First-in-human study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3599-3599 ◽  
Author(s):  
J. H. Schellens ◽  
C. D. Britten ◽  
D. R. Camidge ◽  
D. Boss ◽  
S. Wong ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tyrosine Kinases ◽  
Human Study ◽  
Xenograft Model ◽  
Tumor Growth Inhibition ◽  
Her Family ◽  
Molecule Inhibitor ◽  
Hand Foot Syndrome ◽  
Fdg Pet Ct ◽  
Dose Levels

3599 Background: There are scientific rationale for inhibitors which provide combined and irreversible blockade of HER family members. PF-00299804 is an orally available, potent, irreversible small molecule inhibitor of the HER tyrosine kinases. Methods: The safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles were assessed in patients with advanced solid tumors using an accelerated dose-escalation design. Safety assessments included adverse event (AE), laboratory, ECG, and LVEF assessments. PK parameters were determined after a single lead-in dose and on Day 14 by non-compartmental techniques. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG- PET/CT has been performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Results: 32 pts have been treated across 8 sequential dose levels ranging from 0.5 to 60 mg. The most common AEs were diarrhea, fatigue, nausea, and rash. 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Cmax and AUC of PF-00299804 increased with dose in an approximately proportional manner. Accumulation ranged from 3.3 to 6.8, suggesting a terminal t1/2>24 h. At the 30 mg dose level, mean Day 14 drug concentration was above the predicted efficacious concentration for tumor growth inhibition based on A431 xenograft model. Of 7 sets of PET data evaluated thus far, partial responses (PR) have been observed in 2 patients. A PR as assessed using RECIST criteria has been reported in 1 of 2 patients with advanced refractory NSCLC treated to date. Conclusions: Daily administration of PF-00299804 across many dose levels appears safe and tolerable. Diarrhea, fatigue, nausea, and rash are the most frequent AEs. Evaluation of 45 mg/d as the potential MTD is ongoing. Systemic exposures at doses = 30 mg exceed the threshold for efficacy as predicted from preclinical studies. Clinical and biological activity of PF-00299804 was observed including a PR in 1 of 2 patients with advanced refractory NSCLC. No significant financial relationships to disclose.

A phase I study of sunitinib in combination with sirolimus in adults with advanced refractory malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3554-3554
Author(s):  
J. Li ◽  
H. Kluger ◽  
M. W. Saif ◽  
J. R. Murren ◽  
J. J. Lee ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Dose Schedule ◽  
Molecule Inhibitor ◽  
Hand Foot Syndrome ◽  
Ecog Ps ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Multiple Receptor

3554 Background: Sirolimus, a commercially available oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases (RTKs), by vertical disruption of VEGFr signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients, and also by directly inhibiting tumor cell proliferation. Methods: Sunitinib was given at 50 mg daily (d) x 28 q6w. The dose of sirolimus was escalated in cohorts of 3–6 beginning at 4 mg weekly until the MTD was determined. The first cohort received sunitinib alone 50mg d x 14 followed by 14 days off in cycle #1. After the 4mg sirolimus dose cohorts, sunitinib dose was reduced in subsequent cohorts to 37.5mg, and dose escalation of sirolimus was re-initiated at 4mg. Results: 18 patients (pts) with ECOG PS <2 were enrolled, median age 57yo (r:24–76), M:F: 11:7. Median # of prior treatments (Rx): 2(r:0–5), 6 had no prior systemic Rx. Disease primary sites: GI-5 (28%), renal cell- 4 (22%), melanoma-2, soft tissue sarcoma (STS)-2, adenoca unknown 10-2, breast-1, H&N-1, NSCLC-1. At the 50/4 dose level, 4 of 8 required dose reduction (DR) or early discontinuation (ED) of Rx in cycle #1. At the 37.5/4 and 37.5/8 dose levels, 3/9 required DR or ED in cycle #1 or starting cycle #2. Several pts able to complete 1–2 cycles at full dose had significant toxicities including fatigue and hand-foot syndrome. 1 pt developed interstitial pneumonitis, 1 pt died on day 8 due to progressive disease. Four pts received >4 cycles (5-STS, 5-renal papillary, 13-neuroendocrine pancreas, 17-renal clear cell). Among 16 pts undergoing restaging, there was no CR or PR. 5 other pts demonstrated transient central necrosis or size reduction in some tumors. There was no apparent PK interaction at the 4mg sirolimus dose level, and no clear effect on sunitinib-induced increase in circulating VEGF levels. Conclusions: Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature. [Table: see text]

