EXTH-80. PBI-200: IN VIVO EFFICACY OF A NOVEL, HIGHLY CNS-PENETRANT NEXT GENERATION TRK INHIBITOR

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi181-vi182
Author(s):  
Kollol Pal ◽  
Anthony Regina ◽  
Aram Elagoz ◽  
Vincent Albert ◽  
Johnathan Boudreault ◽  
...  
Keyword(s):  
Second Generation ◽  
Phase 1 ◽  
Xenograft Model ◽  
In Vitro Assays ◽  
Tumor Growth Inhibition ◽  
Next Generation ◽  
Resistance Mutations ◽  
Drug Concentrations ◽  
Cns Penetration

Abstract TRK kinases (TRK) are clinically validated targets for cancers harboring NTRK gene fusions. However, approved TRK inhibitors (TRKi) give rise to mutations reducing long-term clinical efficacy, and display limited CNS penetration that may impact their ability to address primary brain tumors (PBT), including high-grade gliomas. Second generation compounds in development address some resistance mutations, but are not sufficiently CNS penetrant. PBI-200 is a novel, orally active TRK inhibitor designed to overcome resistance, with high CNS penetration. In vitro assays demonstrate picomolar- to nanomolar potency against both wild-type TRK and the major acquired resistance mutations. A BaF3 xenograft model encoding the LMNA-NTRK1 gene fusion and G595R solvent front mutation showed superior efficacy with PBI-200 relative to first-generation compounds larotrectinib and entrectinib, and equivalent efficacy to the second-generation compound selitrectinib, in terms of tumor growth inhibition. Importantly, drug concentrations in the brains of PBI-200 treated mice showed an approximately 4-fold brain/plasma ratio (BPR). In contrast, BPR of other TRKi were < 0.17, indicating that only PBI-200 achieved sustained drug levels in brain. PBI-200 demonstrated statistically superior CNS efficacy and survival in a KM12-Luc intracranial murine model, as compared to other TRKi (chi-squared 45.6, p < 0.0001). By day 41, 50% of mice in the PBI-200 group remained alive, whereas mice in the other treatment groups had died on or before day 32. Of note, no gross or histopathological CNS adverse effects were observed in a 14d CNS Field Observation Battery study. Finally, PBI-200 was the most selective TRKi in a 125 kinase panel (ThermoFisher) with only 1 off-target kinase inhibited > 60% at 1 micromolar. Together, these data suggest that PBI-200 has potential as a best-in-class, highly CNS-penetrant next generation TRKi. A Phase 1/2 clinical trial evaluating PBI-200 in NTRK fusion-positive patients, including patients with PBT, is ongoing (NCT04901806).

scholarly journals 609 Combining bintrafusp alfa with abituzumab enhances suppression of the TGF-β signaling pathway

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A639-A639
Author(s):  
Feng Jiang ◽  
Hong Wang ◽  
Tsz-Lun Yeung ◽  
Guozhong Qin ◽  
Bo Marelli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Culture Medium ◽  
Phase 1 ◽  
Xenograft Model ◽  
Human Tumor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumor Growth Inhibition

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor fused to a human IgG1 antibody blocking PD-L1. The TGF-βRII moiety of bintrafusp alfa functions as a ”trap” to sequester active TGF-β but does not block TGF-β release from its latent form. Multiple mechanisms lead to the release of active TGF-β. Integrins control local activation of latent TGF-β stored in the extracellular matrix and cell-surface reservoirs in the tumor microenvironment (TME). Alpha v integrin mRNA expression is correlated with multiple TGF-β gene signatures. It has been shown that αvβ8 integrin mediates TGF-β activation without releasing it from the latent TGF-β complex, suggesting that the TGF-βRII moiety of bintrafusp alfa may be unable to sequester TGF-β activated by αvβ8 integrin. Therefore, we hypothesize that combining abituzumab, a pan–αv integrin antibody, with bintrafusp alfa may lead to enhanced suppression of TGF-β signaling.MethodsThe expression of αv and β6 integrin mRNA was determined by RNA sequencing of triple-negative breast cancer (TNBC) tumor samples from a phase 1 clinical trial of bintrafusp alfa and correlated with patient response to bintrafusp alfa. The combination of bintrafusp alfa and abituzumab was investigated in vitro and in vivo in a TGF-β–dependent human tumor model, Detroit 562. In this study, CellTiter-Glo 2.0 Assay measured cell proliferation in vitro and enzyme-linked immunosorbent assay measured the level of latency-associated protein (LAP). A TGF-β reporter cell line MDA-MB-231 measured the level of active TGF-β. Antitumor activity in vivo was evaluated via tumor growth of Detroit 562 xenograft model in SCID mice.ResultsIn TNBC, increased expression of αv and β6 integrin mRNA was associated with poor response to bintrafusp alfa, suggesting that TGF-β activated by αv integrin may not be blocked by bintrafusp alfa. In Detroit 562 cells, abituzumab increased LAP levels in the cell culture medium, confirming modulation of the TGF-β pathway. As a result, the amount of active TGF-β released into culture medium was reduced by abituzumab. In vitro, both abituzumab and bintrafusp alfa suppressed Detroit 562 cell proliferation, and the combination suppressed cell proliferation further. In vivo, the combination led to increased tumor growth inhibition of Detroit 562 xenograft tumors relative to either monotherapy, further supporting the potential of this combination.ConclusionsCollectively, these preclinical findings support clinical development of bintrafusp alfa and abituzumab combination therapy to maximally suppress TGF-β signaling in the TME.AcknowledgementsWe thank George Locke for his analysis of the RNAseq data.Ethics ApprovalThis study was approved by the Institutional Animal Care and Use Committee at EMD Serono, Inc.; approval number [17–008].

