Interim results from a first-in-human study with AMG102, a fully human monoclonal antibody that neutralizes hepatocyte growth factor (HGF), the ligand to c-Met receptor, in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3551-3551 ◽  
Author(s):  
M. S. Gordon ◽  
D. S. Mendelson ◽  
C. Sweeney ◽  
N. Erbeck ◽  
R. Patel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Human Study ◽  
Advanced Solid Tumors ◽  
Met Receptor ◽  
Dose Escalation Study ◽  
Grade 3

3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well tolerated. One pt with non-small cell lung cancer had a grade 3 DLT of dyspnea/hypoxia after the first dose (0.5 mg/kg); a second pt with pancreatic cancer had a grade 3 DLT/serious adverse event of gastrointestinal hemorrhage after the first dose (1 mg/kg). The most frequently reported, treatment-related adverse events (AEs) have been fatigue (13%), constipation (10%), anorexia (6%), nausea (6%), and vomiting (6%). No anti-AMG102 antibodies have been detected. Initial PK analysis indicates approximately linear PK in the dose range of 0.5 to 20 mg/kg. The overall mean (SD) [median] clearance and half-life estimates based on day-1 dosing were 12.1 (5.21) [10.7] mL/hr and 15.4 (5.84) [15.5] days, respectively. Tumor response is described ( Table ). Conclusions: In this study, interim results suggest that AMG102 at doses up to 20 mg/kg appears to be well-tolerated, with preliminary PK data supporting every-2-wk administration. [Table: see text] No significant financial relationships to disclose.

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.

Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 318-318 ◽  
Author(s):  
T. Doi ◽  
N. Fuse ◽  
T. Yoshino ◽  
H. Murakami ◽  
N. Yamamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Best Response ◽  
Grade 3

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]

Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2528-2528 ◽  
Author(s):  
Alex A. Adjei ◽  
Patricia LoRusso ◽  
Antoni Ribas ◽  
Jeffrey Alan Sosman ◽  
Anna C. Pavlick ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Human Study ◽  
Mek Inhibitor ◽  
Investigational Drug ◽  
Advanced Solid Tumors ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Grade 3

2528 Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.

Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3027-3027 ◽  
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Imran Ahmad ◽  
Ola Gaber ◽  
Ihab Eldessouki ◽  
Olugbenga Olanrele Olowokure ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Early Stage ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Late Phase ◽  
Survival Rates ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Grade 3

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]

Safety, tolerability, and pharmacokinetics (PK) of rilotumumab in Japanese patients (pts) with advanced solid tumors.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 130-130
Author(s):  
Toshihiko Doi ◽  
Rui Tang ◽  
Yilong Zhang ◽  
Elwyn Loh ◽  
Richard Lizambri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Dose Escalation Study

130 Background: Rilotumumab (R) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the only known MET receptor ligand. The MET pathway has been identified as a potentially useful target for therapeutic blockade in oncology. R has been studied in multiple phase 2 trials either as monotherapy or combination therapy, including a phase 2 trial in gastric cancer combining R with epirubicin, cisplatin, and capecitabine. A phase 1 study was done to evaluate the safety, tolerability, and PK of R in Japanese pts. Methods: An open-label, dose-escalation study was performed with R at 10 mg/kg (Cohort 1A), escalating to 20 mg/kg (Cohort 1B) if no dose-limiting toxicities (DLTs) were observed. Key eligibility criteria were Japanese pts with unresectable locally advanced or metastatic carcinoma, age ≥ 20 yr, ECOG ≤ 1, and refractory to standard treatment (tx). Pts received R as an intravenous infusion on days 1 and 15 of each 28-day cycle, except for cycle 1 in which the day 15 dose was skipped to facilitate PK analysis. DLTs were evaluated in cycle 1. Results: A total of 9 pts were enrolled (1A, n = 3; 1B, n = 6). No DLTs were noted. As of 17 April 13, tx-emergent AEs were reported in 89% of pts. Tx-emergent AEs occurring in > 1 pt overall were vomiting (33%), diarrhea (22%), decreased hemoglobin (22%), hypoalbuminemia (22%), and nausea (22%). One grade 3 tx-emergent AE was observed (decreased hemoglobin; 10 mg/kg). Tx-related AEs were reported in 56% of pts. One grade ≥ 2 tx-related AE was observed (hypoalbuminemia; 20 mg/kg). 8 pts discontinued R due to disease progression; 1 pt remained on the investigational product. Mean exposure of R (Cmax and AUC) appeared to be doubled as dose increased from 10 to 20 mg/kg. The estimated mean CL was approximately 0.2 mL/hr/kg in both cohorts, suggesting a linear PK from 10 to 20 mg/kg. The terminal half-life of R was about 15 days. Conclusions: R monotherapy had an acceptable safety profile in Japanese pts with advanced solid tumors. These phase 1 safety and PK data support the further evaluation of R combined with chemotherapy in Japanese pts with MET-positive metastatic gastric cancer. Clinical trial information: NCT01791374.

