Phase I evaluation of orally-administered CYT997, a novel cytotoxic vascular-disrupting agent, in patients with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3568-3568
Author(s):  
A. Francesconi ◽  
D. Kotasek ◽  
M. Burge ◽  
G. Smith ◽  
J. Lickliter
Keyword(s):  
Phase I ◽  
Oral Absorption ◽  
Disease Stabilisation ◽  
Preliminary Evidence ◽  
Microtubule Assembly ◽  
Vascular Disrupting Agent ◽  
Dce Mri ◽  
Mri Scans ◽  
Grade 3 ◽  
Vascular Disrupting

3568 Background: CYT997 is a novel, small-molecule vascular disrupting agent which binds tubulin and inhibits microtubule assembly. The compound demonstrates potent antitumour and vascular-disrupting activity in preclinical models. A phase I study of CYT997 given by intravenous infusion showed favourable safety and tolerability, pharmacokinetics and preliminary evidence of pharmacodynamic activity. Unlike most other VDAs, CYT997 is orally available and a phase I dose-ranging study with oral capsule dosing is underway. Methods: CYT997 was administered orally every 2 weeks to patients with advanced solid tumours. Doses were escalated using an accelerated phase I design to cohort 6 and thereafter with a standard 3+3 design. Pharmacodynamic effects on tumour vasculature were assessed with DCE-MRI scans, circulating endothelial cell (CEC) assays and von Willebrand factor (vWF) plasma levels. Results: 21 patients (M/F: 16/5; median age 63, range 48–77) have been treated on study. A total of 56 cycles of CYT997 have been administered (median 2/patient, range 1–7) over 8 dose levels (15 - 164 mg/m2). Doses up to 118 mg/m2 were well tolerated. However, dose-limiting toxicities were observed at 164 mg/m2, consisting of grade 3 hypoxia in one patient and grade 3–4 asthenia in two patients. The grade 3 hypoxia was reversible. PK profiles revealed favourable oral absorption which was generally dose-linear. DCE-MRI assessments indicating significant changes in tumour Ktrans values consistent with vascular disruption were observed in 6 of 10 currently evaluated patients. No objective tumour responses were seen; however, disease stabilisation for six weeks or greater was observed in 13 patients. vWf and CEC analysis is currently ongoing. Conclusions: Orally-administered CYT997 is well tolerated at doses associated with vascular targeting activity. Moreover, its good oral bioavailability suggests the potential for novel administration schedules, including metronomic dosing. [Table: see text]

Pharmacokinetic and pharmacodynamic results of a 4-hr IV administration phase I study with EPC2407, a novel vascular disrupting agent

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3569-3569 ◽  
Author(s):  
W. L. Read ◽  
P. Rosen ◽  
P. Lee ◽  
S. Anthony ◽  
R. Korn ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Phase I Study ◽  
Vascular Disrupting Agent ◽  
Dce Mri ◽  
St Depression ◽  
Single Isomer ◽  
Apoptotic Activity ◽  
Clear Clinical Benefit ◽  
Vascular Disrupting

3569 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor with vascular disrupting and apoptotic activity at nanomolar concentrations. In an earlier phase I study dosing by 1 hr infusions daily x3 on a 21 day cycle, DLT at 21 mg/m2 was pain at tumor sites and vasoconstriction with increases of BP and QTc. MTD was 13 mg/m2 over 1 hr (ASCO 2008, Abst 2531). All drug-related toxicities resolved within an hour of stopping the infusion. Prolonged infusion of EPC2407 to extend exposure of tumor vasculature was designed with administration of EPC2407 over 4 hrs for 3 consecutive days of a 21 day cycle. Eleven patients have received this schedule and their cancers included leiomyosarcoma, colo-rectal, ovary, hepatocellular (2), NSCLC, pancreas, carcinoid, hemangiopericytoma, larynx and small bowel. Results: Doses escalated from 13 to 30 mg/m2 over 4 hours, with MTD determined to be 24 mg/m2. DLTs at 30 mg/m2 were similar to those seen in the 1 hr infusion, with pain at tumor sites in 1 participant and asymptomatic ST depression in a second. Other toxicities were also similar and included transient hypertension. QTc increases were not significant and no new toxicities were encountered. T1/2 with 4 hr infusion was ∼2hr, also seen with 1 hr infusion. AUC and Cmax values were similar to that predicted from the 1 hr data except AUC at 13 mg/m2 was lower than expected. DCE-MRI was done at baseline and after infusion on day 3, cycle 1. Analysis to date of DCE-MRI data of 4 patients showed a median decrease of 40% in both tumor permeability (Ktrans) and tumor perfusion volume (Vp). The two patients with hepatocellular carcinoma had notable stable disease and clear clinical benefit. Both patients received 18 mg/m2 dose, with one receiving 7 cycles over 5 months, and the other still on study (cycle 6) with stable disease for at least 4 cycles. Conclusions: EPC2407 shows clinical promise, with infusion-associated toxicities characteristic of the VDA drug class but without sustained or cumulative toxicity. Studies combining EPC2407 with conventional cytotoxic/cytostatic regimens are being designed. [Table: see text]

