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Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history.Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications.Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens.Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49

Supplementary Data from Randomized Phase II Multicenter Trial of Two Schedules of Lapatinib as First- or Second-Line Monotherapy in Patients with Advanced or Metastatic Non–Small Cell Lung Cancer

Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors. Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab. Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis—a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data. Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.

BackgroundThis phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor).MethodsPatients with advanced or metastatic solid tumors were enrolled and received itacitinib (100–400 mg once a day) plus epacadostat (50–300 mg two times per day; group A), or itacitinib (100–400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3–10 mg once a day; group B).ResultsA total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8+ T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8+ T cell infiltration.ConclusionAdverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment.Trial registration numberNCT02559492.

Background IDO1 is the initial rate-limiting enzyme in one breakdown pathway of tryptophan. It reduces tryptophan levels and generates metabolites (e.g., kynurenine [KYN]) that contribute to tumor-associated immune suppression. Epacadostat (EPA) is a novel, potent, selective, reversible inhibitor of IDO1 studied in clinical trials in combination with anti-PD-1 antibodies. Epacadostat-induced decreases in plasma KYN have been used as a pharmacodynamic measure of drug activity and have aided in dose selection for clinical studies. Despite encouraging signs of efficacy in combination with pembrolizumab (PMB) in the ECHO-202 study, a large phase 3 study in melanoma (ECHO-301) failed to reproduce this outcome.1 Methods Longitudinal plasma samples were obtained from participants in EPA clinical studies. Plasma KYN and EPA concentrations were measured by validated liquid chromatography tandem mass spectrometry. Quantitative mass spectrometry imaging (qMSI) of intratumoral tryptophan metabolites was also performed. Results Analysis of plasma KYN levels demonstrated that PMB monotherapy significantly elevated KYN. While blocking the PMB-induced increase, EPA (100 mg BID) in combination with PMB failed to normalize KYN to healthy control levels as was reported for EPA monotherapy.2 Because anti-PD-1 treatment can induce interferon gamma (IFN-γ) production and IDO1 expression is IFNg inducible,3 we hypothesize that PMB-induced IFN-γ may be responsible for the observed increase of plasma KYN levels. Combined analysis of plasma KYN from additional EPA/anti-PD-1 combination (ECHO-202; EPA/PMB, ECHO-204; EPA/nivolumab) and monotherapy (ECHO-210) studies, with EPA doses ranging from 50 to 600 mg BID, suggested that higher EPA doses (≥600 mg BID) may be necessary to overcome the anti-PD-1–associated KYN elevation. Doses ≥600 mg BID are projected to cover the EPA IC90 value for 24h. The POD1UM-102 study is currently evaluating the combination of a novel anti-PD-1 monoclonal antibody (retifanlimab) plus EPA at doses up to 900 mg BID. Preliminary results from this study indicate that 600 mg BID is the maximally tolerated dose and is capable of maintaining suppression of KYN to healthy control levels through treatment cycle 4. Additionally, qMSI of paired pre-treatment and on-treatment biopsies demonstrated intratumoral suppression of KYN production with EPA 600 mg BID. Conclusions Using suppression of plasma KYN as a pharmacodynamic marker of EPA activity, we demonstrated that maximal blockade of IDO1 activity in the context of anti-PD-1 treatment requires doses of EPA substantially higher than those tested in prior clinical studies. These findings are now informing additional proof of concept clinical studies. Acknowledgements These studies were sponsored by Incyte Corporation (ECHO-210, POD1UM-102) and in collaboration with MSD (ECHO-301, ECHO-202) and Bristol Myers Squibb (ECHO-204). Trial Registration ECHO-202 [NCT NCT02178722]; ECHO-204 [NCT02327078]; ECHO-210 [NCT01685255]; ECHO-301 [NCT02752074]; POD1UM-102 [NCT03589651] Ethics Approval These studies were each approved by the institutional review board or independent ethics committee of participating institutions. References Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomized, double-blind study. Lancet Oncol 2019;20:1083–1097 Beatty GL, O’Dwyer PJ, Clark J, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res 2017;23:3269–3276. Munn, DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 2016;37:193–207.

Purpose Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Patients and Methods Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks. Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Purpose: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1. Experimental Design: Fifty-two patients with advanced solid malignancies were treated with epacadostat [50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID)] in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity. Results: One dose-limiting toxicity (DLT) occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period. Although no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7 of 52 patients. Conclusions: Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of ≥100 mg BID. Studies investigating epacadostat in combination with other immunomodulatory drugs are ongoing. Clin Cancer Res; 23(13); 3269–76. ©2017 AACR.

Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO1). Here we report results from the open‐label, dose‐escalation, Phase 1b ECHO‐110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum‐based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose‐limiting toxicities (DLTs). Twenty‐nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty‐three patients (79%) had treatment‐related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment‐related AEs. No fatal treatment‐related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD‐L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD‐L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited., What's new? There has been considerable interest in investigating combination treatment strategies that target separate but complementary immune‐evasion pathways, in patients with advanced non‐small‐cell lung cancer (NSCLC). The goal is to enhance the efficacy of immune checkpoint inhibitors. In this study, the authors found that combining the IDO1 enzyme inhibitor epacadostat with the PD‐L1 checkpoint inhibitor atezolizumab was generally well tolerated. However, clinical activity was limited. These results provide important insights into the challenges associated with developing combination immunotherapies in NSCLC.

Background Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889). Methods Only the phase 1, open-label portion of the study was conducted, per the sponsor’s decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg am, 25 mg pm]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks. Results Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID. Conclusions When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma. Trial registration ClinicalTrials.gov identifier, NCT01604889. Registration date, May 9, 2012, retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s40425-019-0562-8) contains supplementary material, which is available to authorized users.

Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration-time profiles were adequately described by a population PK model comprised of the first-order kinetics of oral absorption with 2-compartment distribution and constant clearance from the central compartment. Body weight was the only significant covariant to influence EPA PK. Determination of EPA's on-target potency, ie, its half-maximal inhibitory concentration (IC50 ) against IDO1, is important for dose selection but complicated by the bioconversion of tryptophan (TRP) to kynurenine (KYN) catalyzed by both IDO1 and TRP 2,3-dioxygenase (TDO). In vitro and ex vivo, the IC50 was estimated following the selective induction of IDO1, rendering the TDO activity relatively insignificant; however, it was desirable to determine the in vivo IC50 without inducing an IDO1 abundance. A mechanistic population PD model was developed based on time-matched EPA, TRP, and KYN plasma concentrations in 44 oncology patients, and EPA in vivo IC50 was estimated to be ∼70 nM, consistent with the ex vivo value independently determined. The model suggests that ∼60% and 40% of TRP→KYN bioconversion was mediated by IDO1 and TDO, respectively, in the cancer patients at baseline. For this study population of limited numbers of subjects, neither age nor sex was a significant covariate for EPA PK or PD.

Purpose Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer. Patients and Methods In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m2 twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation. Results In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation–based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%). Conclusion Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.

Objective To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons. Results An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. Conclusions Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.

5576 Background: DPX-Survivac is a novel T cell activating therapy designed to elicit an effective immune response against recurrent ovarian cancers that express the survivin protein. The survivin specific T cells induced by DPX-Survivac can infiltrate the tumors and are associated with clinical responses. It is likely that achieving an anti-tumor effect requires a favorable ratio of T cells to tumor cells. Epacadostat (E) is an IDO1 enzyme inhibitor that may enhance effector T cell proliferation, shifting the tumor microenvironment (TME) away from an immunosuppressive state toward one supporting productive immune response. Methods: Recurrent ovarian cancer patients with advanced and metastatic progressive disease were treated with DPX-Survivac, intermittent low dose CPA with or without E. In the Phase 1b, 53 subjects were enrolled to receive DPX-Survivac, low dose CPA and E BID. In the Phase 2, 12 subjects were randomized to receive DPX-Survivac and low dose CPA with or without E. The data on immunological responses, biomarkers, and clinical responses were analyzed in relation to the baseline sum of target lesions per RECIST 1.1. Results: The study showed that DPX-Survivac and intermittent low dose CPA with or without E can generate strong T cell responses. The infiltration of tumors with survivin-specific T cells correlates with the observed tumor regression. The sum of target tumor measurements at baseline by RECIST 1.1 correlated with observed clinical benefits. In the group of 15 patients with the baseline sum of target lesions less than 5 cm, all subjects have shown clinical benefits. Four of these subjects reached partial response and remained without progression over a prolonged period. Conclusions: The treatment studied leads to strong survivin-specific T cell responses. Infiltration of tumors by survivin-specific T cells correlated with clinical benefit in treated subjects. A predictive model based on tumor size to improve response to DPX-Survivac in recurrent ovarian cancer is being prospectively explored. Clinical trial information: NCT02785250.