scholarly journals Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy

2014 ◽  
Vol 15 (12) ◽  
pp. 1635-1645 ◽  
Author(s):  
Qiaoling Sun ◽  
Jinghong Zhou ◽  
Zheng Zhang ◽  
Mingchuan Guo ◽  
Junqing Liang ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

A Small-Molecule Inhibitor Screen Rapidly Identifies Therapeutic Targets and Individualized Therapeutic Strategies In Patients with Acute and Chronic Leukemias

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2754-2754
Author(s):  
Jeffrey W Tyner ◽  
Stephen Spurgeon ◽  
Luke B Fletcher ◽  
Wayne Yang ◽  
Tibor Kovacsovics ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Leukemia Cell ◽  
Small Molecule Inhibitor ◽  
Tyrosine Kinase Signaling ◽  
Kinase Activation ◽  
Molecular Abnormalities ◽  
Molecule Inhibitor ◽  
Primary Leukemia

Abstract Abstract 2754 The development of more effective and less toxic therapies for acute and chronic leukemias will require the identification of the molecular abnormalities contributing to leukemogenesis and the identification of drugs that specifically block the activity of these lesions. We hypothesize that aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of a substantial proportion of leukemia cases, and our preliminary data suggest that the molecular abnormalities causing aberrant kinase activation are unique in a significant number of patients. Thus, effective therapies for leukemia will need to be determined on an individual patient basis. To address this need, we have developed a function-first, small-molecule kinase inhibitor assay that can identify therapeutic targets in tyrosine kinase signaling pathways in primary leukemia samples and provide individualized therapeutic options in a clinically relevant time frame. Methods: To rapidly identify drug sensitivity profiles and activated kinase pathways in individual, primary leukemia samples, we have developed a small-molecule inhibitor array which includes 90 small-molecule, cell-permeable inhibitor compounds including a core of 36 tyrosine kinase inhibitors that collectively target the majority of the tyrosine kinome. Many of the inhibitors are available for clinical use or are in clinical development. Inhibitors were placed in 96-well plates at four serial dilutions to allow IC50 calculations. Three days after adding primary leukemia cells to each well, we performed a tetrazolium based cell viability assay to evaluate the effect of each inhibitor. Because most inhibitors affect multiple kinases, we utilized automated scripts to compare target specificities of compounds that uniquely decreased primary leukemia cell viability to identify potential targets. Results: In preliminary proof-of-principal experiments, we tested leukemia cell lines and primary leukemia samples with known activating tyrosine kinase mutations and Ba/F3 cell lines expressing activated tyrosine kinases. As expected, all cells showed hypersensitivity to compounds with activity against the primary, mutated target. In addition, downstream targets were frequently identified. For example, MKPL-1 cells, which depend on an activating CSF1R translocation for viability, also showed sensitivity to phosphoinositol 3-kinase and NFKB inhibitors. To date, we have fully analyzed approximately 150 primary myeloid and lymphoid leukemia samples. Hierarchical clustering of IC50 data for individual patients identifies activated pathways characteristic to specific leukemia subtypes. Pathways include PI3K activation in acute lymphoblastic leukemia, SRC kinase and BTK activation in chronic lymphocytic leukemia, FLT3 and KIT activation in AML patients, and MEK kinase activation in chronic myelomonocytic leukemia. Importantly, the results show heterogeneous inhibitor sensitivity profiles and potential kinase targets for individual samples even within diagnosis groups supporting a need for individualized targeted therapies. We are currently utilizing inhibitor assay results for clinical trial development. Approximately 40% of samples show sensitivity to at least one FDA approved drug in the inhibitor panel, and we are developing phase II proof-of-concept trials to test the ability of the inhibitor assay to predict effective targeted therapies for individual patients. Conclusions: Our data demonstrate that the small-molecule inhibitor functional assay can rapidly identify genes contributing to leukemogenesis, provide insights into their mechanism of action, and suggest therapeutic options. The unique patterns of inhibitor sensitivity in many samples support the hypothesis that tyrosine kinases and related pathways contributing to leukemogenesis in each patient may be different. These findings, in turn, support the concept that targeted therapy will be most effective when administered on an individualized basis. By utilizing our pre-clinical assay to select individualized leukemia therapies, we hope to create a platform upon which we can rapidly test the effectiveness of individualized kinase therapy and apply this information to enhance development of new drugs and new drug combinations in leukemia patients. Disclosures: Kovacsovics: Celator Pharmaceuticals: Research Funding. Druker:Molecular MD: Consultancy, Equity Ownership. Loriaux:Celator Pharmaceuticals: Research Funding.

