Phase I trial of a novel epothilone, KOS-1584, using a weekly dosing schedule

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2041-2041 ◽  
Author(s):  
A. Stopeck ◽  
E. Thomas ◽  
S. Jones ◽  
J. Cohen ◽  
G. Cropp ◽  
...  
Keyword(s):  
Phase 1 ◽  
Dose Range ◽  
Optimal Dose ◽  
Pharmacokinetic Profile ◽  
In Vitro Cytotoxicity ◽  
Epothilone D ◽  
Ecog Ps ◽  
Dose Levels

2041 Background: Several epothilones are progressing through phase 1–3 clinical trials treating solid tumor malignancies. KOS-1584 is a 3rd generation epothilone with 3–12 fold increased potency compared to Epothilone D (as measured by in vitro cytotoxicity, in vivo xenografts or induction of G2/M arrest by flow cytometry) and improved pharmacologic/pharmacokinetic profile (enhanced tumor tissue penetration and reduced exposure to the CNS). This dose-escalation trial explores a weekly administration schedule of KOS-1584. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered to patients with advanced solid malignancies via 1-hour infusion on Days 1, 8 and 15 every 4 weeks. Plasma PK and pharmacodynamics (serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot) were assessed. Results: 12 pts (7 F; median age 60; median ECOG PS 1; median prior regimens 4, range 2–13) enrolled in 5 dose levels (0.8, 1.5, 2.5, 5.0 and 7.5 mg/m2). To date, no Cycle 1 DLT has been seen; one Grade 3 episode of arthritis occurred in Cycle 2. Drug-related toxicities, all Grade 1 or 2 in severity: fatigue (n=3), anorexia (n=2) and individual patients with constipation, nausea, mucositis, dehydration, headache and pruritus. Neurotoxicity has not been observed. PK/parent (n=8): t½ 18.5 ± 6.8h, Vz 504 ± 234 L and CL 19.7 ± 6.1 L/h (none of these parameters showed evidence of dose dependency). 5.0 mg/m2 Cmax 122.4 ± 60.6 ng/mL; AUCtot 688.2 ± 212 ng/mL*h. Dose proportional increase in exposure and Cmax was observed over the dose range tested to date. At 5.0 mg/m2 the1-hr infusion Cmax is 3-fold higher and AUCtot 50% higher than for the same dose delivered over 3 hours. As predicted by allometric scaling from animals, Vz is ∼4-fold and t½ 2-fold higher than that of Epothilone D. Activity consisted of extended stable disease (a patient with colon cancer for 3 cycles). Dose-dependent increases in polymerized microtubules were observed: prior to infusion ∼10% of tubulin was in its polymerized form; this increased to 20%, 30%, 35% and 48% for the 1st 4 dose levels at infusion end. Conclusions: Accrual is continuing in order to define the optimal dose on this regimen. Exposure and Cmax remain linear within this dose range; slower clearance is observed for the same dose administered over 1 hour compared to 3 hours. [Table: see text]

Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of of the Hsp-90 inhibitor, KOS-1022 (17-DMAG), in patients with refractory hematological malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2081-2081 ◽  
Author(s):  
J. Lancet ◽  
I. Gojo ◽  
M. Baer ◽  
M. Burton ◽  
M. Klein ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Phase 1 ◽  
Dose Range ◽  
Hematologic Malignancies ◽  
Hsp90 Inhibitor ◽  
In Vitro Cytotoxicity ◽  
Water Soluble ◽  
Primary Study ◽  
Co Morbidity