FPA144-001: A first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 140-140 ◽  
Author(s):  
Johanna C. Bendell ◽  
Seema Rogers ◽  
Hong Xiang ◽  
Kristen L. Pierce ◽  
Kartik Krishnan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Study ◽  
Growth Factor Receptor ◽  
Metastatic Gastric Cancer ◽  
Advanced Solid Tumors ◽  
Upper Respiratory Infection ◽  
Gastric Cancer Patients

140 Background: FPA144 is a humanized monoclonal IgG1 antibody directed against the 2b Isoform of thefibroblast growth factor receptor (FGFR2b) that has been glycoengineered to enhance ADCC. Amplification of FGFR2 is found in a number of tumors, including 3 – 9% of gastric cancer, and is associated with poor prognosis. FPA144-001 is a phase 1 study in two parts: Part 1 will evaluate the safety and pharmacokinetics (PK) of FPA144 in patients with solid tumors; Part 2 will evaluate efficacy in gastric cancer patients whose tumors overexpress FGFR2b, as determined by a proprietary test. Here we present early safety and PK results from solid tumor patients treated with FPA144. Methods: A standard 3+3 design was used to assess safety, tolerability and PK of escalating doses of FPA144 in patients with advanced solid tumors (Part 1A) or recurrent/metastatic gastric cancer (Part 1B). Tumor testing for FGFR2gene amplification or FGFR2b overexpression was conducted centrally by a proprietary assay consisting of both FISH and IHC. Results: At the time of data analysis, enrollment of FPA144-001 through the 6mg/kg q2w cohort had been completed. In Part 1A, 13 patients with 8 different tumor types have been enrolled. Patients have been treated for an average of 4 cycles (range 1 – 10, median 2) or 101 days (range 28 – 287, median 43). Nine patients have discontinued the study for progressive disease or lack of clinical benefit; all others continue on study treatment. No dose-limiting toxicities have been observed, and no patients have withdrawn due to an adverse drug reaction. Upper respiratory infection, alopecia and fatigue are the AEs reported in more than one patient; one SAE of dyspnea and pyrexia not related to drug has been reported. PK analysis demonstrates non-linear clearance in doses up to 3mg/kg, likely due to receptor-mediated clearance. Conclusions: FPA144 is a glycoengineered monoclonal antibody directed against FGFR2b that is being developed for the treatment of patients with tumors that overexpress FGFR2b. FPA144 has been safely administered at doses up to 6mg/kg q2w; dose escalation continues. Updated safety, PK and anti-tumor activity will be presented. Clinical trial information: NCT02318329.

A phase I study of q3W R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3590-3590 ◽  
Author(s):  
J. Rodon ◽  
A. Patnaik ◽  
M. Stein ◽  
A. Tolcher ◽  
C. Ng ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Systemic Disease ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Immunosuppressive Agents ◽  
Cell Surface Receptor ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Grade 3

3590 Background: Insulin-like growth factor receptor (IGF-1R) is a tyrosine kinase cell surface receptor overexpressed in cancer cells which mediates the mitogenic and anti-apoptotic actions of IGF, playing a key role in malignant transformation. The safety and pharmacokinetics of 3-weekly administration of R1507, a human monoclonal antibody selective for IGF-1R, were explored in this phase I dose escalation study in patients with advanced solid tumors or lymphomas. Materials and Methods: Multiple ascending doses of R1507 were administered as a 1 hour infusion every 3 weeks until the development of dose-limiting toxicity (DLT) or progressive disease. Inclusion criteria: ECOG PS 0–1, adequate hematologic, hepatic, and renal function, CD4 count >200/μl. Exclusion criteria: infection, immunosuppressive agents, diabetes mellitus, uncontrolled systemic disease, NYHA III/IV CHF. DLT defined as ≥ grade 2 hypersensitivity reaction; ≥ grade 3 non-hematologic toxicity; ≥ grade 2 cardiac toxicity; ≥ grade 3 hematologic toxicity = 7 days, or dose delay > 1 week due to toxicity. Blood samples were collected following 1st dose for non compartmental PK analysis and for future analysis of IGF-1R levels. Results: 21 patients (pts) (M:F 14:7) were enrolled in 1 of 4 dose levels (dose range 1–16 mg/kg). Mean pt age 57 yrs (range: 30–81), mean prior treatments 4.6 (range: 1–9). Mean treatment cycles 2.6 (range: 1- 6). Six pts remain on study. Adverse events (AE) included infection (6 pts), fatigue (4); rash, fever, arthralgia, cough, diarrhoea, abdominal and back pain (3 each). No DLT or serious AEs attributed to study drug were reported. Activity: 10 pts showed stable disease (median 33 days). PK: Clearance (CL) decreased from 812 mL/Day (Coefficient of Variation [CV] =19.9%) in the 1 mg/kg group to 418 mL/Day (CV=46.7%) in the 16 mg/kg group; Volume of distribution was in the range of 4.4 - 5.4 L (CV=10.9–34.8%). T1/2 increased from 4 to 9 days. Conclusions: Treatment with R1507 is tolerable at the dose of 16mg/kg q3W. Treatment-related toxicities are mild and clinically manageable. Decrease in CL across doses levels suggests a saturable elimination pathway. T1/2 value of ∼8 days supports a weekly dosing for future trials. [Table: see text]

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