Preliminary Anticancer Activity Research Articles

A first-in-human phase I/II study of HL-085, a MEK Inhibitor, in Chinese patients with NRASm advanced melanoma.

10047 Background: MEK inhibitors have confirmed effects on malignant tumors, especially for those induced by RAS/RAF dysfunction. There is no effective drug in clinic for NRASm advanced melanoma. HL-085 is a selective MEK inhibitor, showing good safety and efficacy in preclinical studies. This study is a phase I/II study to evaluate the safety, tolerability, pharmacokinetic and preliminary anti-cancer activity of HL-085 in patients(pts) with NRASm advanced Melanoma. Methods: The phase I/II study is conducted using a “3+3” regimen for dose escalation. The pts are treated with HL-085 at a starting dose of 0.5mg BID to 18mg BID. Adverse events (AEs) are reported per NCI CTCAE version 5.0. Preliminary anti-cancer activity is evaluated by ORR, DCR, PFS and DoR. Results: Total 33 pts were enrolled in the study. The histologic types were acral (51.4%), mucosal (27.2%) and other (21.2%). The NRAS mutation types were Q61 (72.7%), G12 (18.2%) with half for G12D, and G13 (9.1% ). Most AEs were G1 or G2, and the most common drug-related AEs were rash, increased creatine phosphokinase, peripheral edema, increased alanine aminotransferase and aspartate aminotransferase. No dose-limited toxicity was observed. PK analysis was shown linear PK profile with no obvious accumulation. Among 12 evaluable pts over 9 mg, 4 pts were at the stage of M1c with 1 liver metastasis. Average targeted tumor size was 74.6mm with the largest 184 mm. 10 pts achieved tumor shrinkage [ 60% with Q61, 20% with G12D, 10% each with G12S and G13R]. 4 pts ( 2 acral, 1 mucosal and 1 other, each pt has mutaiton type of Q61R,Q61L, Q61K and G12S respectively ) had confirmed partial response(PR) [median treatment duration 26.6 weeks (wks) with longest 47.6 wks]). 6 pts achieved stable disease (SD) (median treatment duration 15.72 wks with longest 24 wks), and 66.7% were over 14 wks . The median PFS was 17.4 wks, and confirmed best ORR was 33.3% with DCR 83.3% . Conclusions: Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Clinical trial information: NCT 03973151.

A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

467P - Phase I trial of fruquintinib in patients with advanced solid tumors: Results of the dose escalation phase

BackgroundFruquintinib is a potent, highly selective, novel vascular endothelial growth factor receptor (VEGFR) -1, -2, and -3 tyrosine kinase inhibitor. In the phase 3 FRESCO trial1 that led to the drug’s approval in China, fruquintinib improved the median overall survival in patients with metastatic colorectal cancer (mCRC) in a third-line or later setting when compared to placebo (9.3 vs 6.6 months); hazard ratio was 0.65 (95% CI, 0.51-0.83; P<0.001). MethodsThis is a phase 1, open-label, dose escalation/dose expansion study conducted in the United States. The primary objectives are to evaluate the safety and tolerability in patients (pts) with advanced solid tumors and to determine the recommended phase 2 dose (RP2D). A secondary objective is to evaluate anticancer activity. The dose cohorts, 3mg and 5mg qd, were each on a 3 weeks on, 1 week off (3/1) schedule. ResultsThere were 7 pts (6 evaluable) in each dose cohort (14 total). One patient in the 3mg cohort had a dose-limiting toxicity (DLT) of grade 4 hypertension, and no patient in the 5mg cohort had a DLT. The RP2D was determined to be 5mg qd (3/1). Two other serious adverse events, colon obstruction and left breast cellulitis, were reported; neither was suspected to be drug-related. All 14 pts reported AEs; the most common were vomiting (57%), nausea (50%), constipation (50%, proteinuria (50%), hypertension (50%), dysphonia (43%), anorexia (36%), and dyspepsia (36%). Of the 10 pts evaluable for best objective response, 3 had a partial response, 5 had stable disease, and 1 had disease progression. Objective response rate was 3/14 (21.4%) and disease control rate was 9/14 (64.3%). Mean duration on study drug was 5.3 months. ConclusionsFruquintinib is generally well-tolerated in heavily pretreated patients, with the safety profile consistent with that of other anti-angiogenic tyrosine kinase inhibitors. The RP2D in US pts is 5mg qd (3/1), which is also the approved dose in China. Preliminary anticancer activity was evident in these pts with advanced solid tumors. The dose expansion phase of the study is ongoing. Further investigation of fruquintinib in pts with mCRC is planned. 1 JAMA 2018; 319:2486. Clinical trial identificationNCT03251378. Editorial acknowledgementHoang-Lan Nguyen, PhD, Hutchison MediPharma (US), Inc. Legal entity responsible for the studyHutchison MediPharma, Limited. FundingHutchison MediPharma, Limited. DisclosureA. Wang-Gillam: Advisory / Consultancy: Tyme; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bristol-Myer Squibb; Advisory / Consultancy: Jacobio. H. Park: Research grant / Funding (institution): Ambrx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daichi Pharmaceutical; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Gilead; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hoffman-LaRoche; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Vertex Pharmaceuticals; Research grant / Funding (institution): Xencor. F. Songhua: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. N.P. Sauter: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. M. Kania: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. All other authors have declared no conflicts of interest.

Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives.

The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.

A New Approach for Improving the Antibacterial and Tumor Cytotoxic Activities of Pipemidic Acid by Including It in Trimethyl-β-cyclodextrin.

Pipemidic acid (HPPA) is a quinolone antibacterial agent used mostly to treat gram-negative infections of the urinary tract, but its therapeutic use is limited because of its low solubility. Thus, to improve drug solubility, natural cyclodextrins (CDs) are used for their ability of including guest molecules within their cavities. The aim of this work was to evaluate the antibacterial activity and the preliminary anticancer activity of HPPA included into Heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB) as a possible approach for a new innovative formulation. The inclusion complex of HPPA with TRIMEB was prepared in solid state by the kneading method and confirmed by FT-IR and powered X-ray diffraction. The association in aqueous solutions of pipemidic acid with TRIMEB was investigated by UV-Vis spectroscopy. Job’s plots have been drawn by UV-visible spectroscopy to confirm the 1:1 stoichiometry of the host–guest assembly. The antibacterial activity of HPPA, TRIMEB and of their complex was tested on Escherichia coli, Pseudomonas aeruginosa, and Staphilococcus aureus. The complex was able to increase 47.36% of the median antibacterial activity of the free HPPA against E. coli (IC50 = 249 µM vs. 473 µM). Furthermore, these samples were tested on HepG-2 and MCF-7. After 72 h, the median tumoral cytotoxicity exerted by the complex was increased by 78.08% and 94.27% for HepG-2 and MCF-7 respectively, showing a stronger bioactivity of the complex than the single HAPPA.

Abstract CT128: Phase 1 study of FF-21101(90Y), a radioimmunotherapeutic (RIT) targeting P-cadherin, in advanced solid tumors