2081 Background: Disruption of Hsp90-client protein heterocomplexes leads to degradation of a variety of oncoproteins. KOS-1022, an Hsp90 inhibitor and water-soluble geldanamycin derivative, is in trials in patients with solid tumors. Compared to a prior geldanamycin derivative (17-AAG), KOS-1022 is ∼3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies on the same schedule). Primary study objectives: establish safety and MTD of KOS-1022 in patients with advanced hematologic malignancies; characterize PK and PD. Methods: Escalating doses of KOS-1022 are given IV over 1 h twice weekly for 2 out of 3 weeks. Plasma KOS-1022 concentrations (1st and 4th infusion, Cycle 1) are quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts undergo flow cytometry to quantify Hsp70/90, pAKT/total AKT, markers of apoptosis and proliferation. Response in AML pts used IWG criteria. Results: 13 pts have been enrolled at doses of 8 (n=4), 16 (n=6), 24 (n=1) and 32 mg/m2 (n=2). All were AML (except 1 CML). Most (n=11) patients had 2–3 prior induction regimens. DLT was seen in 2 pts at 32 mg/m2 (acute myocardial infarction and elevation of troponin). Both patients had significant co-morbidity, including (1) prior myocardial infarction and (2) progressive AML with a similar troponin elevation during induction chemotherapy prior to study. Common drug-related toxicities (all Grade 1–2): fatigue, nausea, diarrhea and arthralgias. From 8 to 32 mg/m2, approximately linear PK was observed. Mean terminal half-lives varied from 13.0–31.2 hours. Day 1 clearance for 8, 16 and 32 mg/m2 was 5.6, 9.7 and 10.8 L/hr/m2; mean Vz (L/m2) for these groups were 238, 433 and 489. Although pre-infusion drug was quantifiable on Day 11 in most patients, Day 11/Day 1 AUC0–25h ratio was 0.96. Activity in AML: 2 CRi and 1 SD x 9 cycles were observed. Comparing BMAs taken at Day 8 and Day 15 to baseline: decreased Hsp90 (41% to 13%), increased Hsp70 (8% to 84%) with decreased pAKT (Ser), pAKT (Thr) and total AKT in CD34+ cells. Conclusions: KOS-1022 appears to be well tolerated, with preliminary signs of clinical and biologic activity in refractory leukemia. MTD has not been defined. Plasma PK is linear over this dose range. [Table: see text]

scholarly journals CARMUSTINE LOADED NANOSIZE LIPID VESICLES SHOWED PREFERENTIAL CYTOTOXICITY AND INTERNALIZATION IN U87MG CELL LINE ALONG WITH IMPROVED PHARMACOKINETIC PROFILE IN MICE: A STRATEGY FOR TREATMENT OF GLIOMA

2020 ◽  
pp. 240-248
Author(s):  
BHABANI SANKAR SATAPATHY ◽  
JNANRANJAN PANDA
Keyword(s):  
Electron Microscopy ◽  
Cell Line ◽  
Drug Loading ◽  
Lipid Vesicles ◽  
Pharmacokinetic Profile ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Data ◽  
Transmission Electron

Objective: Successful treatment of glioma still remains a tough challenge. The present study aims at the development and evaluation of carmustine loaded nanosize phospholipid vesicles (CNLVs) for the treatment of glioma. Methods: The experimental NLVs were developed by conventional lipid layer hydration technique and were characterized by different in vitro tools such as diffraction light scattering (DLS), zeta potential, field emission scanning electron microscopy (FESEM), cryo-transmission electron microscopy (cryo-TEM), in vitro drug loading capacity, drug release study etc. In vitro cytotoxicity and cellular uptake of the optimized drug-loaded NLVs were carried out in U87MG human glioblastoma cell line. In vivo pharmacokinetic study was conducted in Swiss albino mice. Results: DLS data showed an average vesicle diameter of 92 nm with narrow size distribution. Optimized CNLVs were spherical in shape with a smooth surface as depicted from FESEM data. Cryo-TEM study confirmed formation of unilamellar vesicles with intact outer bilayer. A reasonable drug loading of 7.8 % was reported for the optimized CNLVs along with a sustained release of CS over a 48 h study period. In vitro cytotoxicity assay revealed a considerable higher toxicity of CNLVs than free drugs in the U87MG cells. Confocal microscopy showed a satisfactory internalization of the optimized drug-loaded NLVs in the tested cell line. Pharmacokinetic data demonstrated an enhanced mean residence time of optimized CNLVs in blood than free drug. Conclusion: Results depicted the potential of experimental CNLVs for the treatment of glioma after further in vivo tests.

