A phase I dose finding study of E7080 in patients (pts) with advanced malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14073-14073 ◽  
Author(s):  
H. Glen ◽  
D. Boss ◽  
T. R. Evans ◽  
M. Roelvink ◽  
J. M. Saro ◽  
...  
Keyword(s):  
Phase I ◽  
Umbilical Vein ◽  
Dose Schedule ◽  
Hepatic Function ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Tube Formation ◽  
Dose Finding ◽  
Advanced Malignancies

14073 Background: E7080 is a potent inhibitor of the split-kinase family of transmembrane growth factor receptors including Flt-1 and KDR. In addition, E7080 also potently inhibits FGFR1 and PDGFRβ tyrosine kinase activities. In an in vitro angiogenic model, E7080 inhibited VEGF-driven umbilical vein endothelial cell (HUVEC) proliferation and tube formation. Using H460 and Colo205 mouse xenograft models, E7080 significantly inhibited tumor growth at doses from 1 to 100 mg/kg. Methods: A Phase I and pharmacologic study was conducted to determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of E7080 in pts with advanced malignancies. Eligible pts with adequate hematologic, renal and hepatic function, and with tumors refractory to standard therapies, were treated with E7080 administered orally on a once daily continuous dose schedule in cycles of 4 weeks. Dose escalation was performed according to an accelerated design of 100% dose increases in subsequent cohorts until the first patient experienced ≥ CTC grade 2 toxicity. Results: As of November 17th, 2006, 37 pts with documented progressive disease (PD) have been treated at the following dose levels: 0.2 mg/d, 0.4 mg/d, 0.8 mg/d, 1.6 mg/d, 3.2 mg/d, 6.4 mg/d, 12.5 mg/d and 16 mg/d. Median number of cycles was 1 (0–11). Median age = 60 years (25–84), 20 pts were male, 17 were female. 37 pts were evaluable for toxicity. 1 patient experienced grade 3 hypertension (DLT) in the 16 mg/d cohort, other related toxicities ≥ grade 2 include hemorrhage and thrombosis (n=1), tachycardia (n=1), febrile neutropenia (n=1), proteinuria (n=1), thrombocytopenia (n=1) and hypertension (n=1). MTD has not been reached and this study is continuing to recruit. 24 pts were evaluable for efficacy, 3 are too early to evaluate. 1 patient had a partial response (high grade sarcoma) after 2 cycles, and 15 pts experienced stable disease from 2+ to 11 months, and 11 pts continue on therapy. Pharmacokinetic (PK) studies: preliminary data suggest that the PK is linear over the range 0.2 mg/d to 12.5 mg/d. Conclusions: E7080 is safe and well tolerated at doses acheived so far and has shown promising first signs of anti-cancer activity associated with potent activity in pre-clinical models. Clinical and PK data from subsequent doses and follow- up will be presented. No significant financial relationships to disclose.

A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12008-12008 ◽  
Author(s):  
J. J. Hwang ◽  
J. L. Marshall ◽  
S. Malik ◽  
H. Chun ◽  
T. Ahmed ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Tumor Measurements ◽  
Grade 3

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]

Novel organic arsenic molecule darinaparsin: Development of IV and oral forms

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8501-8501 ◽  
Author(s):  
I. Lossos ◽  
M. D. Craig ◽  
M. S. Tallman ◽  
R. V. Boccia ◽  
P. R. Conkling ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Complete Response ◽  
Median Number ◽  
Two Phase ◽  
Phase I Studies ◽  
Advanced Malignancies

8501 Background: Darinaparsin (ZIO-101) is a novel organic arsenical active against diverse cancers in vitro, and in vivo. Darinaparsin i.v. activity in lymphoma is being evaluated in a phase II study. Darinaparsin is orally bioavailable; the oral form is being investigated in two phase I studies in patients with advanced malignancies. Methods: Phase II trial is being conducted in patients diagnosed with advanced lymphomas who had ≥ 1 prior therapy. Patients receive 300 mg/m2/day of darinaparsin i.v. for 5 consecutive days every 28 days. Efficacy and safety are evaluated by standard criteria. Phase I oral dose escalation studies are being conducted in patients with advanced malignancies and explore safety, MTD, DLTs and preliminary efficacy of continuous and intermittent dosing schedules. Starting continuous dose is 100 mg BID for 3 weeks with 1 week rest, starting intermittent dose is 300 mg twice weekly for 3 weeks followed by 1 week rest. Results: The phase II study has accrued 28 lymphoma patients (21 non-Hodgkin's, 7 Hodgkin's); median age at baseline 61 years, ECOG ≤2, median number of prior therapies 3. Seventeen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 subject (PTCL) has achieved a complete response, 3 - partial responses (2 marginal zone, 1 Hodgkin's), and 4 stable disease (2 PTCL, 1 DLBCL, 1 Hodgkin's). A total of 63 cycles of darinaparsin have been administered to subjects with lymphoma. No Gr. 3 or higher drug-related AEs were reported. Two SAEs were considered possibly drug-related (fall; neutropenic fever). Phase I studies accrued 35 patients; median age at baseline 58 years, ECOG ≤2, median number of prior therapies 3. Predominant tumor types include: colorectal (17), pancreatic (3), NHL (3). Current darinaparsin dose levels: continuous 200 mg BID, 2× weekly 900 mg. Of 18 patients evaluable for efficacy, 10 demonstrate SD ≥ 3 cycles. Oral darinaparsin bioavailability is 58%. Drug-related AEs include nausea/vomiting, fatigue, decreased appetite/anorexia. Conclusions: Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been very well tolerated. Oral darinaparsin is also well tolerated, and shows early activity. [Table: see text]