Objectives Abiraterone acetate (AA) is a CYP17 inhibitor of androgen synthesis approved for use following docetaxel for metastatic castration-resistant prostate cancer (mCRPC); evaluation in the pre-docetaxel setting is ongoing. Given that the reported efficacy of AA is lower following docetaxel vs. pre-docetaxel, the potential exists for cross resistance given docetaxel's partly androgen receptor targeting activity. The efficacy of docetaxel following ketoconazole (KC), a weaker and nonspecific inhibitor of CYP17, may provide some insights into this potential interaction. We retrospectively evaluated the efficacy of every 3-week docetaxel with prednisone (DP) in mCRPC previously exposed to KC compared to KC-naive patients. Materials and methods A randomized phase II trial of men with mCRPC treated with DP + AT-101 (bcl-2 inhibitor) vs. DP plus placebo was analyzed. Both arms were combined for analysis as no significant differences were seen. Overall survival (OS), progression-free survival (PFS), objective response (ORR), pain, and prostate-specific antigen (PSA) response rates were estimated with and without prior KC. Cox proportional hazards regression models were used to estimate the effect of covariates on OS. Results Of 220 evaluable men, 40 (18.2%) received prior KC. The median OS with DP-based therapy of KC-naive patients (18.3 months, 95% CI: 15.0, 24.5) and post-KC patients (17.0 months, 95% CI: 9.9, 20.4) was not statistically different ( P = 0.20). After controlling for prognostic classifications, analyses demonstrated consistent trends for worsening of OS after KC, with (hazard ratios (HRs) 1.33–1.46. Similar unfavorable trends were observed for ORR, PSA declines, and PFS. Conclusions In this hypothesis-generating analysis, patients treated with docetaxel-based chemotherapy following prior KC had numerically and consistently worse outcomes than patients not exposed to prior KC. Although the estimated differences did not attain statistical significance, evaluation of outcomes with docetaxel in particular, and all classes of novel and emerging agents following AA, is of clinical importance, given its more potent androgen synthesis inhibition compared with KC. Drug development should take into account the potential impact of previous therapy.

Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration-time profiles were adequately described by a population PK model comprised of the first-order kinetics of oral absorption with 2-compartment distribution and constant clearance from the central compartment. Body weight was the only significant covariant to influence EPA PK. Determination of EPA's on-target potency, ie, its half-maximal inhibitory concentration (IC

Background Docetaxel clearance appears increased in men who are castrated. Neutropenia in cycle 1 may be a pharmacodynamic marker for docetaxel, which may enable tailored dosing in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods The association of cycle 1 neutropenia with overall survival (OS) was examined post hoc in a randomized phase II trial of 221 men with mCRPC who received docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor); weekly blood cell counts were performed during the first cycle. Patients from both arms were combined because no outcome and toxicity differences were observed. OS was calculated from randomization by the Kaplan-Meier method, and Cox proportional hazards regression models were used to estimate the association with OS. Results The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for trial stratification factors, pain, and performance status (hazard ratio [HR] 0.64; 2 P = .048). Results were similar for logarithmic neutrophil counts adjusted for the risk group based on anemia, visceral metastasis, progression by bone scan and pain (HR 1.18; 2 P = .07) for stratification factors (HR 1.20; 2 P = .052) or both (HR, 1.20; 2 P = .046). Men with ≥grade 3 neutropenia and ≥30% prostate-specific antigen level decline by day 90 had improved OS compared with men exhibiting neither (HR 0.51; 2 P = .014). Conclusions For patients with mCRPC who received docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, which suggests its utility as a pharmacodynamic marker, in this hypothesis-generating analysis. Exploration of dose escalation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted.

Study Type – Retrospective analysis of clinical trial Level of Evidence 3 What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted. OBJECTIVE • Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC. PATIENTS AND METHODS • A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). • Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. • Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. • Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms. RESULTS • C-reactive protein was independently prognostic for OS and PFS (P≤ 0.002) after adjusting for all modeled risk estimates and classifiers. • C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. • A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. • Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone. CONCLUSIONS • Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. • Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted.

Background: The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Objective: A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS). Design, setting, and participants: An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles. Measurements: Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion. Results and limitations: The number of men receiving 10 cycles was similar (p = 0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six-and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9-95.4%) and 74.6% (CI, 67.2-80.5%) in TAX-327, compared with 92.8% (CI, 85.5-96.5) and 63.4% (CI, 51.8-72.9%) in CS-205. Subanalyses suggested that 10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.