scholarly journals 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S322-S322
Author(s):  
Jennifer Woo ◽  
Ken Hearne ◽  
Andy Kelson ◽  
Luisa Yee ◽  
Cecilia Espadas ◽  
...  
Keyword(s):  
Clinical Study ◽  
Phase 1 ◽  
Dose Range ◽  
In Vivo Studies ◽  
Resistance Testing ◽  
Antibiotics Resistance ◽  
Gallium Nitrate ◽  
Bacterial Clearance

Abstract Background Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of gallium citrate (AR-501), which is being tested in a Phase 1/2a clinical study. The in vitro antimicrobial activities, drug resistance profile, activities in combination with selected antibiotics, and in vivo animal efficacy if the inhaled vs. IV formulation is being presented. Methods MIC tests were performed on strains using the CLSI susceptibility test standards. Resistance testing exposed bacteria to 20 cycles at ranges above and below the MIC level of the drug used.SPF mice (C57BL/6J, 7–9 weeks) were inoculated intranasally with P. aeruginosa under ketamine/xylazine anesthesia. Inhalation of AR-501 used an Aeroneb Solo nebulizer. Gallium levels were determined by elemental analysis using atomic absorption spectroscopy. CFU levels were measured by enumeration of bacterial colonies following serial dilution of tissue homogenates. Results In vitro efficacy: MIC testing demonstrates the efficacy of AR-501 against gram (−), gram (+) and several species of mycobacteria of clinical isolates and the comparative antibacterial response with antibiotics. Resistance testing showed that AR-501 exhibited lower propensity to develop resistance than the antibiotics tested. In vivo efficacy: AR-501 Inhalation also increased the median survival time compared with IV dosing in the murine model. Bacterial clearance was increased when Tobramycin and AR-501 are co-administered. Comparative analysis of AR-501 after IH route demonstrate increased gallium levels in BAL and reduced levels in the kidney in contrast to IV route. Conclusion In vitro studies demonstrate the susceptibility of gram (−), gram (+) and mycobacteria pathogens and the dose range of AR-501 compared with SOC antibiotics. In vivo studies confirm the therapeutic efficacy of AR-501 in bacterial pneumonia by IH delivery and demonstrate that bacterial clearance is enhanced when SOC antibiotics are used in combination with AR-501. Disclosures All authors: No reported disclosures.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8022-8022
Author(s):  
Jeroen Elassaiss-Schaap ◽  
Peter van Zandvoort ◽  
Jeannette Lo ◽  
Nitya Nair ◽  
Jackie Walling ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Dose Range ◽  
Serum Levels ◽  
Open Label ◽  
Immune Resistance ◽  
Dosing Regimens ◽  
Low Incidence ◽  
Dose Levels

8022 Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.

scholarly journals In Vivo Toxicity, Pharmacokinetics, and Anti-Human Immunodeficiency Virus Activity of Stavudine-5′-(p-Bromophenyl Methoxyalaninyl Phosphate) (Stampidine) in Mice

2002 ◽  
Vol 46 (11) ◽  
pp. 3428-3436 ◽  
Author(s):  
Fatih M. Uckun ◽  
Sanjive Qazi ◽  
Sharon Pendergrass ◽  
Elizabeth Lisowski ◽  
Barbara Waurzyniak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Peripheral Blood ◽  
Pharmacokinetic Profile ◽  
Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Dose Levels ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We have evaluated the clinical potential of stavudine-5′-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.

scholarly journals Targeting CD70 with Cusatuzumab Eliminates Acute Myeloid Leukemia Stem Cells in Humans

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 234-234 ◽  
Author(s):  
Adrian F Ochsenbein ◽  
Thomas Pabst ◽  
Sabine Höpner ◽  
Vera Ulrike Bacher ◽  
Magdalena Hinterbrandner ◽  
...  
Keyword(s):  
Single Dose ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Employment Equity ◽  
Elderly Aml ◽  
Equity Ownership ◽  
Dose Levels ◽  
Acute Myeloid