Characterization of BMS-911543, a Functionally Selective Small Molecule Inhibitor of JAK2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4112-4112 ◽  
Author(s):  
Ashok V Purandare ◽  
Animesh Pardanani ◽  
Theresa McDevitt ◽  
Marco Gottardis ◽  
Terra Lasho ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cell Types ◽  
Small Molecule Inhibitor ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
In Vivo Models ◽  
Molecule Inhibitor ◽  
Transcriptional Changes ◽  
Dose Levels

Abstract Abstract 4112 We report the characterization of BMS-911543, a potent and functionally selective small molecule inhibitor of the Janus kinase family (JAK) member, JAK2. BMS-911543 is a reversible inhibitor of JAK2 with a biochemical IC50 of 0.001 μ M and Ki of 0.48 nM. It has over 74- and 350-fold selectivity against the other JAK family members, JAK3 and JAK1, respectively. Further, examination of > 450 other kinases did not reveal significant inhibitory activity for this JAK2 inhibitor. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in mutated JAK2-expressing cell lines dependent upon JAK2-STAT signaling and had little activity in cell types dependent upon other pathways such as JAK1 and JAK3. BMS-911543 was evaluated in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative disease (MPD) and resulted in an increased anti-proliferative response in MPD cells as compared with those from healthy volunteers. Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2-pSTAT signaling in multiple species (mouse, rat, dog and monkey) with sustained pathway suppression being observed after a single oral dose. Additionally, BMS-911543 was evaluated for effects in a JAK2V617F-expressing SET-2 xenograft model system and displayed a minimally effective dose of <2 mg/kg on pSTAT5 pathway suppression, which lasted up to 8 hours. BMS-911543 was also compared to pan-JAK inhibitors in a mouse model of immunosuppression. At low dose levels active in JAK2-dependent PD models, no effects were observed on antigen-induced IgG and IgM production whereas a pan-JAK family inhibitor showed pronounced effects at all dose levels tested. The mechanistic selectivity of BMS-911543 to pan-JAK family inhibitors was extended through comparative analysis of these inhibitors in whole genome gene expression profiling experiments performed in sensitive cell types. In this comparison, BMS-911543 modulated a distinct subset of transcriptional changes as compared to pan-JAK inhibitors, thereby defining a minimal set of transcriptional changes underlying the pharmacologic effects of JAK2 inhibition. Collectively these results define the mechanistic basis for a differential therapeutic index between selective JAK2 and pan-JAK family inhibition pre-clinically and suggest a therapeutic rationale for the further characterization of BMS-911543 in patients with MPD and in other disorders characterized by constitutively active JAK2 signaling. Disclosures: Purandare: Bristol-Myers Squibb: Employment. McDevitt:Bristol-Myers Squibb: Employment. Gottardis:Bristol-Myers Squibb: Employment. You:Bristol-Myers Squibb: Employment. Lombardo:Bristol_Myers Squibb: Employment. Penhallow:Bristol-Myers Squibb: Employment. Vuppugalla:Bristol-Myers Squibb: Employment. Trainor:Bristol-Myers Squibb: Employment. Lorenzi:Bristol-Myers Squibb: Employment.