Phase I study of CYT997, a novel cytotoxic and vascular disrupting agent, given as a 24-hour intravenous infusion to patients with advanced solid tumours

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14115-14115 ◽  
Author(s):  
J. Lickliter ◽  
G. Smith ◽  
M. Burge ◽  
A. Coulthard ◽  
D. Wyld ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Central Venous Access ◽  
Tumour Response ◽  
Venous Access ◽  
Microtubule Assembly ◽  
Vascular Disrupting Agent ◽  
Dose Levels ◽  
Vascular Disrupting

14115 Background: CYT997 is a novel tubulin-binding small molecule which inhibits microtubule assembly and also demonstrates potent vascular-disrupting activity in preclinical tumour models. Methods: CYT997 was administered by continuous infusion over 24 hours every 3 weeks to patients with advanced cancer. Dose escalation proceeded by a standard phase I design (3 patients per dose level) for the first 18 patients; subsequently, an accelerated titration design (1 patient per dose level) was utilized. Intrapatient dose escalation was permitted. Pharmacokinetic (PK) analyses were performed in the first cycle. Tumour response was determined every second cycle using RECIST criteria. Pharmacodynamic effects on the tumour vasculature were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 22 patients (M/F: 11/11; median age 57.5, range 28–75) were enrolled with tumour types including melanoma (4), renal cell (4), colorectal (2), non-small cell lung (2) and adenoid cystic (2) carcinomas, mesothelioma (2) and others (6). A total of 66 cycles of CYT997 were administered (median 2/patient, range 1–6) over 10 dose levels (7, 14, 23, 35, 49, 65, 86, 114, 152 and 202 mg/m2). No dose-limiting toxicity was observed. Because of grade-2 injection site reactions in 2 patients (one each at dose levels 3 and 4), all subsequent patients received CYT997 via a central venous access device. Other toxicities included grade-2 renal toxicity at dose- level 8 in one patient with abnormal baseline renal function and grade-1 QTc prolongation in one patient at dose-level 10. No myelosuppression, gastrointestinal toxicity or clinically-significant cardiac toxicity were observed. PK data revealed dose-related increases in Cmax and AUC values. Six patients had stable disease after 4 cycles of CYT997. Conclusions: CYT997 was well tolerated at the doses studied and accrual to the 269 mg/m2 dose level will now proceed. No significant financial relationships to disclose.

scholarly journals Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

2010 ◽  
Vol 103 (5) ◽  
pp. 597-606 ◽  
Author(s):  
J D Lickliter ◽  
A B Francesconi ◽  
G Smith ◽  
M Burge ◽  
A Coulthard ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

scholarly journals Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

2013 ◽  
Vol 19 (17) ◽  
pp. 4832-4842 ◽  
Author(s):  
Cristiana Sessa ◽  
Patricia Lorusso ◽  
Anthony Tolcher ◽  
Françoise Farace ◽  
Nathalie Lassau ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

Phase I Study of AVE9633, an AntiCD33-Maytansinoid Immunoconjugate, Administered as an Intravenous Infusion in Patients with Refractory/Relapsed CD33-Positive Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4548-4548 ◽  
Author(s):  
Francis Giles ◽  
Rodica Morariu-Zamfir ◽  
John Lambert ◽  
Srdan Verstovsek ◽  
Deborah Thomas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Disulfide Bonds ◽  
Phase I Study ◽  
Dose Range ◽  
Microtubule Assembly ◽  
Treatment Schedule ◽  
Specific Tumor ◽  
M Phase ◽  
Grade 3