Introduction Acute myeloid leukemia (AML) is a heterogenous hematological malignancy driven by leukemia stem cells (LSCs) (Lapidot et al, 1994). LSCs resistant against conventional chemotherapy represent the major cause of relapse. Elderly or unfit AML patients not eligible for intensive chemotherapy are treated in a palliative setting with hypomethylating agents (HMA) or low dose Ara-C, but responses are modest and not durable. The reason for the low efficacy of HMA treatment is their insufficient action on the disease initiating- and -maintaining LSC population (Craddock et al, 2013). We recently demonstrated that CD34+ AML cells (progenitors and LSC) consistently express the tumor necrosis factor family ligand CD70 as well as its receptor CD27 and that cell-autonomous CD70/CD27-signaling propagates the disease (Riether et al. 2017). The aim of the current study was to evaluate whether resistance to HMA treatment can be overcome by combining HMA with an anti-CD70 monoclonal antibody treatment. Experimental design The effect of HMA treatment on the expression of CD70 on primary human CD34+CD38- AML LSCs was determined in vitro cultures and in patients treated with HMA in vivo. The therapeutic potential of targeting CD70-expressing LSCs in presence and absence of HMA was assessed using the anti-CD70 ADCC-optimized monoclonal antibody (mAb), cusatuzumab, and an effector-dead anti-CD70 mAb in colony formation and re-plating assays as well as patient-derived xenograft models (Silence et al, 2014). The clinical relevance of the findings was determined in a clinical phase 1 trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine (AZA, NCT03030612). Four different dose levels of cusatuzumab (1, 3, 10 and 20 mg/kg Q2W) were studied; AZA was administered at 75 mg/m² for 7 days every 28 days. Results We found that resistance of AML LSCs to HMA treatment is mediated by the up-regulation of the CD70. The up-regulation of CD70 triggered cell-autonomous CD70/CD27 signaling on AML LSCs. Based on these findings we hypothesized that the upregulation of CD70 by HMA may render LSCs more susceptible to CD70-targeting interventions. Targeting CD70-expressing LSCs by a blocking anti-CD70 mAb and the anti-CD70 mAb cusatuzumab, which blocks CD70/CD27-signaling and additionally mediates ADCC and CDC, eradicated LSCs in colony and re-plating assays in vitro and in xenotransplantation experiments in vivo. HMA in combination with blocking αCD70 mAb synergistically reduced LSC numbers in vivo and this was even more efficient when ADCC-enhanced αCD70 mAb cusatuzumab was added in the presence of NK cells. In order to test the hypothesis that targeting CD70 in combination with HMA eliminates LSCs in AML patients, we initiated a phase 1 dose-escalation trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with azacitidine. No dose-limiting toxicities (DLT) were observed in the dose-escalation phase 1 trial and responses were observed across the dose levels (1-20 mg/kg). A single dose of cusatuzumab reduced bone marrow blasts in just two weeks in all patients on average by 32%. Cusatuzumab monotherapy significantly reduced LSC numbers and frequencies in all patients analyzed in the bone marrow as assessed in limiting dilution colony assays. Single cell sequencing analysis revealed that cusatuzumab induced gene signatures related to myeloid differentiation and apoptosis in LSCs. In combination with azacitidine, cusatuzumab induced CR/CRi in 10 out of 12 patients. Responses were observed at all dose levels of cusatuzumab and median time to response was 3.3 months. Conclusions Blocking CD70/CD27-signaling and targeting CD70-expressing LSCs by the ADCC-optimized mAb, cusatuzumab, eliminated LSCs in vitro and in xenotransplantation experiments. In a phase 1 study promising activity of cusatuzumab in combination with HMA was observed in AML patients, in which translational data indicate that cusatuzumab selectively eliminates CD70-expressing LSCs. Disclosures Van Rompaey: argenx: Employment, Equity Ownership, Patents & Royalties. Moshir:Argenx: Employment, Equity Ownership. Delahaye:argenx: Employment, Equity Ownership. Gandini:Argenx: Employment, Equity Ownership. Erzeel:argenx: Employment, Equity Ownership. Hultberg:Argenx: Employment. Fung:argenx: Consultancy, Equity Ownership. De Haard:Argenx: Employment, Equity Ownership, Patents & Royalties. Leupin:Argenx: Employment, Equity Ownership, Patents & Royalties.