Efficacy of vemurafenib (V), a selective V600EBRAF inhibitor, as monotherapy or in combination with erlotinib (Erl) or erbitux (Erb) and irinotecan (Iri) doublets and triplets in a colorectal cancer (CRC) xenograft model.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 494-494
Author(s):  
Brian Higgins ◽  
Kenneth Daniel Kolinsky ◽  
Kathleen Schostack ◽  
Gideon Bollag ◽  
Richard J. Lee ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mapk Pathway ◽  
Single Agent ◽  
Xenograft Model ◽  
Optimal Dose ◽  
Tumor Growth Inhibition ◽  
Egfr Inhibition ◽  
Final Study ◽  
Molecule Inhibitor ◽  
Better Than

494 Background: B-Raf mutations, particularly at V600 occur in 10% of CRCs resulting in constitutive activation of the MAPK pathway. V (RG7204, PLX4032) is a first-in-class, V600B-Raf-selective small molecule inhibitor previously shown to potentiate anti-tumor effects in the V600E CRC xenograft model HT29 in combination (combo) with capecitabine ± bevacizumab (ASCO GI, 2008). V600E CRC respond poorly to EGFR inhibition (EGFRi) both preclinically and clinically. We aimed to determine whether antitumor activity could be potentiated by combining V with EGFRi. Methods: The monotherapy (mono) activities of V, Erl, Erb and Iri were compared to combo of these agents in the HT29 model. V was tested as a mono at its optimal dose (OD), Erl was tested at its MTD or 2/3 MTD, and a combo of V OD + 2/3 MTD Erl were tested. V was subsequently tested as mono or combo at the OD and suboptimal-OD with OD Erb. A final study included Iri as mono, doublets of Iri + V or Erb, and triplet combo of Iri, V, and Erb. Results: Tumor growth inhibition (TGI) and increase in life span (ILS) for combo of OD V + 2/3 MTD Erl was superior to all mono arms. TGI in mono arms was equivalent for V, Erb and Iri. ILS was better for V vs Iri and Erb mono, while Iri vs Erb ILS were equivalent. TGI and ILS for Iri + Erb doublet was equivalent to V mono. Otherwise, TGI and ILS in all other doublets and triplets were superior to mono groups. TGI in V + Erb and V + Iri were equivalent, but ILS was better for V + Iri. TGI and ILS for V + Iri was better than Iri + Erb. TGI in V + Erb was better than Iri + Erb, but ILS was equivalent. TGI in the triplet was superior to all doublets except V + Erb, however ILS was superior to all doublets tested. Conclusions: V potentiates anti-tumor activity in a V600E CRC model when used in combo with Erl, Erb and Iri. Although a V + Erb doublet provided impressive TGI equivalent to a triplet with Iri, the triplet yielded sustained antitumor activity as demonstrated by a significant increase in survival as compared to the doublet. Combo with V may afford V600E CRC patients a differential response to what is seen traditionally with single agent EGFi and is worthy of clinical exploration.

