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HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a “3+3” design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m2/day for QD, and 210.7 mg/m2/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non–small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor. This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.

We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed dynamic changes in 52 phosphoproteins caused by an acute exposure (1 hour) to clinically relevant concentrations of seven targeted anticancer drugs in 35 non–small cell lung cancer (NSCLC) cell lines and 16 samples of NSCLC cells isolated from pleural effusions. We studied drug sensitivities across 35 cell lines and synergy of combinations of all drugs in six cell lines (252 combinations). We developed orthogonal machine-learning approaches to predict drug response and rational combination therapy. Our methods predicted the most and least sensitive quartiles of drug sensitivity with an AUC of 0.79 and 0.78, respectively, whereas predictions based on mutations in three genes commonly known to predict response to the drug studied, for example, EGFR, PIK3CA, and KRAS, did not predict sensitivity (AUC of 0.5 across all quartiles). The machine-learning predictions of combinations that were compared with experimentally generated data showed a bias to the highest quartile of Bliss synergy scores (P = 0.0243). We confirmed feasibility of running such assays on 16 patient samples of freshly isolated NSCLC cells from pleural effusions. We have provided proof of concept for novel methods of using acute ex vivo exposure of cancer cells to targeted anticancer drugs to predict response as single agents or combinations. These approaches could complement current approaches using gene mutations/amplifications/rearrangements as biomarkers and demonstrate the utility of proteomics data to inform treatment selection in the clinic.

The RAS/RAF/MEK/ERK (MAPK) pathway is a frequently deregulated oncogenic pathway in cancer driven by RAS and RAF mutations as well as being a key signaling pathway downstream of deregulated receptor tyrosine kinases. Although RAF and MEK have been validated as anticancer targets and several BRAF and MEK inhibitors are FDA approved, acquired resistance develops in most patients. Preclinically, inhibition of RAF or MEK has been found to activate AKT/mTOR signaling as a potential resistance mechanism, and combination of MEK inhibition with an inhibitor of the AKT/mTOR pathway yields improved anti-tumor activity. However, combined inhibition of MEK with an AKT or mTOR inhibitor has typically shown poor clinical tolerability. VS-6766 is a unique dual RAF/MEK inhibitor which blocks MEK activity without the compensatory MEK activation that limits the efficacy of other MEK inhibitors. VS-6766 has shown clinical responses as a single agent in gynecological cancers and KRAS mutant non-small cell lung cancer (NSCLC) (Guo Lancet Oncology 2020), and has shown clinical responses in combination with the focal adhesion kinase (FAK) inhibitor defactinib in patients with low-grade serous ovarian cancer and KRAS mutated NSCLC. To explore the combination of VS-6766 with blockade of the AKT/mTOR pathway, we tested the combination of VS-6766 with the mTOR inhibitor everolimus for potential synergy across a variety of RAS pathway mutations and tumor types in preclinical experiments. In 3D proliferation assays in vitro, VS-6766 was synergistic with everolimus in reducing viability of cell lines representing multiple MAPK pathway alterations, including KRAS (G12C, G12D, G12V and G13D), BRAF V600E, NRAS and NF1 mutations. Synergy of VS-6766 with everolimus was observed in 8/9 NSCLC, 16/20 colorectal cancer, 7/10 melanoma and 5/7 pancreatic cancer cell lines tested. These preclinical data support testing the combination of VS-6766 with everolimus in patients with KRAS mutant NSCLC as well as in numerous other cancer indications with various MAPK pathway alterations. A phase I study is ongoing to assess the combination of VS-6766 with everolimus with an intermittent dosing schedule. The clinical trial uses a rule-based design of 3+3 dose escalation cohorts, initially with once weekly dosing of VS-6766 in combination with everolimus. If this was found to be tolerable, the combination of twice weekly dosing of both compounds was to be explored. Following establishment of the recommended phase 2 dose (RP2D) for the combination, an expansion cohort (n = 10) in patients with KRAS mutant NSCLC was planned. The trial is currently recruiting into an expansion cohort of patients with KRAS mutated NSCLC ;NCT02407509, (Trial in Progress). Citation Format: Thubeena Manickavasagar, Chara Stavraka, Kaiser Anam, Silvia Coma, Sanjib Chowdhury, Jonathan A. Pachter, Tom Parker, Mona Parmar, Laura Finneran, Emma Hall, James Spicer, Anna Minchom, Udai Banerji. Trial in progress: Combination of the dual RAF/MEK inhibitor VS-6766 with the mTOR inhibitor everolimus with expansion in patients with KRAS mutant NSCLC [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 P036.

KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergize with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB family receptor tyrosine kinase signaling and mTOR signaling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB family or mTOR was synergistic with PI3K inhibition in spheroid, stromal cocultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB–PI3K signaling axis were associated with decreased survival of patients with pancreatic cancer. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signaling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.

It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in re-wiring of signal transduction. We aimed to study differences in dynamic signaling changes within mutant KRAS (KRAS(MT)), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC) cells. We used an antibody-based phosphoproteomic platform to study changes in 50 phosphoproteins caused by seven targeted anticancer drugs in a panel of 30 KRAS(MT) cell lines and cancer cells isolated from 10 patients with KRAS(MT) cancers. We report for the first time significant differences in dynamic signaling between CRC and NSCLC cell lines exposed to clinically relevant equimolar concentrations of the pan-PI3K inhibitor pictilisib including a lack of reduction of p-AKTser473 in CRC cell lines (P = 0.037) and lack of compensatory increase in p-MEK in NSCLC cell lines (P = 0.036). Differences in re-wiring of signal transduction between tumor types driven by KRAS(MT) cancers exist and influence response to combination therapy using targeted agents.

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although often this is done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. The most potently inhibited off-targets are CDK16 for rucaparib (IC50 = 381 nM) and DYRK1B for niraparib (IC50 = 254 nM). These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Citation Format: Albert A Antolin, Malaka Ameratunga, Udai Banerji, Paul Clarke, Paul Workman, Bissan Al-Lazikani. The kinase polypharmacology landscape of clinical PARP inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C01. doi:10.1158/1535-7163.TARG-19-LB-C01

MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines, and sphingomyelins that were significantly altered in two B-RAF-mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non-tumor-bearing animals and mice bearing the PTEN-null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pretreatment levels of seven lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment-related changes were greater than baseline physiological variability in nontreated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor.

Evidence that the phosphoinositide 3-kinase (PI3K) pathway is deregulated in ovarian cancer is largely based on the analysis of surgical specimens sampled at diagnosis and may not reflect the biology of advanced ovarian cancer. We aimed to investigate PI3K signaling in cancer cells isolated from patients with advanced ovarian cancer. Ascites samples were analyzed from 88 patients, of whom 61 received further treatment. Cancer cells were immunomagnetically separated from ascites, and the signaling output of the PI3K pathway was studied by quantifying p-AKT, p-p70S6K, and p-GSK3β by ELISA. Relevant oncogenes, such as PIK3CA and AKT, were sequenced by PCR-amplified mass spectroscopy detection methods. In addition, PIK3CA and AKT2 amplifications and PTEN deletions were analyzed by FISH. p-p70S6K levels were significantly higher in cells from 37 of 61 patients who did not respond to subsequent chemotherapy (0.7184 vs. 0.3496; P = 0.0100), and this difference was greater in patients who had not received previous chemotherapy. PIK3CA and AKT mutations were present in 5% and 0% of samples, respectively. Amplification of PIK3CA and AKT2 and deletion of PTEN was seen in 10%, 10%, and 27% of samples, respectively. Mutations of PIK3CA and amplification of PIK3CA/AKT2 or deletion of PTEN did not correlate with levels of p-AKT, p-p70S6K, and p-GSK3β. In patients with advanced ovarian cancer, there is an association between levels of p-p70S6K and response to subsequent chemotherapy. There is no clear evidence that this is driven specifically by PIK3CA or AKT mutations or by amplifications or deletion of PTEN. Mol Cancer Ther; 11(7); 1609–17. ©2012 AACR.

Oncogenic BRAF and NRAS mutations are frequent in malignant melanoma. BRAF that is activated by the common V600E and other mutations, as well as by upstream NRAS mutations, has been shown to require the molecular chaperone heat shock protein 90 (HSP90) for stabilization and is depleted by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)]. Here, we explore the possible relationship between tumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with metastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial. One patient with disease stabilization for 49 months had a G13DNRAS mutation and WTBRAF. A second patient who had stable disease for 15 months had a V600EBRAF mutation and WTNRAS. These preliminary results suggest that BRAF and NRAS mutation status should be determined in prospective phase II studies of HSP90 inhibitors in melanoma. [Mol Cancer Ther 2008;7(4):737–9]

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7. Citation Format: David M. Hyman, Lillian Smyth, Philippe L. Bedard, Amit Oza, Emma Dean, Anne Armstrong, Joao Lima, Hideaki Bando, Peter Kabos, J. Alejandro Perez-Fidalgo, Kathleen Moore, Shannon N. Westin, Benoit You, Sarat Chandarlapaty, Leila Alland, Helen Ambrose, Andrew Foxley, Justin Lindemann, Martin Pass, Paul Rugman, Shaista Salim, Gaia Schiavon, Kenji Tamura, Jose Baselga, Udai Banerji. AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B109.