A Phase I, Multi-Center, Dose Escalation Study of Atiprimod in Patients with Refractory or Relapsed Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 111-111 ◽  
Author(s):  
Michael Wang ◽  
Moshe Talpaz ◽  
Sundar Jagannath ◽  
Asher Alban Chanan-Khan ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Treated Group ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
M Proteins ◽  
Dose Levels

Abstract Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.

Phase I dose-finding and pharmacokinetic study of a combination of elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3093-3093
Author(s):  
Sanjay Goel ◽  
Teresa Moran ◽  
Cinthya Coronado ◽  
Santiago Viteri Ramirez ◽  
Imran Chaudhary ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Standard Dose ◽  
Therapeutic Option ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Grade 3

3093 Background: E is a new marine compound that has shown synergism with T in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines. Based on these findings, a phase I clinical trial was undertaken to identify the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary objectives were evaluation of safety and feasibility, PK and preliminary efficacy results. Methods: Patients (pts) with advanced solid tumors with no standard therapeutic option were recruited. Cohorts of 3-6 pts were included at each dose level (DL), with escalating doses of E in increments of 25-50% according to toxicities, and 2 different T doses (100 and 150 mg/day). Results: Thirty pts (median age, 57 years; 19 females) were evaluable. Main tumor types included NSCLC, colorectal, melanoma, and ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg + T 100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin increase) was observed at DL3 (E 0.75 mg + T 150 mg). Another DLT (dose omissions due to ALT increase) was found at DL6 (E 2.25 mg + T 100 mg). Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%), rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis (17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4 pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological abnormalities were observed. Most toxicities were related to T; therefore, T dose was reduced to 100 mg/day. No PK interaction between E and T was observed. No objective responses were reported. Six pts attained stable disease >3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1 invasive thymoma). Conclusions: E + T was a manageable combination; however, the difficulty of combining E with the standard dose of T (150mg) and the lack of activity made this combination unattractive for further development in the current schedule. Possibly, other schedules may demonstrate more efficacy.

A Phase I Study of OMN54 (Aneustat™) in Patients with Advanced Malignancies

2020 ◽  
Vol 7 (2) ◽  
pp. 125-132
Author(s):  
Karen A. Gelmon ◽  
Christian Kollmannsberger ◽  
Stephen Chia ◽  
Anna V. Tinker ◽  
Teresa Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Salvia Miltiorrhiza ◽  
Performance Status ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Advanced Malignancies ◽  
Gi Toxicity ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

Background/Objective: With the increasing interest in natural products, a phase I openlabel study of OMN54 (Aneustat™) in patients with advanced malignancies was initiated to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent, combining three Chinese botanicals; Ganoderma lucidium, Salvia miltiorrhiza and Scutellaria barbata. Methods: Eligible patients (pts) were >18 years of age with advanced solid tumors, able to swallow oral capsules, ECOG performance status < 2, measurable disease as defined by RECIST 1.1 and adequate organ function. Results: Twenty-two patients were enrolled in 6 dose levels, 2 with daily dosing and 4 with twicedaily dosing ranging from 1 to 5 grams daily. All were evaluated for toxicity and 20 for response. No treatment-related dose-limiting toxicities (DLTs) were reported and the recommended phase II dose (RP2D) was determined to be 2.5 g twice daily. Seven adverse events in 5 patients were reported as possibly drug-related; 6 were GI toxicity and 1 was a skin disorder. All were grade 1 except one grade 2 vomiting. No RECIST responses were seen. Six pts were treated with > 2 cycles; one for 8 cycles. Four patients had reductions in TGF –β and EGF, exploratory biomarkers possibly suggestive of a drug effect. Plasma half-lives of 1 -2 hours were noted for all parent drug chemical markers with no accumulation over time. Conclusion: OMN54 was well tolerated, with no DLTs observed. Further studies at the RP2D will assess the biological activity.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

scholarly journals SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

2015 ◽  
Vol 35 (3) ◽  
pp. 875-884 ◽  
Author(s):  
Hongyuan Song ◽  
Dongyan Pan ◽  
Weifeng Sun ◽  
Cao Gu ◽  
Yuelu Zhang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Annexin Ii ◽  
Mmp9 Expression ◽  
Cell Arrest ◽  
Umbilical Vein Endothelial Cells