A Phase 1 and Correlative Biological Study of CSL360 (anti-CD123 mAb) in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2956-2956 ◽  
Author(s):  
Andrew W. Roberts ◽  
Simon He ◽  
Kenneth F Bradstock ◽  
Mark S Hertzberg ◽  
Simon T S Durrant ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Level ◽  
De Novo ◽  
Biological Effects ◽  
Phase 1 ◽  
Dose Range ◽  
Clinical Signs ◽  
Biological Study

Abstract CD123 (IL-3Rα) is a phenotypic marker of putative leukemic stem cells (LSC) in AML (Jordan, Leukemia2000;14:1777). We and others have found that CD34+38− cells from AML patients (pts) express high levels of CD123, in contrast to absence of expression on CD34+38− cells in normal individuals. Binding of CD123 by monoclonal antibody (mAb) 7G3 inhibits IL-3-dependent signalling and proliferation in vitro. In a NOD-SCID xenograft model 7G3 inhibits human AML engraftment, but not normal human hematopoiesis (Lock ASH2007; Abs161). CSL360, a recombinant chimeric IgG1 mAb derived from 7G3, binds the same epitope. CSL360 concentrations ≥ 0.1μg/mL in vitro inhibited 90% AML cell growth in the presence of supraphysiological IL-3 levels. Preclinical toxicology studies with doses up to 100 mg/kg weekly × 4 in cynomolgus monkeys showed no CSL360-related effects in clinical signs, hematology, chemistry, urinalysis, gross pathology or histopathology. A Phase 1 study of safety, pharmacokinetics (PK) and bioactivity of CSL360 in relapsed, refractory or high risk AML began in March 2007. Pts receive 12 weekly iv infusions if not withdrawn early due to treatment-related toxicity or disease progression. Additional treatments may be given to pts who achieve a response. Bone marrow aspirates/trephine samples are obtained at screening, after dose 3 and before doses 5 and 11. More than 180 infusions have been administered to 26 AML pts (21 M, 5 F; 17 de novo, 8 MDS-related, 1 treatment-related AML) in 5 dose level cohorts: 0.1, 0.3, 1.0, 3.0 and 10 mg/kg. There is no intra-patient dose escalation. PK parameters over the dose range, estimated in 19 pts over 7 days after doses 1 and 4, were linear with dose-proportional increases in the AUC and Cmax; dose 1 Cmax ranged from 0.62 – 287.33 μg/mL and dose 4 Cmax from 1.02 – 178.22 μg/mL. CSL360 mean plasma half-life (dose 1, 83 ± 33 h; dose 4, 117 ± 59 h) appears to be independent of dose and treatment number. Dose 1 systemic clearance (0.21 ± 0.16 L/h) and volume of distribution (0.39 ± 0.22 L/kg) were relatively low, consistent with this size IgG. In all pre-treatment samples anti-CSL360 antibody titers were negative, determined by enzyme immunoassay. Anti-CSL360 antibodies were detected post-treatment in 8/12 pts; these antibodies have not been fully quantified or characterised. CSL360 has been well tolerated; a MTD has not been defined. Seven pts received all 12 doses, 13 pts were withdrawn due to progressive disease or investigator’s decision, 3 pts were withdrawn in association with infections, 2 pts withdrew consent, and 1 pt is ongoing. Three serious adverse events have been considered possibly related or related to CSL360: 1 invasive fungal infection (Gr 5), and 2 infusion reactions (Gr 2; hospitalised). Other adverse events are consistent with expectations for the disease population. Of 8 pts in the 3 mg/kg and 10 mg/kg cohorts who are evaluable for response after ≥ 4 doses, 1 complete response (CR) has been observed. A 22 yr old male, de novo FAB M1 cytogenetically normal AML, who had relapsed post-2 allogeneic SCT, achieved a morphologic leukemia free state after 3 doses (3.0 mg/kg) and CR after 12 doses, sustained for > 9 weeks. The pt received 17 doses before withdrawal to treat co-morbidities. Flow cytometry studies with anti-CD123 antibodies demonstrated dose-dependent CSL360 coating of both AML blasts and LSC. Saturation of target antigen on marrow and blood cells was observed 1 day after dosing at 0.3mg/kg, associated with decreased expression of CD123 detected by an antibody to a different epitope. At higher dose levels saturation of CD123 was maintained 7 days post dosing, associated with ongoing reduction in surface CD123 expression. In a representative sample, plasma from a pt treated at 10 mg/kg specifically inhibited IL-3-induced proliferation of AML blasts ex vivo, indicating sufficient circulating concentration of CSL360 to inhibit IL-3 mediated effects in vivo. Effects of CSL360 on proliferation and apoptosis of AML cells in treated patients are being investigated. These preliminary results show anti-CD123 mAb therapy with CSL360 is safe and tolerable; biological effects have been demonstrated; a sustained CR was achieved in 1 advanced, refractory AML pt. The study is continuing, with 20 evaluable patients to be accrued and treated at 10 mg/kg weekly; at this dose level the PK and correlative assays predict that complete blockade of IL-3 signalling through CD123 can be achieved in vivo.