Background: ATR mediates the homologous recombination DNA repair pathway and cellular response to replication stress. VX-970 is a potent and selective inhibitor of ATR (Ki Methods: Pts with advanced solid tumors enrolled in 2 sequential parts. Part A: pts received IV VX-970 mono weekly in single-pt cohorts, with 3+3 cohorts initiated if grade (G) ≥2 VX-970-related adverse events (AEs) were observed. Part B: pts received CP on day 1 and VX-970 on days 2 and 9 of a 21-day cycle in a 3+3 dose-escalation design. Paired VX-970 tumor biopsies were obtained in selected CP treated pts pre- and post-VX-970, and pS345 Chk1 levels assessed by IHC. Results: 25 pts were treated; M/F 10/15; median age 67 yr (range 49-76 yr); ECOG PS 0/1: 11/14. In Part A, 11 pts (colorectal [CRC; n = 2]; mesothelioma [n = 2]; other [n = 7]; median prior lines of therapy = 3) received VX-970 at 60 mg/m2 (n = 1), 120 mg/m2 (n = 2), 240 mg/m2 (n = 1) and 480 mg/m2 (n = 7). In Part B, 14 pts (CRC [n = 6]; ovarian [n = 2]; other [n = 6]; median prior lines of therapy = 3) received VX-970 240 mg/m2 + CP AUC5 (n = 3; dose level 1 [DL1]), VX-970 120 mg/m2 + CP AUC5 (n = 3; DL2), VX-970 120 mg/m2 + CP AUC4 (n = 3; DL3) and VX-970 90 mg/m2 + CP AUC5 (n = 5; DL4). In Part A, no dose-limiting toxicities (DLT) or drug-related G3-4 AEs were seen. In Part B, 2 pts had DLT: G4 neutropenia and fever (n = 1; DL1) and G3 hypersensitivity (n = 1; DL2). Non-DLT G3-4 AEs were neutropenia (n = 4; DL1-2) and thrombocytopenia (n = 1; DL2) requiring dose delays. No G3-4 AEs were seen at DL3-4. RP2D cohort expansion is ongoing at DL4. VX-970 displayed linear AUC and Cmax at all DLs; median half-life was 16h with no accumulation. Based on preclinical models, efficacious exposures were achieved. When combined with CP, DL1 and DL2 showed similar VX-970 exposure, suggesting no apparent drug interactions. Decreased Chk1 phosphorylation was seen in 2/2 paired tumor biopsies (74% at DL4; 94% at DL2). An advanced CRC pt (serosal disease and abdominal lymphadenopathy; 3 prior lines of chemotherapy) with complete ATM loss by IHC achieved RECIST complete response to VX-970 mono at 60 mg/m2 and remains on trial at 59+ wks. RECIST stable disease (SD) was seen with VX-970 mono in 4 pts (median duration of SD = 11 wks [11-17.4 wks]) and VX-970 + CP in 7 pts, who were still ongoing (duration of SD = 5+ to 20+ wks), including several pts who had progressed on prior platinum therapy. Conclusion: VX-970 is well tolerated as monotherapy and in combination with CP, with preliminary evidence of target modulation and antitumor activity. VX-970 will be further explored in early phase II studies; in multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer; and in patients with DDR aberrations. Citation Format: Timothy A. Yap, Maria J. de Miguel Luken, Brent O'Carrigan, Desam Roda, Dionysis Papadatos-Pastos, David Lorente, Nina Tunariu, Raquel Perez Lopez, Sasha Gayle, Ruth Riisnaes, Ines Figueiredo, Susana Miranda, Suzanne Carreira, Fang Yang, Sharon Karan, Marina Penney, John Pollard, L. Rhoda Molife, Udai Banerji, Mohammed Asmal, Scott Z. Fields, Johann S. de Bono. Phase I trial of first-in-class ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation and antitumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR14.

