A single-center, open-label, dose escalation, safety, and pharmacokinetic study of ENMD-1198 administered orally to patients (pts) with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3562-3562
Author(s):  
S. Nallapareddy ◽  
D. Gustafson ◽  
S. Leong ◽  
W. Messersmith ◽  
J. Arnott ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Significant Treatment ◽  
Elimination Half ◽  
Label Dose

3562 Background: ENMD-1198 (2-methoxyestra-1, 3, 5, (10) 16-tetraene-3-carboxamide), an analog of 2-methoxyestradiol (2ME2), has both antiangiogenic and antiproliferative effects in various tumor types. ENMD-1198 inhibits MT polymerization by binding to β-tubulin at the colchicine-binding site and inhibits HIF-1alpha. This Phase 1 study is evaluating the safety of ENMD-1198 to determine the maximum tolerated dose. Methods: Eligible pts had advanced cancer for which no effective therapy exists that is either evaluable by RECIST criteria or tumor markers that could be monitored for clinical benefit. Phase 1 dose escalation in 3+3 design for first 5 cohorts; modified to 1 pt cohorts for subsequent cohorts until Grade 2 treatment related toxicity, and then standard 3+3 design. All pts treated with once daily oral ENMD-1198 in 28-day cycles (with post-treatment drug-free observation period of 7–14 days in Cycle 1 only). Pts are treated until the appearance of significant treatment-emergent toxicities or disease progression (PD) occurs. Results: To date, 27 pts have been enrolled in 12 dose cohorts (range 5 to 550 mg/m2/d). Median age/performance status is 61/1. Total # of treatment cycles to date is 68, with a median of 2 cycles (range <1 to 15 cycles). Most frequent toxicities (all grades, n=22) were pain (77%), fatigue (55%), constipation (36%), neuropathy and nausea (both 32%), and anemia (27%). 4 pts have experienced stable disease (SD) for more than 2 cycles. There have been no objective responses to date. 2 pts experienced dose limiting toxicity with Grade 4 neutropenia in the 550 mg/m2/d cohort. Following drug holiday, pts restarted at 425 mg/m2/d and continued for at least 1–2 more cycles before being removed from study for PD. One pt (neuroendocrine ca pancreas) is experiencing prolonged SD at 60 mg/m2/d >14 cycles and a 2nd pt (prostate ca) experienced SD at 30mg/m2/d for 10 cycles. ENMD-1198 was absorbed rapidly after oral administration. There was a linear relationship between dose and drug exposure as measured by AUC across all doses (5 - 550 mg/m2). The elimination half-life of ENMD- 1198 averaged more than 12 hours after a single dose. Conclusions: DLT was identified at 550 mg/m2/d. Cohort expansion at 425mg/m2/d is ongoing. [Table: see text]

An open-label, dose escalation, safety, and pharmacokinetic study of ENMD-2076 administered orally to patients with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3520-3520 ◽  
Author(s):  
B. R. Bastos ◽  
J. Diamond ◽  
R. Hansen ◽  
D. Gustafson ◽  
J. Arnott ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Preliminary Evidence ◽  
Open Label ◽  
Once Daily ◽  
Number Of Treatment

3520 Background: ENMD-2076, a novel, orally-active antimitotic and antiangiogenic molecule inhibits Aurora A as well as tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and the FGF receptors. This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of ENMD-2076 administered once daily to patients (pts) with advanced cancer. Methods: The dose escalation scheme utilizes 3 (or 4) + 3 (or 2) design. Pts receive ENMD-2076 once daily in 28-day cycles (followed by 7–14 days of rest between cycles 1 and cycle 2 only). Results: 14 pts have been enrolled in 3 dose cohorts (range 60 to 120 mg/m2/d). Median age/performance status is 62/1. The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 to 9 cycles). Most frequent, related toxicities (all grades, n=14) were hypertension (29%), fatigue (21%), proteinuria and diarrhea (both 14%). One pt experienced dose limiting toxicity of Grade 4 hypertension and Grade 3 cholecystitis in the first dose cohort of 60 mg/m2/d. Following drug interruption, the pt restarted at 30 mg/m2/d and continued for 4 additional cycles before being removed for progressive disease. Noncompartmental PK analysis of the first two dose levels shows that the plasma concentration of ENMD-981693 (the active free base of ENMD-2076) is dose- linear, as reflected in AUC and Cmax. The estimated terminal half-life (t1/2) is unaltered regardless of dose; however, t1/2 is approximately 50% greater at steady state than following single dose administration. Four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11–61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). Serum KDR concentrations assayed by ELISA decreased from baseline in all patients on treatment from a mean of 9153 pg/mL (SEM 464.2) at D1 to 6987 pg/mL (SEM 460.0) at D28 (p <0.05). Conclusions: ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers. [Table: see text]

Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study

2015 ◽  
Vol 16 (9) ◽  
pp. 1133-1142 ◽  
Author(s):  
Tony Reid ◽  
Bryan Oronsky ◽  
Jan Scicinski ◽  
Curt L Scribner ◽  
Susan J Knox ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Open Label ◽  
Phase 1 Study ◽  
Label Dose

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

scholarly journals A phase 1/2, open‐label, dose‐escalation study of midostaurin in children with relapsed or refractory acute leukaemia

2018 ◽  
Vol 185 (3) ◽  
pp. 623-627 ◽  
Author(s):  
C. Michel Zwaan ◽  
Stefan Söderhäll ◽  
Benoit Brethon ◽  
Matteo Luciani ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Acute Leukaemia ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Phase 1, open-label, dose-escalation study of sorafenib in combination with eribulin in patients with advanced, metastatic, or refractory solid tumors

2018 ◽  
Vol 81 (4) ◽  
pp. 727-737 ◽  
Author(s):  
Frederik Marmé ◽  
Carlos Gomez-Roca ◽  
Kristina Graudenz ◽  
Funan Huang ◽  
John Lettieri ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

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.

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