Abstract Background: Overexpression of P-cadherin, a calcium-dependent cell-to-cell adhesion glycoprotein, correlates with increased tumor cell invasiveness in breast, colon, lung and pancreatic tumors. FF-21101 is a human-mouse chimeric monoclonal antibody directed against P-cadherin, conjugated with 111In for dosimetry and biodistribution and 90Y for therapy. We report the biodistribution and preliminary anti-cancer activity of FF-21101(90Y) in a first-in-human study. Methods: Patients (pts) received 5 mCi/5mg FF-21101(111In) 1 week before the FF-21101(90Y) therapeutic dose to assess biodistribution and ensure 90Y radiation dose estimates did not exceed the maximum tolerated dose (MTD) for each organ. Single therapeutic dose cohorts were planned for FF-21101(90Y) (8 mCi/mg) at 5, 10, 15, 20 or 25 mCi/m2 (3+3 dose escalation schema), with repeat doses allowed every 4 months in pts demonstrating clinical benefit. Disease assessments were based on RECIST V1.1. Pre-treatment tumor samples were assessed for P-cadherin expression by immunohistochemistry (IHC). Pharmacokinetics (PK) of FF-21101 were also assessed. Results: Fourteen pts (6M, 8F) with advanced primary solid tumors and loco-regional metastases were treated in the 5 dose cohorts. Median (range) values: age 58 years (31 – 69), number of prior systemic treatments 3 (0 – 9), tumor types: soft-tissue sarcoma (3), ovarian carcinoma (CA) (2), and vaginal CA, pancreatic neuroendocrine tumor (PNET), desmoplastic small round cell tumor, colorectal CA, appendiceal CA, cholangiocarcinoma, squamous cell CA (SCC) of the anus, papillary thyroid CA and carcinoid (1 each). Primary and/or metastatic tumors from 12 of 14 pts (85.7%) demonstrated uptake of FF-21101(111In) with highest uptake seen in epithelial tumors, consistent with P-cadherin targeting. Median (range) time on study following the therapeutic dose was 21 (2 - 62) weeks, with 3 pts on study &amp;gt; 1 year (2 ovarian CA, 1 carcinoid). Four pts have received multiple treatments. One ovarian CA pt achieved a partial response (65% reduction); this pt also had the highest H score by IHC staining. High H scores (≥ 100) were demonstrated in 5 of 13 pts: 2 ovarian, 1 PNET, 1 SCC of the anus, 1 cholangiocarcinoma; 4 remained on study for 49 - 62 weeks, thus demonstrating the potential predictive utility of pre-treatment tumor P-cadherin expression. FF-21101(90Y) has been well-tolerated; the MTD has not been reached. The most frequently reported drug-related AEs include lymphopenia (n = 8), thrombocytopenia (n = 4) and leukopenia (n = 3); Gr 3 lymphopenia was observed in 3 pts, all reversible. There have been no drug-related serious AEs. Mean FF-21101 Cmax and AUC0-t increased with dose, suggesting linear PK. Conclusions: Tumor P-cadherin overexpression provides an attractive target for RIT. Radiolabeled FF-21101 exhibits favorable dosimetry and biodistribution, good tolerability and preliminary evidence of anti-cancer activity. Pre-treatment tumor P-cadherin expression may be an important biomarker for patient selection. Citation Format: Vivek Subbiah, William Erwin, Osama Mawlawi, Carlos Gonzalez-Lepera, Masahiko Tokura, Michael Kurman, Holly Liu, David S. Hong, Funda Meric-Bernstam, Shubham Pant, Mary Johansen, Timothy Madden, Elmer Santos, Gregory Ravizzini. Phase 1 study of FF-21101(90Y), a radioimmunotherapeutic (RIT) targeting P-cadherin, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT128.

Synthesis and Preliminary Anticancer Activity Study of New 6-Mercaptopurine Derivatives

Synthesis and Preliminary Anticancer Activity Study of New 6-Mercaptopurine Derivatives

Design, synthesis and biological evaluation of chrysin benzimidazole derivatives as potential anticancer agents

A series of chrysin benzimidazole derivatives were synthesised and evaluated for their anticancer activity in the search for potential anticancer agents. Among them, compound 18 displayed the most potent anti-proliferative activity against MFC cells with IC50 values of 25.72 ± 3.95 μM. The flow cytometry results displayed that compound 18 induced apoptosis of MFC cells in a dose-dependent manner and caused the cell cycle to be arrested in the G0/G1 phase. Furthermore, the preliminary anticancer activity in vivo was also studied in tumour-bearing mice, and the compound 18 exerted good inhibition effect on tumour growth. These results suggested that compound 18 had good anticancer activity, which could be a potential anticancer agent after further optimisation and evaluation.

A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated non-squamous non-small cell lung cancer.