Abstract AVE9633 is an immunoconjugate created by conjugation of the cytotoxic maytansinoid, DM4, to the monoclonal IgG1 antibody, huMy9-6 (average of 3.5 molecules of DM4 per antibody). The huMy9-6 antibody is a humanized version of a murine monoclonal antibody, My9-6, which is specific for the CD33 antigen expressed on the surface of myeloid cells, including the majority of cases of AML. Because CD33 has little expression outside the hematopoietic system, it represents an attractive target for antibody-based therapy in patients with AML. The humanized antibody, huMy9-6, binds to the CD33 antigen with an apparent KD in the range of 10−10 M. Maytansinoids are anti-mitotics that inhibit tubulin polymerization and microtubule assembly, inhibiting cells during the G2/M phase of the mitotic cycle. In order to link maytansinoids to antibodies via disulfide bonds, a new thiol-containing maytansinoid (DM4) was synthesized. Attachment of potent maytansinoids to an antibody via disulfide bonds provides a satisfactory stability in the bloodstream. After the conjugate is bound at the specific tumor site it is internalized and the cytotoxic agent is released within the target cell. A phase I study of AVE9633 is being conducted in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 of a 3 weeks cycle. To date dose levels of 15 (N=3), 30 (N=5), 50 (N=4), 75 (N=4), 105 (N=2), 200 (N=3) and 260 (N=1) mg/m2 have been investigated. Hypersensitivity reactions during perfusion were noted, requiring prophylaxis with steroids. No other AVE9633- attributable extramedullary Grade 3 AE has been observed to date. Free DM4, measured by LC/MS/MS was detectable from the 75 mg/m2 dose level; its Cmax (at the end of infusion) increased from 10 ng/mL at the 75 mg/m2 dose level to 70 ng/mL at 200 mg/m2. Neither AVE9633-associated myelosuppression nor responses have been noted. Using Flow Cytometry Assay on peripheral blasts and monocytes, total saturation and down regulation of CD33 were observed following administration of doses ≥ 30 mg/m2. AVE9633 exposure (measuring, by ELISA method, all antibodies containing at lease one molecule of DM4) increased proportionally with the administered dose in the dose range 15 to 200 mg/m2. Updated PK results and potential explanations for the lack of efficacy using this treatment schedule will be presented.

Phase I study of BAY 73–4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3593-3593 ◽  
Author(s):  
S. Hedbom ◽  
S. Steinbild ◽  
A. Frost ◽  
M. Büchert ◽  
C. Unger ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Exposure Level ◽  
Phase Ii Trials ◽  
Multikinase Inhibitor ◽  
Dce Mri ◽  
Grade 3

3593 Background: BAY 73–4506 is a multikinase inhibitor targeting both the tumor and its vasculature. BAY 73–4506 inhibits VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf). This drug shows potent, oral activity in a wide variety of preclinical xenograft models. Methods: This phase I dose-escalation trial investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers included dynamic contrast-enhanced MRI (DCE-MRI) and circulating sVEGFR-2 and VEGF levels assessed at each cycle. Tumor response was evaluated per RECIST criteria. Results: 22 patients (pts) with documented progressive disease were enrolled at doses of 10 mg to 120 mg once daily. Tumor types included CRC (27%), RCC (18%) and pancreatic cancer (14%). Pts had received a median of 3 prior therapies, including anti-VEGF agents in 5 pts. BAY 73–4506 PK appeared linear with dose; the AUC target exposure level of 13 mg*h/L (from preclinical models) was reached at 30 mg. The major metabolite of BAY 73–4506 (active in vitro) reached a similar AUC(0–24)ss as the parent drug at 120 mg. Commonly reported drug-related adverse events (=10% of pts) were hoarseness (7 [32%], all CTC grade 1), hypertension (5 [23%], all CTC grade 1–2), fatigue (3 [14%], CTC grade 3 in 1 pt [5%]), hand-foot-skin reaction (HFSR) (3 [14%], CTC grade 3 in 1 pt [5%], mucositis (3 [14%], all CTC grade 1). Maximum tolerated dose was exceeded at 120 mg with dose-limiting toxicities including fever without documented infection, HFSR, fatigue, and leukopenia. 2 pts (RCC & osteosarcoma) achieved RECIST partial response. 4 pts had stable disease, one of them a cervical cancer pt with extensive tumor cavitation. PD parameters (decrease in sVEGFR-2 levels, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure. Conclusions: BAY 73–4506 was well tolerated at 60 mg with report of dose-limiting toxicities at 120 mg. 6 (28%) of 22 pts demonstrated antitumor activity. Optimal dose and regimen are under evaluation in preparation for phase II trials. No significant financial relationships to disclose.

Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Amita Patnaik ◽  
Soonmo Peter Kang ◽  
Anthony W. Tolcher ◽  
Drew Warren Rasco ◽  
Kyriakos P. Papadopoulos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Preliminary Evidence ◽  
Open Label ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Multiple Tumor ◽  
Label Dose ◽  
Grade 3 ◽  
Tumor Types

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]

A phase I study of the vascular-disrupting agent BNC105P in combination with gemcitabine-carboplatin in platinum-sensitive ovarian cancer patients in first or second relapse.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 5524-5524 ◽  
Author(s):  
Danny Rischin ◽  
Philip James Beale ◽  
Emma Caroline Rossi ◽  
Jeffrey C. Goh ◽  
Michelle Margaret Vaughan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Phase I Study ◽  
Vascular Disrupting Agent ◽  
Platinum Sensitive ◽  
Vascular Disrupting

A phase I dose escalation study of SCB01A, a micro-tubular inhibitor with vascular disrupting activity, in patients with advanced solid tumors refractory to standard therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2531-2531 ◽  
Author(s):  
Nai-Jung Chiang ◽  
Her-Shyong Shiah ◽  
Chia-Chi Lin ◽  
Chia-Jui Yen ◽  
Hui-Jen Tsai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumor ◽  
Safety Concern ◽  
Lower Limbs ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Dose Levels ◽  
Vascular Disrupting

2531 Background: SCB01A is a novel anti-microtubular agent with vascular disrupting activity. The Phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and pharmacokinetic (PK) profiles of SCB01A in patients with advanced solid tumor. Methods: This was an open-label, phase I clinical trial with a rapid titration followed by a 3 x 3 study design. Eligible patients would receive a 3-hr intravenous infusion of SCB01A, every 21 days as one cycle. All adverse events were classified according to the CTCAE V4.0. DLT was defined as the occurrence of grade 3 with complications and grade 4 hematoloigcal, or ≥grade 3 non-hematological toxicities. Results: From June 2011 to November 2015, a total of 33 eligible patients were enrolled to eight dose levels: 2 mg/m2 (n = 1), 3 mg/m2 (n = 1), 4 mg/m2 (n = 6), 6.5 mg/m2 (n = 9, with 3 additional subjects were recruited for safety concern), 10 mg/m2 (n = 3), 16 mg/m2 (n = 3), 24 mg/m2 (n = 6) and 32 mg/m2 (n = 4). Six episodes of DLTs were observed in 5 patients (each one in dose levels of 4/6.5/24 mg/m2 and two in dose level of 32 mg/m2), including grade 4 blood creatine phosphokinase elevation (4 mg/m2), grade 3 gastric hemorrhage (6.5 mg/m2), grade 2 venous thrombosis (24 mg/m2), grade 3 peripheral neuropathy manifested as weakness of lower limbs, grade 3 aspartate aminotransferase elevation, and grade 3 hypertension (32 mg/m2). The MTD was determined to be 24 mg/m2. Pharmacokinetic profiles revealed a linear AUC-dose response with an average elimination half-life (t1/2) of 2.5 hours. Partial response was observed in one subject with buccal cancer. A total of 57.6% (19/33) subjects had stable disease for at least 2 cycles. Conclusions: SCB01A is safe and tolerable in patients with solid tumor. The MTD of SCB01A is 24 mg/m2 every 21 days, which deserves further development. Clinical trial information: NCT011159522.

Sign in / Sign up

Export Citation Format

Share Document