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Primer sequences and SUSD2 protein-protein interaction database

RNA-seq genes_FC 1.2, P 0.05

RNA-seq IPA analysis and gene list of adipocytes cocultured with OVCAR5-RFP cells

Supplemental Figures 1-6

Mecap-Seq genes altered by guadecitabine_FC 10, FDR 0.05

Mecap-Seq hypomethylated, hypermethylated genes that were also upregulated, downregulated, respectively in RNA-seq

Mecap-Seq, RNA-seq, and Integrated IPA pathways

Purpose:Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer.Patients and Methods:Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).Results:Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.Conclusions:Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.

Table S1 shows dose levels of ASTX660 by cohort

Table S1. Efficacy Table S2. Descriptive Statistics of Guadecitabine Plasma Pharmacokinetic Parameters Table S3. Descriptive Statistics of Decitabine Plasma Pharmacokinetic Parameters Table S4. Genes Tested for Methylation and Expression Analysis of Tumor Biopsies Table S5. All AEs of CTCAE Grade 3 or Higher

Figure S1 shows ASTX660 dose proportionality-power model analyses on AUC0-24 and Cmax by formulation.

Materials and Methods

Description of cell lines used in the study

Supplementary Data from Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer

Supplementary Figure S1 and supplementary tables

Purpose:Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P.Patients and Methods:Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (regimen 1); or at 120 mg/m2 on day 1 and day 2 weekly for 3 of 4 weeks (regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTC) and in fresh tumor tissue biopsies.Results:Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose limiting at 260 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients showed an objective or PSA response.Conclusions:Onalespib in combination with AA/P showed mild evidence of some biological effect; however, this effect did not translate into clinical activity, hence further exploration of this combination was not justified.

Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC).Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4.Results: Twenty patients were enrolled and treated. Median age was 56 years (38–72 years). The median number of prior regimens was 7 (1–14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ≥3 adverse events ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded.Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285–93. ©2018 AACR.

Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status.Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed.Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP “trapping” by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models.Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers. Clin Cancer Res; 24(13); 3163–75. ©2018 AACR.

Purpose:This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma.Patients and Methods:ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D.Results:Forty-five patients received ASTX660 (range 15–270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5–1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma.Conclusions:ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing.

Supplementary methods

Supplemental Figure S1: PEO1 cells ectopically expressing vector control or BRCA2 were subjected to (A) RAD51 foci formation assay or (B) treated with increasing concentrations of Cisplatin (CDDP) and subjected to MTT assay for IC50 determination. DNMT1 expression was measured in PEO1 and PEO4 cells treated with or without 1nM Talaz by (C) qRT-PCR or (D) Western blot analysis (bottom: Images were quantified using ImageJ software and quantification is representative of three independent experiments {plus minus} SEM; two-tailed student's t-test). (E) PEO1 (Top) and PEO4 (Bottom) cells were treated with 20nM guadecitabine (Guad) and 1nM talazoparib (Talaz), alone or in combination for 72hrs. 24hrs post treatment caspase 3/7 activity assay was performed. Results are representative of at least three independent experiments. (F) Ovarian cancer cells were treated with the indicated dose of 5- azacytidine (AZA) and talazoparib (Talaz), alone or in combination for 72hrs. Supplemental Figure S2: A panel of OC cell lines (see table for description: Supplemental Table 1) was treated with (A-G) 20nM guadecitabine (Guad), (H-I) 5-azacytidine (AZA), or 1nM talazoparib (Talaz), alone and in combination. Following treatment cells were subjected to clonogenic survival assays and drug synergism analysis; x-axis is indicative of Fraction affected (FA); y-axis is indicative of combination index (CI). Combinations beneath dashed black line are synergistic. Combination treatment schemas are as followed: Priming ('Prime') daily treatment with 20nM Guad for 3 days, 24hrs recovery, followed by one treatment with 1nM Talaz or Co-administration ('Co-ad') treatment with both 20nM guadecitabine (Guad) and 1nM talazoparib (Talaz) on day 1, and 20nM Guad on days 2 and 3. Results are representative of at least three independent experiments {plus minus} SEM. * p