9052 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for pts with advanced non-small cell lung cancer (NSCLC). Methods: Pts with metastatic non-squamous NSCLC were enrolled to confirm safety and preliminary anti-cancer activity. Prior platinum-based systemic therapy was required, and patients with an EGFR or ALK mutation required appropriately targeted therapy. Napabucasin was administered orally at a starting dose of 240 or 480 mg BID with PTX 80 mg/m2 IV weekly 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed every 8 weeks per RECIST 1.1. Results: A cohort of 23 pts with advanced non-squamous NSCLC was evaluated. The median number of prior systemic treatment lines was 3, including taxane-based therapy in 100% and immune checkpoint inhibitor in 48% (n = 11). Treatment was well tolerated; related grade 3 AE included diarrhea (n = 4) and fatigue (n = 1). The objective response rate was 26% (6 partial responses [PR]) and the disease control rate (DCR; proportion with SD at 8 weeks plus PR per RECIST) was 70% (n = 16). Tumor regression, including PR, occurred in 35% (n = 8). The median progression-free survival (mPFS) was 5.4 months, and 43% (n = 10) of pts were alive and free of progression at the 24 week time-point or longer. The median overall survival (mOS) was 11.0 months, and 30% (n = 7) of pts were alive for 52 weeks or longer. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with heavily pretreated non-squamous NSCLC who received napabucasin plus weekly paclitaxel. The objective response rate, progression free survival, and overall survival in this population warrant further clinical evaluation and a controlled phase 2/3 trial (CanStem43L) has been initiated. Clinical trial information: NCT01325441.

Spectral Characteristic and Preliminary Anticancer Activity in vitro of Selected Rhodanine‐3‐carboxylic Acids Derivatives

Selected rhodanine‐3‐carboxylic acids derivatives were synthesized to determine the influence of the structure and the length of the linker between the carboxyl group and the nitrogen atom (N‐3) in the 2‐thioxo‐4‐thiazolidinone ring on their activity, monitored via interactions with human serum albumin. Based on fluorescence studies, we concluded that the length of the linker has a limited impact on these interactions. Additionally, we proposed the static mechanism of quenching for all the tested compounds. These derivatives seem to possess an anticancer activity in the nanomolar range with 3 as the most potent compound in both A2780 and A2780cisR cell lines.

Bioassay-guided isolation of cytotoxic flavonoids from aerial parts of Coronopus didymus

Ethnopharmacological relevance:Coronopus didymus Linn. (Brassicaceae) is a medicinal plant used traditionally as antipyretic, expectorant, to purify blood and for alleviating symptoms of pain, inflammations, malaria, wounds and cancer. Aim of the study:The present study was designed to isolate and identify the cytotoxic compounds responsible for anticancer activity from this traditionally useful medicinal plant. Materials and methods:Bioassay-guided fractionation of the ethanolic extract of aerial parts of C. didymus allowed the isolation of compounds responsible for anticancer activity. Their structures were elucidated by UV Spectroscopy (with shift reagents), ESI-MS and NMR spectral data. Preliminary anticancer activity of ethanolic extract, different fractions and isolated compounds was assessed through MTT in vitro cytotoxicity assay in a dose dependent manner against human cancer cell lines (HeLa and LN18) and normal 293T cells. Results:Three flavonoids namely 5,7,4′-trihydroxy-3′-methoxyflavone-4′-O-β-D-glucoside (1), 5,7,4′-trihydroxy-3′-methoxyflavone-4′-O-(6''-acetyl)-β-D-glucoside (2) and 5,7,4′-trihydroxy-3′-methoxy flavone (3), were isolated from aerial parts. Compound 1 was identified for the first time from the genus Coronopus. All the compounds 1–3 showed promising activity against HeLa cells with IC50 values of 43.50, 0.63 and 3.67 µM, respectively. Significant result was also obtained with compound 3 against LN18 cells with IC50 value of 46.63 µM. Conclusion:The cytotoxic activity of the crude extract and fractions which may largely be due to its major isolated constituents, flavonoids 1–3, against both HeLa and LN18 cells provides a scientific basis for the ethnopharmacological use of C. didymus as anticancer agent.

Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway.