Background/Aims: Annexin II receptor (AXIIR) is able to mediate Annexin II signal and induce apoptosis, but its role in angiogenesis remains unclear. This study tries to investigate the role of AXIIR in angiogenesis and the plausible molecular mechanism. Methods/Results: RNA interference technology was used to silence AXIIR, and the subsequent effects in vitro and in vivo were evaluated thereafter. Our data indicated that human umbilical vein endothelial cells (HUVECs) expressed AXIIR and knockdown of AXIIR significantly inhibited HUVECs proliferation, adhesion, migration, and tube formation in vitro and suppressed angiogenesis in vivo. Furthermore, AXIIR siRNA induced cell arrest in the S/G2 phase while had no effect on cell apoptosis. We found that these subsequent effects might be via suppressing the expression of matrix metalloproteinase 2and matrix metalloproteinase 9. Conclusion: AXIIR participates in angiogenesis, and may be a potential therapeutic target for angiogenesis related diseases.

A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade

2012 ◽  
Vol 123 (3) ◽  
pp. 147-159 ◽  
Author(s):  
Ting-Hsing Chao ◽  
Shih-Ya Tseng ◽  
Yi-Heng Li ◽  
Ping-Yen Liu ◽  
Chung-Lung Cho ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
No Production ◽  
Angiogenic Effect

Cilostazol is an anti-platelet agent with vasodilatory activity that acts by increasing intracellular concentrations of cAMP. Recent reports have suggested that cilostazol may promote angiogenesis. In the present study, we have investigated the effect of cilostazol in promoting angiogenesis and vasculogenesis in a hindlimb ischaemia model and have also examined its potential mechanism of action in vitro and in vivo. We found that cilostazol treatment significantly increased colony formation by human early EPCs (endothelial progenitor cells) through a mechanism involving the activation of cAMP/PKA (protein kinase A), PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial NO synthase) and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) signalling pathways. Cilostazol also enhanced proliferation, chemotaxis, NO production and vascular tube formation in HUVECs (human umbilical vein endothelial cells) through activation of multiple signalling pathways downstream of PI3K/Akt/eNOS. Cilostazol up-regulated VEGF (vascular endothelial growth factor)-A165 expression and secretion of VEGF-A in HUVECs through activation of the PI3K/Akt/eNOS pathway. In a mouse hindlimb ischaemia model, recovery of blood flow ratio (ipsilateral/contralateral) 14 days after surgery was significantly improved in cilostazol-treated mice (10 mg/kg of body weight) compared with vehicle-treated controls (0.63±0.07 and 0.43±0.05 respectively, P<0.05). Circulating CD34+ cells were also increased in cilostazol-treated mice (3614±670 compared with 2151±608 cells/ml, P<0.05). Expression of VEGF and phosphorylation of PI3K/Akt/eNOS and ERK/p38 MAPK in ischaemic muscles were significantly enhanced by cilostazol. Our data suggest that cilostazol produces a vasculo-angiogenic effect by up-regulating a broad signalling network that includes the ERK/p38 MAPK, VEGF-A165, PI3K/Akt/eNOS and cAMP/PKA pathways.

scholarly journals Novel Nargenicin A1 Analog Inhibits Angiogenesis by Downregulating the Endothelial VEGF/VEGFR2 Signaling and Tumoral HIF-1α/VEGF Pathway

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 252
Author(s):  
Jang Mi Han ◽  
Ye Seul Choi ◽  
Dipesh Dhakal ◽  
Jae Kyung Sohng ◽  
Hye Jin Jung
Keyword(s):  
Capillary Tube ◽  
Umbilical Vein ◽  
Hypoxia Inducible Factor ◽  
Chorioallantoic Membrane ◽  
Tube Formation ◽  
Ags Cells ◽  
Vegf Pathway ◽  
Vegfr2 Signaling

Targeting angiogenesis is an attractive strategy for the treatment of angiogenesis-related diseases, including cancer. We previously identified 23-demethyl 8,13-deoxynargenicin (compound 9) as a novel nargenicin A1 analog with potential anticancer activity. In this study, we investigated the antiangiogenic activity and mode of action of compound 9. This compound was found to effectively inhibit in vitro angiogenic characteristics, including the proliferation, invasion, capillary tube formation, and adhesion of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF). Furthermore, compound 9 suppressed the neovascularization of the chorioallantoic membrane of growing chick embryos in vivo. Notably, the antiangiogenic properties of compound 9 were related to the downregulation of VEGF/VEGFR2-mediated downstream signaling pathways, as well as matrix metalloproteinase (MMP)-2 and MMP-9 expression in HUVECs. In addition, compound 9 was found to decrease the in vitro AGS gastric cancer cell-induced angiogenesis of HUVECs by blocking hypoxia-inducible factor-1α (HIF-1α) and VEGF expression in AGS cells. Collectively, our findings demonstrate for the first time that compound 9 is a promising antiangiogenic agent targeting both VEGF/VEGFR2 signaling in ECs and HIF-1α/VEGF pathway in tumor cells.

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