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Overactivation of mitogen-activated protein kinase (MAPK) signaling is a frequently observed driver of many cancers. Targeted MAPK pathway inhibitors have been approved as therapies in patient populations with genomic alterations to MAPK pathway genes (e.g. dabrafenib in BRAF-mutant melanoma), with multiple other MAPK-targeted therapies in development. We have previously demonstrated that cell lines with MAPK pathway genomic alterations show increased sensitivity to ASTX029, our potent and selective dual-mechanism ERK inhibitor which is currently undergoing clinical development. However, MAPK oncogene status alone is not a universal indicator of sensitivity, nor is it clear that genomic markers of sensitivity to single agent inhibition represent the optimal approach to predicting response to MAPK targeted agents in the combination setting (e.g. sotorasib + trametinib). We therefore analysed MAPK pathway related transcriptional signatures to assess predictability for response to ASTX029 in combination with a SHP2 inhibitor. We previously presented data from large-scale viability screens assessing the response to ASTX029 as a single agent treatment (437 cell lines), as well as in combination with an inhibitor of SHP2 (491 cell lines), an upstream adaptor protein in the MAPK pathway. Using these data, several published transcriptional signatures related to the MAPK pathway were assessed for their ability to stratify sensitive vs resistant cell lines when benchmarked against MAPK oncogene genomic status alone. All assessed transcriptomics-based scores had a significant positive correlation with growth inhibition for ERK inhibitor single agent treatment as well as in combination with a SHP2 inhibitor. Transcriptomics-based scores were shown to be more sensitive than the use of mutant MAPK oncogene status alone based on assessment of binomial regression models. The significant increase in sensitivity enables the identification of additional cell lines responsive to MAPK pathway inhibition. The sensitivity was further increased when considering response to the combination of an ERK and SHP2 inhibitor compared to the ERK inhibitor as a single agent. This analysis demonstrates the potential use of MAPK pathway-related transcriptomics-based scores for the stratification of MAPK pathway inhibitor response. ASTX029 is currently undergoing clinical development in advanced solid tumours (NCT03520075) and transcriptomics-based methods may provide utility in refining patient selection in the clinic for single agent or combination approaches. Citation Format: Jessica Brothwood, Andrea Biondo, Kim-Hien Dao, Keisha Hearn, Chris Hindley, Navrohit Kandola, Harold Keer, John Lyons, Yoko Nakatsuru, Marc O'Reilly, Nicola Wallis, Harpreet Saini. Transcriptomics-based stratification of response to MAPK inhibition in vitro better predicts sensitivity to single agent and combination treatment than MAPK genomic alteration status alone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3365.

