A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Hongming Pan ◽  
Tianshu Liu ◽  
Jason Tsai ◽  
Yapeng Zhao
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Single Agent ◽  
Left Ventricular ◽  
Chinese Patients ◽  
Vegf Receptor ◽  
Advanced Solid Tumors

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]

A phase I dose-escalation and expansion study of JPI-547, a dual inhibitor of PARP/tankyrase in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3113-3113
Author(s):  
Seock-Ah Im ◽  
SeungHwan Lee ◽  
Keun Wook Lee ◽  
Youngjoo Lee ◽  
Joohyuk Sohn ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Dose Range ◽  
Single Agent ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Dual Inhibitor ◽  
Expansion Phase

3113 Background: JPI-547 is an oral inhibitor of PARP 1/2 and Tankyrase 1/2. JPI-547 demonstrated anti-tumor activity in BRCA-deficient xenograft models as a single-agent and in combination with chemotherapy and immune checkpoint inhibitors. Methods: This is the first in human (FIH) phase I study of JPI-547 in patients (pts) with advanced solid tumors. For the dose escalation phase, a 3+3 design was used with 4 doses from 50 to 200 mg QD on 21-day cycles. Primary objectives were to assess safety and tolerability to determine RP2D, and secondary objectives included pharmacokinetics and preliminary antitumor activities. DLT monitoring period was 21 days. Pharmacodynamics and information of HRR mutation were also explored. For the dose expansion phase, pts with documented pathogenic germline or somatic BRCA/HRR mutations were enrolled to assess the preliminary efficacy and safety. Tumor response (RECIST 1.1) was evaluated every 6 weeks. Centralized germline BRCA testing was conducted to confirm pathogenic gBRCA mutations. Results available at the cut-off date of 31-Dec-2020 are presented. Results: For dose escalation phase, 22 pts were enrolled. JPI-547 was well absorbed with Tmax of 0.25-8 h post-dose and apparent half-life of 18-31 h. Mean Cmax and AUC increased proportionally (within the dose range of 50-200 mg). PAR level measured from PBMC was 53% inhibited at Cmax. One DLTs was observed at 100 mg (elevated ALT, G3) and 200 mg (elevated ALT/AST, G3) respectively. MTD was determined as 200 mg after considering DLTs and myelosuppression observed from cycle 2. RP2D was determined to be 150 mg based on the pharmacokinetic data and safety. Thirteen pts (59.1%) had at least one grade 3/4 TRAE and 12 had dose interruption/reduction due to TRAE. The most common ( > 20%) TRAE were anemia, thrombocytopenia and neutropenia. In dose expansion phase, 40 pts were enrolled, and response was evaluable in 39 pts. The best overall responses were 11 confirmed PR (cPR) and 15 SD with ORR of 28.2% (11/39) and DCR of 64.1 % (25/39). The mPFS was 3.5 mos and mDoR was 3.4 mos. At the time of data cut-off, three pts were ongoing as following response and cancer types: cPR (breast, ATMm, 9.0 mos), cPR (NSCLC, gBRCA2m, 3.8 mos) and SD (breast, gBRCAm, 9.3 mos). Five pts (2 ovarian, 3 breast) previously treated with olaparib and discontinued due to progressive disease were enrolled in this JPI-547 trial and one ovarian cancer pt showed cPR with 37% tumor shrinkage. Conclusions: These results demonstrate that JPI-547 is adequately absorbed with acceptable safety profile. Preliminary efficacy results suggest that JPI-547 monotherapy is effective in pts with BRCA/HRR mutation. Further investigation is warranted in pts with solid tumor including PARP inhibitor resistant cases. Clinical trial information: NCT04335604.

scholarly journals A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors

2014 ◽  
Vol 20 (8) ◽  
pp. 2192-2204 ◽  
Author(s):  
Eric Angevin ◽  
Josep Tabernero ◽  
Elena Elez ◽  
Steven J. Cohen ◽  
Rastilav Bahleda ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Interleukin 6 ◽  
Multiple Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 554-554 ◽  
Author(s):  
Patricia LoRusso ◽  
J. Randolph Hecht ◽  
Dung Luong Thai ◽  
Michael J. Hawkins ◽  
Hua Dong ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Lysyl Oxidase ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Tumor Growth And Metastasis ◽  
Line Setting