Ratiometric dosing of irinotecan (IRI) and floxuridine (FLOX) in a phase I trial: A new approach for enhancing the activity of combination chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2549-2549 ◽  
Author(s):  
G. Batist ◽  
W. Miller ◽  
L. Mayer ◽  
A. Janoff ◽  
C. Swenson ◽  
...  
Keyword(s):  
Phase 1 ◽  
Therapeutic Benefit ◽  
Outpatient Setting ◽  
Extension Phase ◽  
Molar Ratio ◽  
Highly Active ◽  
Ecog Ps ◽  
Anti Tumor Activity

2549 Background: Like many pairs of chemotherapy agents, the combination of IRI and FLOX displays ratio-dependent activity in vitro. CPX-1, a liposome formulation of IRI:FLOX, was developed to maintain a synergistic 1:1 molar ratio in vivo, was highly active in preclinical models, and was evaluated in a phase 1 trial (CLTR0104–101). Methods: Doses were escalated from 30U/m2 (1U= 1 mg IRI + 0.36 mg FLOX) to 270 U/m2 given on day 1 and 15 of each 28 day cycle. Adult patients (pts) with advanced solid tumors, ECOG PS<2, adequate bone marrow, liver, and renal function were eligible; 4 pts per cohort. After defining the MTD, additional pts with CRC were enrolled (extension phase). IRI completed greater than 12 months prior to this trial was allowed in the absence of resistance to IRI. PK was done on day 1 and 15 of the 1st cycle. Results: Safety: The dose escalation phase enrolled 24 pts in 6 cohorts and added 2 pts in the 5th cohort (210U/m2; the MTD) after noting dose limiting diarrhea (3 pts) and neutropenia (1 pt) including one death from dehydration and renal failure due to prolonged diarrhea (gr3) & vomiting (gr2) at 270U/m2. An additional 7 pts with CRC received 210U/m2 in the extension phase. Grade 3/4 adverse events included diarrhea, nausea, vomiting, neutropenia and thrombocytopenia with most occurring at 270U/m2. No new toxicities were observed for this combination. Response: 30/33 pts were evaluable with 2 confirmed PRs (NSCLC and CRC), 21 SD and 7 PD. Median PFS was 5.4 mos. (0.3–11.8 mos.) in 15 pts w/CRC. PK: All pts maintained synergistic plasma IRI:FLOX ratios for 24h. IRI and FLOX AUCs (0-inf) were greater for CPX-1 than expected for conventional drugs. AUCs for SN-38 and 5FU at 210U/m2 were 0.8 ± 0.1 and 10 ± 8.7 μg-hr/mL, respectively, indicating bioavailability for both drugs. Conclusion: CPX-1 was well tolerated in the outpatient setting and evidence of anti-tumor activity was obtained. This is the first clinical evaluation of ratiometric dosing in which a synergistic drug ratio, pre-selected in vitro based on optimal anti-tumor activity, was maintained systemically to enhance therapeutic benefit. [Table: see text]