The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3616-3616 ◽  
Author(s):  
Alexander E. Drilon ◽  
Dayong Zhai ◽  
Evan Rogers ◽  
Wei Deng ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Phase 1 ◽  
Xenograft Model ◽  
Next Generation ◽  
Tumor Models ◽  
Diverse Range ◽  
Tt Cells ◽  
Proliferation Assays

3616 Background: RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391).

scholarly journals Doxorubicin Embedded into Nanofibrillated Bacterial Cellulose (NFBC) Produces a Promising Therapeutic Outcome for Peritoneally Metastatic Gastric Cancer in Mice Models via Intraperitoneal Direct Injection

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1697
Author(s):  
Hidenori Ando ◽  
Takashi Mochizuki ◽  
Amr S. Abu Lila ◽  
Shunsuke Akagi ◽  
Kenji Tajima ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Delivery ◽  
Tumor Growth ◽  
Bacterial Cellulose ◽  
Anticancer Agents ◽  
Intraperitoneal Administration ◽  
In Vitro Release ◽  
Xenograft Model ◽  
Tumor Growth Inhibition

Natural materials such as bacterial cellulose are gaining interest for their use as drug-delivery vehicles. Herein, the utility of nanofibrillated bacterial cellulose (NFBC), which is produced by culturing a cellulose-producing bacterium (Gluconacetobacter intermedius NEDO-01) in a medium supplemented with carboxymethylcellulose (CMC) that is referred to as CM-NFBC, is described. Recently, we demonstrated that intraperitoneal administration of paclitaxel (PTX)-containing CM-NFBC efficiently suppressed tumor growth in a peritoneally disseminated cancer xenograft model. In this study, to confirm the applicability of NFBC in cancer therapy, a chemotherapeutic agent, doxorubicin (DXR), embedded into CM-NFBC, was examined for its efficiency to treat a peritoneally disseminated gastric cancer via intraperitoneal administration. DXR was efficiently embedded into CM-NFBC (DXR/CM-NFBC). In an in vitro release experiment, 79.5% of DXR was released linearly into the peritoneal wash fluid over a period of 24 h. In the peritoneally disseminated gastric cancer xenograft model, intraperitoneal administration of DXR/CM-NFBC induced superior tumor growth inhibition (TGI = 85.5%) by day 35 post-tumor inoculation, compared to free DXR (TGI = 62.4%). In addition, compared with free DXR, the severe side effects that cause body weight loss were lessened via treatment with DXR/CM-NFBC. These results support the feasibility of CM-NFBC as a drug-delivery vehicle for various anticancer agents. This approach may lead to improved therapeutic outcomes for the treatment of intraperitoneally disseminated cancers.

scholarly journals Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization

2020 ◽  
Vol 21 (18) ◽  
pp. 6672
Author(s):  
Zora Novakova ◽  
Nikola Belousova ◽  
Catherine A. Foss ◽  
Barbora Havlinova ◽  
Marketa Gresova ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Xenograft Model ◽  
In Vitro Assays ◽  
Experimental Therapy ◽  
Single Chain ◽  
Single Chain Fv ◽  
Murine Xenograft Model ◽  
Single Target