5510Background: DPX-Survivac is a novel T cell activating therapy containing a mix of HLA class I peptides designed to evoke a T cell response against survivin and previously optimized for immunoge...

Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49

Objectives: Many patients with metastatic nonsmall cell lung carcinoma (NSCLC) cannot tolerate intravenous chemotherapy. Orally active agents would be more convenient and thus could improve their quality of life. Methods: A total of 189 patients were randomized 2:1, 181 patients received treatment, 120 PO and 61 IV vinorelbine, 158 patients had stage IV and 31 stage IIIB disease. Among patients who received PO vinorelbine, the median age was 72 years, 62% were males; the Karnofski Performance Status (KPS) was 80-100 in 71%. These compare with a median age of 70 years, 56% male, and KPS of 80-100 in 65% of patients who received IV vinorelbine. Oral vinorelbine 60 mg/m 2 was to be dose-escalated to 70 mg/m 2 after the initial 3-weekly doses if there was no unacceptable toxicity. Intravenous vinorelbine was to be given 30 mg/m 2 weekly. Results: Five patients (4%) on PO and 8 (13%) on IV vinorelbine had a confirmed partial response, 56 (44%) and 29 (46%) had stable disease, respectively. Median time-to-disease-progression was 16.6 weeks (PO) versus 23.9 weeks (IV), and the median survival was 26 weeks (PO) versus 40.9 weeks IV vinorelbine. Median survival on PO vinorelbine for patients with KPS 60-70 was 8.3 weeks versus 43 weeks (IV). On PO vinorelbine 59 patients (57%) were dose escalated, 9 (7.5%) were dose reduced, and 10 (8.3%) did not receive PO vinorelbine at week 4. Pharmacokinetic studies confirmed PO vinorelbine exposure was significantly less than IV exposure. Conclusion: The inability to escalate the dose of PO vinorelbine above 60 mg/m 2 weekly resulted in inferiority to IV vinorelbine at 30 mg/m 2 weekly, especially in patients with poor performance status.

Meeting abstracts Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that is expressed in many cancers and induces immune tolerance by suppressing T cell responses. Epacadostat is a potent, selective oral inhibitor of IDO1. A dose-escalation study of epacadostat with

BACKGROUND In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg®), an antibody-targeted chemotherapy for CD33-positive acute myeloid leukemia (AML). METHODS Patients with CD33-positive AML in first recurrence were entered in 3 open-label, single-arm, Phase II studies. Patients received monotherapy with GO 9 mg/m2 as a 2-hour intravenous infusion in 2 doses separated by 2 weeks. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS Two hundred seventy-seven patients (median age, 61 yrs) were treated with GO, and 71 patients (26%) achieved remission, which was defined as ≤ 5% blasts in the bone marrow without leukemic blasts in the peripheral blood, neutrophil recovery to ≥ 1500/μL, hemoglobin ≥ 9 g/dL, and independence from red blood cell and platelet transfusions. Complete remission (CR) with platelet recovery (≥ 100,000/μL) or without full platelet recovery (< 100,000/μL) (CRp) was observed in 35 patients (13%) and 36 patients (13%), respectively. The median recurrence-free survival was 6.4 months for patients who achieved CR and 4.5 months for patients who achieved CRp. Although expected incidences of Grade 3 or 4 neutropenia (98%) and thrombocytopenia (99%) were observed, the incidence of Grade 3 or 4 sepsis (17%) and pneumonia (8%) was relatively low. Grade 3 or 4 hyperbilirubinemia and hepatic aspartate aminotransferase and alanine aminotransferase elevations were reported in 29%, 18%, and 9% of patients, respectively; 0.9% of patients who did not undergo prior or subsequent hematopoietic stem cell transplantation developed hepatic venoocclusive disease after GO treatment. CONCLUSIONS When it was administered to patients with CD33-positive AML in first recurrence, single-agent GO induced a 26% remission rate with a generally acceptable safety profile. Cancer 2005. © 2005 American Cancer Society.