The preliminary anti-cancer activity of Naringenin (Nar) has been proven in several cancers. However, the therapeutic activity of Nar on gastric cancer SGC-7901 cell line is not yet well understood. The aim of the present study was to investigate the effect and mechanisms of Nar on proliferation, apoptosis, migration, and invasion of SGC-7901 cells. In this in vitro study, SGC-7901 cells were treated with Nar at serial concentrations. Our data showed that Nar efficiently inhibited SGC-7901 cell proliferation in a time- and concentration-dependent manner, as well as downregulated proliferating cell nuclear antigen (PCNA) levels in a concentration-dependent manner. Meanwhile, the cell migration and invasion also dramatically decreased after Nar incubation, and the expressions of MMP2 and MMP9 were significantly downregulated. In addition, a strong proapoptotic effect was observed in the SGC-7901 cells after Nar treatment. Apoptosis-related proteins Bax and cleaved caspase-3 were up-regulated, whereas Bcl-2 and Survivin were downregulated. After administration with Nar, we found that phosphorylation of AKT was inhibited, and this inhibitory action could be mildly enhanced by the combination treatment of Nar and AKT inhibitor LY294002. In conclusion, our study confirmed that Nar could inhibit SGC-7901cell proliferation, migration, and invasion as well as induces apoptosis, and Nar might provide a new potential therapeutic strategy for treating gastric cancer.

Synthesis of hexahydrofuro[3,2-c]quinoline, a martinelline type analogue and investigation of its biological activity.

BackgroundCandida susceptibility commonly occurs in breast cancer patients. Of which, Candida albicans is considered as a common pathogen causing candidiasis. Martinella iquitosensis (Bignoniaceae) is one of the species belonged to Martinella, distributed widely in Amazon basin. Its root extract yielded two complex substituted tetrahydroquinolines, Martinelline and Martinellic acid which were the first natural non-peptide bradykinin receptor antagonists identified.FindingsIn this study, a novel martinelline type analogue, named 2,3,3a,4,5,9b-hexahydro-8-phenoxy-4-(pyridin-2-yl)furo[3,2-c]quinoline, was synthesized and its preliminary anticancer activity and antifungal potential were investigated. This compound showed potential anticancer activity against MDAMB-231 breast cancer cells. Meanwhile it could enhance the fungistatic activity of miconazole against Candida albicans.ConclusionsThese findings provide an implication for the continue investigation and development of martinelline type analogues as therapeutic agents in the future.

A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer.

196 Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.

A phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 in combination with gemcitabine and nab-paclitaxel (nab-PTX) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).

284 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that works by blocking STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo, in mono- and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with mPDAC was performed to determine RP2D, safety, tolerability, and preliminary anti-cancer activity of BBI-608 in combination with Gemcitabine and nab-PTX. BBI-608 was administered at 240 mg BID in combination with Gemcitabine 125 mg/m2 and nab-PTX 1000 mg/m2administered weekly for 3 out every 4 weeks until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 31 pts were enrolled and received BBI-608 in combination with Gemcitabine and nab-PTX for a total sum of 83 study cycles. 25 of 31 pts (80.6%) were treatment-naïve and 6 pts (19.4%) received 1 prior line of systemic therapy. Most common adverse events included grade 1 diarrhea, abdominal pain, nausea, and fatigue. Combination treatment was well tolerated with no dose-limiting toxicity observed and safety profile similar to that of each agent individually. One patient experienced grade 3 event of dehydration related to protocol therapy which resolved with hydration. Of the 8 pts enrolled in the RP2D determination portion of the study, 7 pts were evaluable for response with disease control (PR + SD) was observed in 7/7 pts (100%). Tumor regression was observed in 6/7 (85.7%) with 3 PR (41.3%, 37.6% and 33.3% regression) and 3 SD (25.8%, 21.1%, and 19.9% regression). The median progression free survival was 7.8 months with PR or SD of &gt; 6 months in 6/8 pts (75%). Conclusions: This phase Ib study demonstrated that BBI-608 at 240 mg BID can be safely combined with Gemcitabine and nab-PTX. Encouraging anti-tumor activity with durable response was observed in pts with mPDAC. Clinical trial information: NCT02231723.