Prostate-Specific Membrane Antigen (PSMA) is an established biomarker for the imaging and experimental therapy of prostate cancer (PCa), as it is strongly upregulated in high-grade primary, androgen-independent, and metastatic lesions. Here, we report on the development and functional characterization of recombinant single-chain Fv (scFv) and Fab fragments derived from the 5D3 PSMA-specific monoclonal antibody (mAb). These fragments were engineered, heterologously expressed in insect S2 cells, and purified to homogeneity with yields up to 20 mg/L. In vitro assays including ELISA, immunofluorescence and flow cytometry, revealed that the fragments retain the nanomolar affinity and single target specificity of the parent 5D3 antibody. Importantly, using a murine xenograft model of PCa, we verified the suitability of fluorescently labeled fragments for in vivo imaging of PSMA-positive tumors and compared their pharmacokinetics and tissue distribution to the parent mAb. Collectively, our data provide an experimental basis for the further development of 5D3 recombinant fragments for future clinical use.

scholarly journals Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Laura L. Kovanda ◽  
Sean M. Sullivan ◽  
Larry R. Smith ◽  
Amit V. Desai ◽  
Pete L. Bonate ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Binding Model ◽  
Saturable Binding ◽  
Drug Concentrations ◽  
Over Time

ABSTRACT VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.

scholarly journals A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

2020 ◽  
Vol 176 (1) ◽  
pp. 236-252 ◽  
Author(s):  
Maria T Baltazar ◽  
Sophie Cable ◽  
Paul L Carmichael ◽  
Richard Cubberley ◽  
Tom Cull ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Biological Effects ◽  
In Vitro Assays ◽  
Next Generation ◽  
Animal Testing ◽  
Immunomodulatory Effects ◽  
Margin Of Safety

Abstract Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 and BioMap Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure to calculate a margin of safety with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with margin of safety higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer-relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modeling and in vitro bioactivity data, to reach a safety decision without animal data.

scholarly journals Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Qinchao Hu ◽  
Jianmin Peng ◽  
Laibo Jiang ◽  
Wuguo Li ◽  
Qiao Su ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Xenograft Model ◽  
Neck Squamous Cell Carcinoma ◽  
In Vitro Assays ◽  
Anticancer Efficacy

Abstract CDK4/6 inhibitors show promising antitumor activity in a variety of solid tumors; however, their role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. The senescence-associated secretory phenotype (SASP) induced by CDK4/6 inhibitors has dual effects on cancer treatment. The need to address the SASP is a serious challenge in the clinical application of CDK4/6 inhibitors. We investigated whether metformin can act as a senostatic drug to modulate the SASP and enhance the anticancer efficacy of CDK4/6 inhibitors in HNSCC. In this study, the efficacy of a combination of the CDK4/6 inhibitor LY2835219 and metformin in HNSCC was investigated in in vitro assays, an HSC6 xenograft model, and a patient-derived xenograft model. Senescence-associated β-galactosidase staining, antibody array, sphere-forming assay, and in vivo tumorigenesis assay were used to detect the impacts of metformin on the senescence and SASP induced by LY2835219. We found that LY2835219 combined with metformin synergistically inhibited HNSCC by inducing cell cycle arrest in vitro and in vivo. Metformin significantly modulated the profiles of the SASP elicited by LY2835219 by inhibiting the mTOR and stat3 pathways. The LY2835219-induced SASP resulted in upregulation of cancer stemness, while this phenomenon can be attenuated when combined with metformin. Furthermore, results showed that the stemness inhibition by metformin was associated with blockade of the IL6-stat3 axis. Survival analysis demonstrated that overexpression of IL6 and stemness markers was associated with poor survival in HNSCC patients, indicating that including metformin to target these proteins might improve patient prognosis. Collectively, our data suggest that metformin can act as a senostatic drug to enhance the anticancer efficacy of CDK4/6 inhibitors by reprogramming the profiles of the SASP.

A Humanized Anti-Ganglioside GM2 Antibody, BIW-8962, Exhibits ADCC/CDC Activity against Multiple Myeloma Cells and Potent Anti- Tumor Activity in Mouse Xenograft Models.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1718-1718 ◽  
Author(s):  
Toshihiko Ishii ◽  
Asher Alban Chanan-Khan ◽  
Jazur Jafferjee ◽  
Noreen Ersing ◽  
Takeshi Takahashi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Phase 1 ◽  
Xenograft Model ◽  
Surface Expression ◽  
Scid Mice ◽  
Subcutaneous Xenograft ◽  
Anti Tumor Activity