Phase Ia, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic, or biliary cancers.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 713-713 ◽  
Author(s):  
Andrew H. Ko ◽  
Andrew L. Coveler ◽  
Benjamin L. Schlechter ◽  
Tanios S. Bekaii-Saab ◽  
Brian M. Wolpin ◽  
...  
Keyword(s):  
Human Study ◽  
Duration Of Treatment ◽  
Antibody Drug Conjugate ◽  
Eligibility Criteria ◽  
Best Response ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels

713 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in pts with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility criteria: locally adv or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). DLTs were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Pts were treated until dz progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 pts experienced Grade 3 or 4 neutropenia, all at higher dose levels, with 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs include grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. MTD was not reached at either 1.2 mg/kg Q4W or 0.8 mg/kg Q2W; the 1.0 mg/kg Q2W cohort will complete enrollment in Oct 2019. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days); best response observed to date is stable dz lasting > 6 months at 0.8 mg/kg Q4W and Q2W cohorts (n = 1 each). Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy (prolonged dz control) in non-biomarker selected pts with advanced GI cancers. Pre-screening for high AG-7 expression is underway for subjects with G, CRC, PDA, and BIL cancers for the cohort expansion phase of this study, which will be open across multiple sites in U.S. and Taiwan. Clinical trial information: NCT02908451.

Phase-1 trial of ZIO-101, a novel organic arsenic in patients with advanced cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13041-13041 ◽  
Author(s):  
L. H. Camacho ◽  
D. S. Hong ◽  
C. Gutierrez ◽  
S. Vertovsek ◽  
N. Tannir ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Phase 1 ◽  
Cell Cancer ◽  
Pharmacokinetic Profile ◽  
Blood Levels ◽  
In Vitro Tests ◽  
Clinical Activity ◽  
Anti Cancer

13041 Background: Arsenics are potent anti-cancer drugs. Organic arsenics are much less toxic than inorganic arsenics (like arsenic trioxide [As2O3]). We synthesized ZIO-101 (S-dimethylarsino-glutathione) by conjugating dimethylarsenic to glutathione. ZIO-101 is active against multiple cancers in in vitro tests and animals. In mice, the LD50 of ZIO-101 is about 50-fold higher than As2O3. At equimolar extracellular arsenic concentrations of ZIO-101 and As2O3, intracellular arsenic concentrations are about 15-fold higher with ZIO-101 than As2O3. In cancer cells this results in dramatically more mitochondrial damage and more apoptosis induction. Preclinical data suggest ZIO-101 may induce apoptosis by different mechanisms than As2O3 and can kill As2O3-resistant cancer cells. Methods: A phase-1 study evaluating the safety and pharmacokinetic profile of ZIO-101 in pts with advanced cancers. 18 patients enrolled in 5 cohorts. Mean Age 63 (42–79). Starting dose was 78 mg/m2/d IV for 5 days every month with 40% dose increases. Results: Thirty-three courses of ZIO-101 have been delivered. Therapy with ZIO-101 was safe. Toxicities ≥ grade-2 include Fatigue (N = 4), Vomiting (N = 4), and Anorexia (N = 2). One patient with rapidly progressing metastatic renal cell cancer had complete resolution of a brain metastasis and stable disease elsewhere (beyond 6 months). Pharmacokinetic (PK) studies at 214 mg/m2/d showed a tmax = 1 h (no SD), Cmax = 685 μg/mL (SD ± 130 μg/mL), t1/2 = 13.9 h (SD ± 0.3 h) and AUC0-∞ = 14.9 μg.h/mL (SD ± 2.6μg.h/mL). Conclusions: Clinical and PK data show ZIO-101 is safe at doses that result in blood levels that have substantial anti-cancer activity at in vivo concentrations. There is early evidence of clinical activity. Dose-escalation continues. Results on subsequent dose-levels will be presented. [Table: see text]

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