2-Alkyl(aryl)-quinazolin-4(3H)-thiones, 2-R-(quinazolin-4(3H)-ylthio)carboxylic acids and amides: synthesis, molecular docking, antimicrobial and anticancer properties

In this study, a series of novel 2-alkyl(aryl)-quinazolin-4(3H)-thiones, 2-R-(quinazolin-4(3H)-ylthio)carboxylic acids and amides were synthesized and evaluated for antimicrobial and anticancer activities. Their structure was confirmed by elemental analysis and spectral data (FT-IR, LC-MS, 1H-NMR). Antimicrobial activity was tested in vitro against Staphylococcus aureus, Enterococcus faecalis, Enterobacter aerogenes, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, Candida albicans and NCI in vitro preliminary anticancer activity against nine different cancer types. The most active antibacterial and antifungal compounds were: 2.1, 2.2 and 2.4. The introduction of the carboxylic acid or amide residue into the fourth position of quinazolin-4(3H)-thione resulted in the absence of antimicrobial activity. Substance 3.8 inhibited renal cancer UO-31 line and 2.18 – leukemia CCRF-CEM. The results of in silico molecular docking for DHFR and CK2 kinase had no correlation with in vitro properties, proposing the presence of other biological activity pathways.

Combining anti-cancer drugs with artificial sweeteners: Synthesis and anti-cancer activity of saccharinate (sac) and thiosaccharinate (tsac) complexes cis-[Pt(sac)2(NH3)2] and cis-[Pt(tsac)2(NH3)2

The new platinum(II) complexes cis-[Pt(sac)2(NH3)2] (sac=saccharinate) and cis-[Pt(tsac)2(NH3)2] (tsac=thiosaccharinate) have been prepared, the X-ray crystal structure of cis-[Pt(sac)2(NH3)2].H2O reveals that both saccharinate anions are N-bound in a cis-arrangement being inequivalent in both the solid-state and in solution at room temperature. Preliminary anti-cancer activity has been assessed against A549 human alveolar type-II like cell lines with the thiosaccharinate complex showing good activity.

439O - A First-In-Human Dose-Finding Study of the Alk/Egfr Inhibitor AP26113 in Patients with Advanced Malignancies

ABSTRACT Disclosure G.J. Weiss: GJW has received funds and other support related to participation in this clinical trial from ARIAD Pharmaceuticals, Inc. through his employer, Scottsdale Healthcare. GJW has served on Speakers Bureaus for Genentech, Pfizer, and Eli Lilly. N.I. Narasimhan: NIN is an employee of ARIAD Pharmaceuticals, Inc. D.J. Dorer: DJD is an employee of ARIAD Pharmaceuticals, Inc. V.M. Rivera: VMR is an employee of ARIAD Pharmaceuticals, Inc. J. Zhang: JZ is an employee of ARIAD Pharmaceuticals, Inc. T. Clackson: TC is an employee of ARIAD Pharmaceuticals, Inc. F. Haluska: FH is an employee of and owns stock/stock options in ARIAD Pharmaceuticals, Inc. A.T. Shaw: ATS has received consulting fees/honorarium from ARIAD, Pfizer, Chugai, and Daiichi. ATS has received support in the form of grants paid to her employer by Novartis and AstraZeneca. D.R. Camidge: DRC has received consulting fees/honorarium from ARIAD and has served on advisory boards for Pfizer, Chugai, Novartis, and ARIAD. All other authors have declared no conflicts of interest. AP26113 is a novel, synthetic, orally-active tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), as well as TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. This is the initial report of a phase 1/2 open-label, multicenter study of AP26113. The dose finding phase (3 + 3 design) is ongoing in patients (pts) with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is once daily. As of 07 May 2012, 15 pts were enrolled: 30 mg n = 3, 60 mg n = 3, 90 mg n = 5, 120 mg n = 4; 67% female, median age 65 (41–77) yrs. Diagnoses were: 11 non-small cell lung cancer (NSCLC), 4 other (1 pancreatic, 1 colon, 1 cholangiocarcinoma, 1 adenocarcinoma of unknown primary [ACUP]). Ten pts had a documented history of ALK+ (n = 5; 4 NSCLC, 1 ACUP) or EGFRm (n = 5; all NSCLC). Pts were heavily pretreated. Four ALK+ NSCLC pts failed prior crizotinib therapy. Four pts with EGFRm failed prior EGFR-targeted therapy. Eight pts discontinued (7 disease progression, 1 investigator decision). The most common adverse events (AEs; >3 patients) were: fatigue (n = 4; 3 grade 1/2, 1 grade 3), nausea (n = 4; grade 1). No treatment-related serious AEs were observed. No DLTs were observed; the 120 mg dose level remains under evaluation. At 90 mg (n = 3), Day 29 geometric mean Cmax, Ctrough, AUC(0-24hr), and t1/2 were: 402 ng/mL, 170 ng/mL, 6130 ng*hr/mL, 29 hr, respectively. At the time of analysis, 8 pts had ≥1 set of tumor response measurements starting ≥8 weeks after first dose. Partial responses were observed in 4 of 4 ALK+ pts (60 mg n = 1; 90 mg n = 3, including the crizotinib-naive ACUP pt). Anti-tumor activity at 120 mg remains to be evaluated. In summary, AP26113 was well tolerated with preliminary anti-cancer activity in ALK+ pts naive to or failing prior crizotinib. The phase 2 expansion will include 4 cohorts: ALK+ NSCLC that is 1) naive or 2) resistant to prior ALK-targeted therapy; 3) EGFRm NSCLC that is resistant to EGFR-targeted therapy; 4) other cancers with abnormalities in ALK or other AP26113 targets. ClinicalTrials.gov: NCT01449461.