Abstract BIW-8962 is a humanized anti-ganglioside GM2 (GM2) monoclonal antibody, produced by Poteligent technology to enhance ADCC activity. GM2 is expressed on many cancer cells including multiple myeloma (MM), small cell lung cancer and glioma cells. In this study, we evaluated the anti-myeloma activity of BIW-8962 in preclinical myeloma models both in vitro and in vivo. Expression of GM2 was analyzed in 15 human MM cell lines by FCM. Eleven out of 15 MM cell lines had positive surface expression of GM2. GM2 as a potential target was then verified in primary MM samples obtained from patients. Eleven out of 15 samples were positive for GM2. We then used two GM2 positive MM cell lines (U266B1 and KMS-11) and evaluated ADCC and CDC activity of BIW-8962 in vitro. BIW-8962 exhibited a potent ADCC and less potent CDC activity. In vivo anti-tumor activity of BIW-8962 was then examined using the standard subcutaneous xenograft model; KMS-11 was inoculated in the flank of SCID mice. BIW-8962 (intravenously administered biweekly for 3 weeks) exhibited a potent anti-tumor activity from as low a dose level as 0.1 mg/kg. Furthermore, in a more clinically relevant model, in which OPM-2/GFP (GM2 positive MM cell line) cells were intravenously inoculated into SCID mice with preferentially tumor growth within the bone marrow microenvironment, BIW-8962 (intravenously administered biweekly for 4 weeks, 10 mg/kg) suppressed OPM-2/GFP cell growth and serum M protein elevation, demonstrating in vivo anti-myeloma effect of BIW-8962. Our preclinical investigations rationalize clinical evaluation of BIW-8962 in patients with MM. Currently BIW-8962 is being investigated in a Phase 1 study in patients with multiple myeloma.

A Phase 1/2 Study Of KW-2478, An Hsp 90 Inhibitor, In Combination With Bortezomib (BTZ) In Patients (Pts) With Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1967-1967
Author(s):  
Cavanagh Jamie ◽  
Honorata Giongco Baylon ◽  
Priscilla B. Caguioa ◽  
Faith E. Davies ◽  
Mecide Gharibo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Hsp 90

Abstract Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

Survival study of RTA 744 (currently a single agent phase I study) alone and in combination with temozolomide in orthotopic model of glioma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1577-1577
Author(s):  
C. A. Conrad ◽  
C. Meyer ◽  
T. Madden ◽  
W. Priebe ◽  
F. F. Lang
Keyword(s):  
Median Survival ◽  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Combination Group ◽  
Current Phase ◽  
Preclinical Model ◽  
Orthotopic Model ◽  
Combination Methods

1577 Background: Treatment for high-grade gliomas represents an area of significant unmet medical need, largely because few agents cross the blood-brain barrier (BBB). RTA 744744 (WP744, 4’-O-benzyldoxorubicin hydrochloride) is a potent topoisomerase II poison and novel anthracycline screened for its ability to circumvent P-gp and MRP1allowing it to cross the BBB. To assess the drug’s potential in gliomas, RTA 744 was tested alone or in combination with temozolomide in an intracranial xenograft model of glioblastoma multiforme (GBM). It was hypothesized that a DNA repair inhibitor such as RTA 744 would enhance the effects of temozolomide. In vitro cell based assays confirmed this hypothesis and led to in vivo testing of this novel combination. Methods: U87MG cells were implanted into the right basal ganglia of nu/nu mice via an implantable screw system. In all studies, groups of 5 or 6 mice received PBS, temozolomide, RTA 744, or the combination of RTA 744 and temozolomide administered IP. PBS and temozolomide were given on a QDx5 schedule, and several schedules were tested for RTA 744. The primary endpoint in these studies was survival. Results: In the single agent study, by day 33, all 5 of the control animals had died compared with just one of the RTA 744-treated animals. Median survival for control animals was 28 days versus 37 for RTA 744-treated animals (T/C=132%). In the combination study, median survival was 30 days for controls, 40 days for temozolomide alone (T/C=133%), and 48 days for animals receiving the optimal combination of RTA 744 and temozolomide (T/C=160%). One animal in the combination group survived to day 78, whereas no control or Temodar treated animals survived past days 32 and 45, respectively. Conclusions: RTA 744 demonstrated potent single agent activity in a rigorous preclinical model of GBM. The combination of RTA 744 and temozolomide produced survival results significantly better than those from any chemotherapeutics tested in this model. This data supports the current Phase 1 trial of RTA 744 in patients with brain tumors as well as future trials testing the combination of RTA 744 and temozolomide. [Table: see text]

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