Development of a Small-Molecule Inhibitor Screen to Rapidly Identify Key Signaling Pathways in Leukemogenesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 708-708
Author(s):  
Jeffrey W Tyner ◽  
Luke Fletcher ◽  
Wayne Yang ◽  
Stephen T Oh ◽  
Jason R. Gotlib ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Viability ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Leukemic Cell ◽  
Small Molecule Inhibitor ◽  
Kinase Activation ◽  
Molecule Inhibitor

Abstract Abstract 708 Aberrantly activated tyrosine kinases and their associated signaling pathways are critical to leukemogenesis and primary acute myeloid leukemia (AML) cell viability. While aberrant kinase activation has been confirmed in a significant percentage of AML, constitutive phosphorylation of STAT5, a marker of tyrosine kinase activation, is present in the majority of AML samples indicating that as yet unidentified tyrosine kinases can be aberrantly activated and contribute to leukemogenesis. Efforts to identify activating tyrosine kinase mutations using high-throughput sequencing have identified low frequency mutations of uncertain functional significance. Because these studies failed to detect additional high-frequency kinase mutations, the identity and mechanism of tyrosine kinase activation may be unique in many AMLs. To avoid the imitations of high-throughput sequencing, we have developed a functional assay that can rapidly and simultaneously identify therapeutic targets while providing therapeutic options. Methods: To rapidly identify activated kinase pathways in individual, primary AML samples, we have developed a small-molecule inhibitor array which includes 90 small-molecule, cell-permeable inhibitor compounds including a core of 36 tyrosine kinase inhibitors that covers the majority of the tyrosine kinome. Many of the inhibitors are available for clinical use or are in clinical development. In this assay, inhibitors were placed in 96-well plates at four serial dilutions to allow IC50 calculations. Three days after adding primary AML cells to each well, we performed an MTS cell viability assay to evaluate the effect of each inhibitor on cell viability. Because most inhibitors affect multiple kinases, we compared target specificities of compounds that decrease primary AML cell viability with those that have no effect to identify potential targets. Results: In preliminary proof-of-principal experiments, we tested leukemia cell lines with known activating tyrosine kinase mutations and Ba/F3 cell lines expressing activated tyrosine kinases. Appropriate inhibitor sensitivity profiles were obtained in CMK cells which depend on a JAK3 A572V mutation for viability, MKPL-1 cells with an activating CSF1R translocation, and in a Ba/F3 line expressing JAK2 V617F. In addition to the primary target, downstream targets were frequently identified; MKPL-1 cells also showed sensitivity to phosphoinositol 3-kinase and NFKB inhibitors. Thus, not only primary targets but the downstream signaling pathways critical to leukemic cell viability can be highlighted using this assay. To date, we have analyzed approximately 150 primary leukemia and lymphoma samples. In some cases, targets could be identified by comparison of overlapping kinase specificities for compounds that decreased leukemic cell viability and subtraction of possible kinase targets inhibited by compounds that had no effect on viability. However, many cases exhibited complex, often unique, inhibitor sensitivity profiles that complicated target identification. Comparison with sensitivity profiles for known aberrantly activated kinases was useful when available. Accordingly, additional leukemia cell lines and Ba/F3 lines that depend on a single aberrantly activated tyrosine kinase for viability are being evaluated. Automated scripts that correlate the leukemic cell inhibitor sensitivity with the inhibitor target specificity are also in preparation. Conclusions: These preliminary data demonstrate that the small-molecule inhibitor functional assays can rapidly identify disease causing genes, provide insights into their mechanism of action, and suggest therapeutic options. The distinct patterns of tyrosine kinase sensitivity in these samples support the hypothesis that tyrosine kinases and related pathways contributing to leukemogenesis in each patient may be different and that targeted therapy will be most effective when administered on an individualized basis. Disclosures: Druker: OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding.

scholarly journals A Small Molecule Inhibitor of ETV1, YK-4-279, Prevents Prostate Cancer Growth and Metastasis in a Mouse Xenograft Model

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e114260 ◽  
Author(s):  
Said Rahim ◽  
Tsion Minas ◽  
Sung-Hyeok Hong ◽  
Sarah Justvig ◽  
Haydar Çelik ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Xenograft Model ◽  
Small Molecule Inhibitor ◽  
Cancer Growth ◽  
Mouse Xenograft ◽  
Molecule Inhibitor ◽  
Mouse Xenograft Model
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