Background: The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently deregulated in cancer due to mutations in PIK3CA and AKT, hyperactivation of upstream receptor kinases, and loss of function of PTEN. DS-3078a is a dual inhibitor of mTOR complex 1 (TORC1) and 2 (TORC2) that modulate the PI3K/AKT/mTOR pathway. This first-in-human study was conducted to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DS-3078a. Methods: Dose escalation was performed using an accelerated titration method with single patient cohorts starting at 20 mg followed by a continuous reassessment method according to a Bayesian regression logistic model. DS-3078a was administered orally in a continuous once daily (QD) schedule in 28-day cycles. PK parameters including area under the curve (AUC) and maximum plasma concentration (Cmax) were assessed on cycle 1 days 1 and 8. PD analyses were performed on cycle 1 days 1 and 15 in platelet-rich plasma (PRP) for changes in phospho-AKT and, when available, in paired tumor biopsies for phospho-AKT and -S6. Results: Seventeen patients (pts) with a median age of 61 years (range 38-72 years) were evaluable for dose limiting toxicities (DLT) according to NCI-CTCAE v 4.0. Mesothelioma (n=4) and neuroendocrine carcinoma (n=3) were the most common tumor types. Other tumor types included adenoid cystic, renal, ovarian, cervical, peritoneal, colorectal, and lung carcinoma, and unknown primary. Pts were treated at seven different dose levels of DS-3078a (20, 40, 80, 160, 320, 450, and 640 mg). MTD had been exceeded at 640 mg with DLT of grade 3 vomiting and grade 2 refractory nausea resulting in two pts not being able to complete 75% of the cycle 1 dose. The lower dose of 450 mg QD was well tolerated by 6 pts and 4 additional pts will be treated at this dose level to confirm MTD. The most common non-DLT drug-related toxicities at any cycle included grade ≤2 nausea (61%), vomiting (56%), diarrhea (50%), fatigue (33%), anorexia (28%), mucositis (28%), and hyperglycemia (17%). The mean Cmax and AUC value on day 1 at 450 mg QD was 542 ng/ml and 1898 ng.h/ml, respectively. Preliminary PD data showed up to 89% inhibition of Akt phosphorylation in platelets and up to 60% inhibition retained at 24 hours post-dose at ≥320 mg QD in some pts. The best response according to RECIST v1.1 was stable disease ≥6 months in 3 pts (ovarian, renal, and peritoneal carcinoma) with minor tumor response observed in a pt with renal carcinoma. Conclusion: DS-3078a was well tolerated up to and pharmacodynamically active at 450 mg QD. A continuous twice daily dosing schedule has been opened to explore other schedules which may optimize the biological effects of DS-3078a. Clinical trial information NCT01588676. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C173. Citation Format: Marta Capelan, Prasana Kumar, Anthony W. Tolcher, Andrea Zivi, Madhuri Desai, Kyriakos P. Papadopoulos, Giorgio Senaldi, Amita Patnaik, Udai Banerji, Drew D. Rasco. A first-in-human Phase I study of DS-3078a, an oral TORC1/2 inhibitor, in patients with advanced solid tumors: Preliminary results. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C173.

Background: HDACi have demonstrated activity as anticancer agents and are licensed for use in cutaneous and peripheral T cell lymphoma. Cardiac effects including arrhythmias and QTc prolongation have previously been associated with HDACi administration in humans. This report summarizes the cardiac adverse event (AE) profile observed during the recently completed FIH Phase I trial of JNJ26481585. Methods: Continuous oral daily dosing (QD) of JNJ26481585 in 21-day (D) cycles (C) was investigated initially in 20 patients (pts) demonstrating activity (including 1 partial response, 1 minor response, 1 prolonged stable disease in melanoma) but ventricular arrhythmia (2 pt) and fatigue (1 pt) were dose-limiting. To improve tolerability, 3 intermittent schedules (QD Mon/Wed/Fri (MWF); QD Mon/Tue/Wed/Thu (MTWT); QD Mon/Thu (MT)) also in 21-D C were subsequently explored in 38 (including expansion cohort), 19 and 15 pts respectively. All pts had triplicate 12-lead ECG (tECG), 24 hour ECG (Holter) and echocardiography or MUGA scan for assessment of left ventricular ejection fraction (LVEF) at baseline and during treatment. Analysis of mean QTcF, categorical QTcF and preliminary assessment of cardiac rhythm/morphology was performed. Results: 12mg QD MWF was identified as the recommended Phase II dose (RP2D) based on safety, tolerability, PK predictions and PD activity. Maximum average increase in mean QTcF from baseline ranged from 0 to 8 milliseconds (ms) during cycles 1 and 2 across the 4 schedules. At RP2D, the maximum average increase in mean QTcF observed was 6ms. 1 out of 38 pts (2.6%) treated on the MWF schedule experienced a Grade (G) 3 QTcF prolongation, possibly related to ST-T segment changes identified as a class effect of HDACi. QTcF prolongation G1–2 was rarely observed across schedules and mostly occurred as an isolated reversible observation whilst on study drug. Reversible, non-sustained ventricular tachycardia (NSVT) was observed as a dose limiting toxicity (DLT) in 3 out of 39 pts (7.7%) receiving QD or MTWT dosing but was not observed on the MWF or MT schedules. Other reversible, but dose-limiting, cardiac effects were T-wave inversion (2 pts on MT and MTWT), supraventricular tachycardia (1 pt on MT) and hypertension with raised troponin (1 pt on MWF). Non-specific, reversible, asymptomatic ST-T segment changes were frequently observed. LVEF was unaffected during treatment with JNJ26481585. Conclusion: The RP2D of JNJ26481585 was determined as 12 mg on the MWF schedule and demonstrated an acceptable cardiac safety profile. One pt had QTcF>500 ms but no clinically significant effect on the QTcF interval was observed across schedules. Reversible NSVT was identified as a DLT in some patients on the QD and MTWT dosing schedules but not on the MWF and MT schedules. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A164.