554 Background: Simtuzumab (SIM) is a monoclonal antibody that inhibits lysyl oxidase like molecule 2 (LOXL2), an extracellular matrix enzyme involved in tumor growth and metastasis. Methods: A phase I dose escalation study evaluated the safety and pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Dose escalation occurred at doses up to 20 mg/kg of SIM every 2 weeks by IV infusion followed by a dose expansion of 20 pts at 10 mg/kg of SIM every 2 weeks. PK was evaluated following the first and fourth doses. In a separate Phase IIa study, 11 pts with KRAS mutant colorectal cancer (CRC) were given SIM at 700 mg IV combined with FOLFIRI every 2 weeks in the 2nd line setting. All pts continued until disease progression or unacceptable toxicity. CT or MRI was performed every 8 weeks. Results: In the phase I study, 12 pts (3 per cohort) received SIM at doses of 1, 3, 10 and 20 mg/kg. Tumor types included CRC (5), pancreatic neuroendocrine (PNE, 1), and other tumors (1 each). In the dose expansion, 20 CRC pts (11 KRAS mutant and 9 KRAS wild-type) received SIM at 10 mg/kg. Treatment-emergent AEs (TEAEs) included fatigue and constipation. No DLTs or drug-related SAEs were observed. The mean terminal T1/2 was ~20 days, and exposure was dose proportional between 1 and 20 mg/kg. Decreased tumor size (-56% for PNE and -17%, -8%, -5%, -5%, and -4% for CRC) as measured by the sum of the linear diameter of the target lesions was observed in 6 pts following treatment with SIM alone. In the Phase IIa trial of SIM/FOLFIRI, the most common TEAEs were diarrhea, fatigue, and nausea. Median PFS was 7.8 months. Conclusions: SIM was well tolerated as a single agent and when combined with FOLFIRI and showed promising efficacy in pts with CRC. A randomized, double-blind, placebo controlled phase II study in KRAS mutant CRC pts is ongoing. Clinical trial information: NCT01323933.

Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3640-3640
Author(s):  
Filip Janku ◽  
Elena Elez ◽  
Gopa Iyer ◽  
Noboru Yamamoto ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Mapk Pathway ◽  
Single Agent ◽  
Human Study ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Grade 3

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

scholarly journals Phase I Dose‐Escalation Study of Ramucirumab in Chinese Patients with Advanced Solid Tumors

2017 ◽  
Vol 22 (6) ◽  
pp. 638 ◽  
Author(s):  
Junning Cao ◽  
Dongmei Ji ◽  
Zhiyu Chen ◽  
Weina Shen ◽  
Jin Wang ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Chinese Patients ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3023-3023 ◽  
Author(s):  
Carlos Becerra ◽  
Jeffrey R. Infante ◽  
Lawrence E. Garbo ◽  
Michael S. Gordon ◽  
David A. Smith ◽  
...  
Keyword(s):  
Growth Factors ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Post Dose

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with bevacizumab (BEV) for advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Lee S. Rosen ◽  
Francisco Robert ◽  
Daniela Matei ◽  
Jonathan Wade Goldman ◽  
David S. Mendelson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Cell Cancer ◽  
Single Agent ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials

3059 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, PK and preliminary efficacy of TRC105 in combination with BEV. Methods: Pts with advanced solid tumors, ECOG PS 0-1, and normal organ function were treated with escalating doses of IV TRC105 (3, 6, 8 or 10 mg/kg/wk) plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk. Results: Thirty one pts (median age = 62; M:F 14:17; median 4 prior regimens; primarily metastatic colorectal or ovarian cancer) were treated with TRC105 wkly + BEV. TRC105 3 mg/kg wkly + 15 mg/kg q3wk BEV was well tolerated. Concurrent administration of TRC105 6 mg/kg wkly + 15 mg/kg BEV q3wk resulted in headaches in 4 of 5 pts on cycle 1 day 1 (two grade 3). Dose escalation to the recommended single-agent phase II dose of 10 mg/kg TRC105 weekly + BEV (10 mg/kg q2wk) was tolerated when the initial TRC105 dose was introduced one week after BEV dosing and administered over 2 days. Headache was the only serious adverse drug reaction observed. Adverse events characteristic of each individual drug were not increased in frequency or severity. Target TRC105 serum concentrations were achieved at 6 mg/kg. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed beginning at 6 mg/kg and was dose proportional. Five of 19 heavily pretreated, BEV or VEGF receptor tyrosine kinase inhibitor (TKI) refractory pts with colorectal and ovarian cancer, each with marked tumor burden, experienced radiographic reductions in tumor volume (10-17%). Three of these patients remained on study longer than the prior VEGF inhibitor treatment and two are ongoing. Seven ongoing patients have been treated for 2-8 months. Conclusions: TRC105 10 mg/kg wkly was well tolerated with BEV 10 mg/kg q2wk. The combination demonstrated activity in BEV and VEGF TKI refractory pts. Randomized phase II trials of BEV +/- TRC105 have commenced in renal cell cancer and glioblastoma. Clinical trial information: NCT01332721.

scholarly journals First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors

2021 ◽  
Vol 39 (2) ◽  
pp. 145-154
Author(s):  
Richard D. Baird ◽  
Constanza Linossi ◽  
Mark Middleton ◽  
Simon Lord ◽  
Adrian Harris ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Single Agent ◽  
Human Study ◽  
Drug Candidate ◽  
Advanced Solid Tumors ◽  
Open Label

PURPOSE A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.

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