A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours.

9542 Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK &amp; ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged &gt;2 to &lt;19 years with relapsed/ refractory solid tumours. Results: Eighteen patients treated with a median age of 10 (range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2/day. The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 neuroblastomas, 3 sarcomas &amp; 3 others. There has been only one dose limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2/day. The majority of adverse events (AEs) have been grade 1/2 &amp; considered unrelated/ unlikely related to study drug. Two patients have experienced Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m2/day &amp; Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count and aspartate transaminase in a patient treated at 11.5 mg/m2/day. Pharmacokinetics of AT9283 in this population are largely in keeping with those seen in adult patients at similar doses (Arkenau et al., 2011) although there may be greater variability. Pharmacodynamic evidence of aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation in normal skin biopsies pre &amp; post infusion, has been documented at all dose levels tested. Stable disease (up to 6 cycles) has been observed in 3 patients. Conclusions: This paediatric phase I study has demonstrated AT9283 administered as a 72 hour continuous infusion can be given at a dose level of 11.5 mg/m2/day which is higher than the maximum tolerated dose observed in adult patients (9 mg/m2/day) with advanced solid tumours. Myelosuppresion is the main toxicity but the regimen is well tolerated with preliminary anticancer activity seen in heavily pre-treated paediatric patients. [Table: see text]

Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with renal cell carcinoma (RCC) from a phase I study.

4545 Background: Inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptor are standard therapy for RCC, and the MET signaling pathway is implicated in tumor angiogenesis. Tivantinib is an oral, selective MET inhibitor. In several tumor models, tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Previously, dose escalation established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with RCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. Results: 20 pts (mean age, 60 yr) including 16 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts received treatment at the RP2D (n = 19) or tivantinib 360 mg BID plus sorafenib 200 mg BID (n = 1). 4 pts are still on study. 16 pts (13 with clear cell RCC) received ≥ 1 previous systemic therapy (median, 2; range, 0-4) including VEGF (14 pts) and/or mTOR (5 pts) inhibitors. The most common (≥ 25%) adverse events were rash (65%), diarrhea (45%), alopecia (40%), hypophosphatemia (35%), and fatigue, stomatitis, palmar-plantar erythrodysesthesia syndrome, and pruritus (25% each). Best response was partial response (PR) in 3 pts (all clear cell RCC pts) and stable disease (SD) in 15 pts (11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts). 7 pts with SD had ≥ 10% tumor size reduction. The overall response rate (ORR) and disease control rate (DCR; PR + SD) were 15% and 90%, respectively. Median progression-free survival (mPFS) was 12.7 mo (95% CI, 7.1-14.5 mo). In 14 pts previously treated with a VEGF inhibitor, best response was 2 PR and 10 SD, the ORR and DCR were 14% and 86%, respectively, and mPFS was 12.7 mo (95% CI, 5.3-NR mo). Conclusions: Oral combination therapy with tivantinib plus sorafenib was well tolerated and exhibited preliminary anticancer activity in pts with RCC, including pts pretreated with VEGF inhibitors.