Background: AZD8055 is a dual mTORC1/mTORC2 inhibitor with properties that prevent the feedback activation of AKT seen with rapalogues. This is the first-in-man study of AZD8055 to determine the safety, PK and preliminary efficacy of two oral formulations in patients (pts) with advanced solid tumors (NCT00731263). Methods: In an open-label, ascending dose study, cohorts of 3 or 6 pts received a single dose of AZD8055 followed 1 week later by continuous, twice-daily dosing. Starting at 10 mg, each subsequent cohort received an increased dose until a non-tolerated dose was reached. The study included a formulation switch from oral solution to tablet. Assessments included safety, PK, FDG-PET and RECIST. Modulation of AKT phosphorylation on serine 473 (pAKT) and of 4EBP1 phosphorylation on threonine 37/46 (p4EBP1) was measured in peripheral tissue after single administration of AZD8055 to confirm proof-of-mechanism. Results: 49 pts (42 evaluable) were dosed in seven cohorts: oral solution; 10, 20, 40 mg BD, tablet; 40, 60, 90, 120 mg BD. The most frequent adverse events (AEs) across all cohorts, regardless of causality, were: fatigue (55%), nausea (35%), decreased appetite (33%), diarrhea (31%), constipation (27%), increased ALT (22%), increased AST (22%), dyspnea exertional (22%) and vomiting (22%). The most frequent AEs assessed by the investigator to be potentially drug-related were increased ALT (22%) and increased AST (22%). Three pts (6%) had a dose reduction due to an AE and 11 pts (22%) had a dose interruption due to an AE. Non-tolerated dose was 120 mg BD; maximum tolerated dose (MTD) was 90 mg BD. Dose limiting toxicities of CTC grade 3 transaminases were reported with the 40 mg BD solution (n=1), 90 mg BD tablet (n=1), and 120 mg BD tablet (n=3). No cases of Hy's law were observed. Onset of increased transaminases was typically between day 35 and 45. AZD8055 was orally bioavailable and rapidly absorbed following single and multiple doses with median tmax of ∼0.5 h. Elimination was rapid across all dose groups with mean t1/2 of 1.9–3.1 h. Exposure increased approximately proportionally with increasing dose although variability within cohorts was high and exposures across dose groups overlapping. At the MTD, 5 pts had data available for change in p4EBP1. A decrease was observed in 2 pts at 2 h, although there was significant variability in pre-dose marker levels. Change in pAKT was measured in 10 pts at the MTD; a decrease at 2 h was noted in all 6 pts who had a baseline pAKT value >5%, although the majority of pts had low pre-dose levels ( Conclusions: The MTD for AZD8055 is 90 mg BD. Apart from transaminitis, which occurred at most dose levels, the drug had an acceptable toxicity profile. Toxicities frequently associated with administration of rapalogues such as rash and mucositis were not dose limiting. No conclusions can be drawn from changes in p4EBP1 and pAKT because of variability in pre-dose levels and the small number of pts. The biological relevance of the decreases in pAKT is difficult to interpret due to very low pre-dose levels in the majority of pts. A more sensitive PRP assay is being pursued for future projects to mitigate against low baseline values of pAKT. No RECIST responses were observed. Clinical development of AZD8055 has been discontinued. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A168.