
Tomohiro Kinoshita ◽  
Kiyohiko Hatake ◽  
Kazuhito Yamamoto ◽  
Yusuke Higuchi ◽  
Satsuki Murakami ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Japanese Patients ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma

Abstract Objective A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Methods Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling. Results Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43–7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study. Conclusions This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.

scholarly journals Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

2020 ◽  
Vol 38 (5) ◽  
pp. 1472-1482 ◽  
Author(s):  
Frank Kroschinsky ◽  
Jan Moritz Middeke ◽  
Martin Janz ◽  
Georg Lenz ◽  
Mathias Witzens-Harig ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

Phase 1 study of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in patients with advanced solid tumors: Final results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3075-3075
Author(s):  
Jodi A. Kagihara ◽  
Bradley Corr ◽  
Jose Maria Pacheco ◽  
S. Lindsey Davis ◽  
Christopher Hanyoung Lieu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Significant Inhibition ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Human Dose ◽  
Continuous Dosing

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: A phase 1 dose escalation study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3019-3019
Author(s):  
Jordi Rodon Ahnert ◽  
Cesar Augusto Perez ◽  
Kit Man Wong ◽  
Michael L. Maitland ◽  
Frank Tsai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Urothelial Cancer ◽  
Phase 1 ◽  
Dose Range ◽  
Median Number ◽  
Splicing Factor ◽  
Dose Escalation Study ◽  
Study Objective ◽  
Dose Dependent

3019 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates known to be dysregulated in cancer, including components of the spliceosome machinery. PF-06939999 is a selective small-molecule inhibitor of PRMT5. Here we report the safety, PK, PD, and preliminary activity of PF-06939999 in patients (pts) with selected advanced/metastatic solid tumors. Methods: This phase 1 dose escalation trial (NCT03854227) enrolled pts with solid tumor types marked by potential frequent splicing factor mutations, including advanced/metastatic endometrial cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), urothelial cancer, cervical cancer, or esophageal cancer. PF-06939999 monotherapy was continuously administered orally QD or BID in 28-day cycles. A Bayesian Logistic Regression Model was used to inform dose level decisions. Primary objectives were to assess dose limiting toxicities (DLTs), AEs and laboratory abnormalities. Tumor response was assessed using RECIST v1.1. PK and PD were assessed by determining PF-06939999 plasma concentration after dosing and changes in plasma levels of symmetric di-methyl arginine (SDMA), the product of PRMT5 enzymatic activity. Results: 28 pts received PF-06939999 at doses from 0.5-12 mg daily (QD or BID) during dose escalation. Median number of cycles was 2 (range, 1-13). Most were female (54%) with a median age of 61.5 (range, 32-84) y. Median number of prior therapies was 4. Overall, 4/24 (17%) pts reported DLTs: thrombocytopenia (n=2, 6 mg BID); anemia (n=1, 8 mg QD); and neutropenia (n=1, 6 mg QD). Treatment-related AEs occurred in 24 (86%) pts. Most common (≥20%) treatment-related AEs across all cycles were anemia (43%), thrombocytopenia (32%), dysgeusia, fatigue and nausea (29% each). Grade ≥3 treatment-related AEs included anemia (25%), thrombocytopenia (21%), fatigue, neutropenia and lymphocyte count decreased (4% each). One pt (6mg BID) had Grade 4 treatment-related thrombocytopenia. All cytopenias were dose-dependent and reversible with dose modification. No pts discontinued treatment for treatment-related toxicity. There were no treatment-related deaths. Exposure to PF-06939999 increased with doses in the dose range tested. Plasma SDMA was reduced at steady state (58.4-87.5%), indicating robust PD target inhibition. Two pts had confirmed partial response (HNSCC and NSCLC). 6 mg QD was identified as the recommended monotherapy dose for expansion. Conclusions: PF-06939999 showed dose-dependent and manageable toxicities in this phase 1 dose escalation study. Objective tumor responses were observed in pts with HNSCC and NSCLC. Analysis of archival tissue for the presence of splicing factor mutations and other potential predictive biomarkers is ongoing. Enrollment to part 2 dose expansion is ongoing in pts with NSCLC, HNSCC and urothelial cancer. Clinical trial information: NCT03854227.

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