The inhibition of aberrant MAPK pathway activity is a clinically validated approach which has resulted in the approval of agents targeting tumors driven by activating mutations in BRAF and KRAS. Although the overall response rate to MAPK-targeting agents is high, duration of response is often limited by the emergence of acquired resistance. In contrast, immune checkpoint inhibitors (ICI) such as the anti-PD1 therapy, pembrolizumab, have a lower response rate but induce more durable responses. It has been demonstrated that inhibition of aberrant MAPK pathway activity enhances immune activation. For example, preclinical studies show that treatment with the BRAFV600E inhibitor dabrafenib or the KRASG12C inhibitor sotorasib induces a pro-inflammatory tumor microenvironment (TME), which is associated with increased anti-tumor immunity. Further, studies using syngeneic, MAPK-activated in vivo models have demonstrated that the combination of MAPK-targeting agents and ICI results in synergistic inhibition of tumor growth. ASTX029 is a dual-mechanism ERK1/2 (ERK) inhibitor, inhibiting both the catalytic activity and phosphorylation of ERK, which is currently undergoing clinical development as part of a Phase 1/2 trial in advanced solid tumors (NCT03520075). ASTX029 has good oral bioavailability and shows potent inhibition of tumor growth in preclinical models bearing activating mutations in the MAPK pathway. We have previously investigated the immunomodulatory effects of ASTX029 using an in vivo syngeneic tumor model and observed that treatment with ASTX029 resulted in a pro-inflammatory TME, with increased interferon signaling consistent with published data describing the effects of treatment with dual-mechanism ERK inhibitors (Kidger et al., Mol Cancer Ther, 2020). We also observed an increased expression of antigen presentation genes. Using digital spatial profiling, we evaluated the expression of 31 proteins in immune infiltrates and observed a significant decrease in CD14 and a significant increase in MHC class II in ASTX029-treated tumors compared to untreated tumors. We therefore investigated the immunomodulatory effects of ASTX029 using primary human monocytes under conditions that induce macrophage differentiation and polarisation. Treatment with ASTX029 induced a decrease in CD14 and an increase in MHC class II cell surface expression, consistent with our previous in vivo mouse model data. In addition, we observed changes in cell surface expression of phenotypic markers, such as CD206, following treatment with ASTX029. These data support our previous observations and demonstrate that ERK inhibition by ASTX029 leads to phenotypic changes during monocyte to macrophage differentiation. Our data provide a strong rationale for the combination of ASTX029 with agents which aim to modulate the myeloid compartment or response to myeloid signaling. Citation Format: Christopher Hindley, Andrea Biondo, Kim-Hien Dao, Lynsey Fazal, Alpesh Shah, Martin Sims, Nicola Wilsher, Harold Keer, John Lyons. Treatment with the dual-mechanism ERK inhibitor, ASTX029, alters myeloid cell differentiation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P112.

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.

Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional “3+3” design. Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non–dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses. Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507–16. ©2010 AACR.

This multicenter phase II trial evaluated the therapeutic activity and safety profile of pivaloyloxymethyl butyrate (Pivanex, AN-9) as a single agent in refractory non-small cell lung cancer (NSCLC). Pivanex (2.34g/m 2 per day) was administered as a 6-h continuous intravenous infusion, daily for 3 days, and repeated every 21 days until disease progression. Forty-seven patients were treated. More than 90% of patients had received both a platinum compound and a taxane and 32% had received three or more prior chemotherapy regimens. The most common toxicities were transient grade 1–2 fatigue (34%), nausea (17%), and dysgeusia (11%). Three patients had partial responses (6.4 and 95%; CI 1.4–18.7%) and 14 patients had stable disease for ≥12 weeks (30%). Median survival for all patients was 6.2 months with 1-year survival of 26%. For patients who received fewer than three prior chemotherapy regimens, median survival was 7.8 months and 1-year survival was 31%. Pivanex is well tolerated and appears to be active as a single agent in patients with advanced NSCLC refractory to previous chemotherapy. Based on its therapeutic activity and favorable safety profile, further studies of Pivanex in NSCLC, particularly in combination with current chemotherapeutic agents, are warranted.

Purpose The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. Patients and Methods Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. Results From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25–88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9–7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment. Conclusion These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer. Trial Registration ClinicalTrials.gov NCT00725712

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P

4572 Background: XL880 is a potent, orally available small molecule inhibitor of MET and VEGFR2/KDR. Gastric cancer cell lines with MET amplification at 7q31 are sensitive to MET inhibition. Since, in retrospective clinical series, 7q31 amplification has been associated with PDGC, this phase II study examines the safety and efficacy of XL880 in pts with metastatic PDGC. Methods: The primary endpoint is response rate (RR), with 30 pts required to test the hypothesis that the RECIST confirmed RR with XL880 is 29% with 81% power and type I error of.041, versus Ho RR 11%. Eligibility requirements include: 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG 0–2. Pts receive XL880 240 mg/day on d1–5 of 14 day treatment cycles, and response is assessed every 8 weeks. MET amplification, determined by FISH of archival tissue, is defined as > 3 copies of 7q31. Optional pre- and on-treatment tumor biopsies are analyzed by immunohistochemistry for XL880 effects on direct and downstr...

Summary Background Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN. Results Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43 % of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for ≥13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule. Conclusion Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best-observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN. Electronic supplementary material The online version of this article (doi:10.1007/s10637-012-9861-3) contains supplementary material, which is available to authorized users.