Background: INCB024360 (epacadostat) is an oral, potent, selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. Preliminary results from the phase I study of INCB024360 with pembrolizumab, an anti-PD-1 monoclonal antibody, exhibited an acceptable safety profile and promising clinical activities. This first-in-Japanese phase 1 study assessed the safety and the tolerability of INCB024360 monotherapy and in combination with pembrolizumab in Japanese patients with advanced solid tumors (ClinicalTrials.gov: NCT02862457). Materials and Methods: Patients with advanced solid tumors who had previously received standard-of-care were enrolled; patients previously treated with checkpoint inhibitors were excluded. Patients received INCB024360 25 mg or 100 mg BID monotherapy, or in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W). Dose-limiting toxicities (DLTs) were evaluated for INCB024360 monotherapy and in combination with pembrolizumab. Response rate was also assessed by RECIST 1.1. Patients who had INCB024360 monotherapy subsequently received pembrolizumab combination after DLT evaluation. Results: Fifteen patients were enrolled (53% men; median age, 68.0 y; 33% ECOG PS 1): urothelial cancer, colon cancer, gastric cancer, ovarian cancer, urachal cancer, and cancer of unknown primary (n=2, each); duodenal papilla cancer, mesothelioma, and pancreatic cancer (n=1, each). Three patients each received 25 mg and 100 mg of INCB024360 monotherapy, showed no DLTs. In combination with pembrolizumab, three and six patients received INCB024360 dose of 25 mg and 100 mg, respectively. One DLT (grade 4, rhabdomyolysis) was observed in 100 mg cohort. Twelve patients (80.0%) experienced drug-related AEs (DRAEs); 2 patients (13.3%) had grade 3 DRAEs: grade 3 liver disorder and grade 4 rhabdomyolysis. There were no treatment-related deaths. In 15 patients who had target lesion, partial responses were observed in 4 patients (26.7%) and stable disease were 4 (26.7%). As of 2 June 2017, all responders with pancreatic cancer, urothelial cancer, colon cancer with MSI-high and cancer of unknown primary (n=1, each) remain on treatment at 21, 24, 31, and 34 weeks, respectively. Conclusion: INCB024360 monotherapy and in combination with pembrolizumab demonstrated tolerability and encouraging efficacy in the Japanese patients with advanced solid tumors. Latest safety as well as efficacy data will be presented. Citation Format: Yutaka Fujiwara, Kohei Shitara, Toshio Shimizu, Kan Yonemori, Nobuaki Matsubara, Izumi Ohno, Takahiro Kogawa, Yoichi Naito, Lance Leopold, Kahori Sasahara, Naoyoshi Yatsuzuka, Tomoko Takami, Takashi Shimamoto, Noboru Yamamoto, Toshihiko Doi. INCB024360 (Epacadostat) monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: primary results from first-in-Japanese phase I study (KEYNOTE-434) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A204.

Purpose: To determine if epacadostat, an oral indoleamine 2,3-dioxygenase (IDO1) inhibitor has therapeutic benefit against GBM when administered as single agent and with PD-1 blocking antibody. Methods: An initial survival experiment was performed to assess efficacy and was followed by an identical repeat experiment for validation. 1X105 luciferized GL261 cells, a murine GBM tumor line derived from intracerebral methylcholanthrene implantation, were stereotactically implanted intracranially in albino syngeneic C57BL/6 mice. Mice with increasing bioluminescence on days 3 and 6 were randomized (n=8/group) to receive treatment beginning on day 6: anti-PD-1 (332.8H3, mouse IgG1; 500 μg intraperitoneal (IP) on day 6, 250 μg q 3 days X 7); epacadostat (Incyte Corporation, orally dosed at 300 mg/kg/day for 5 days on/2days off for 3 weeks); anti-PD-1 + epacadostat; and control therapy (isotype IgG antibody IP and 0.5% methocel in water). Tumor response assessments were performed by quantifying bioluminescence and survival. A re-challenge experiment was performed in long-term survivors to assess for tumor immune responses capable of preventing relapse. All long-term surviving mice (defined as ≥ 100 days) from the efficacy experiment were injected with 1X105 GL261 cells in the contralateral hemisphere and followed for survival. Results: In both preclinical efficacy experiments, median survival in the epacadostat monotherapy group did not differ from controls (approximately 30 days). Four of 8 mice (50%) treated with anti-PD-1 were long-term survivors in both efficacy experiments. In the epacadostat plus anti-PD-1 combination group, 81% of the mice were long-term survivors (7 of 8 in experiment 1 and 6 of 8 in experiment 2). Of note, none of the long-term surviving mice developed evidence of tumor; thus the median survival among the anti-PD-1 and epacadostat plus anti-PD-1 combination groups were both > 100 days. In the re-challenge study, all of the mice who underwent GL261 re-inoculation survived > 100 more days with no evidence of tumor recurrence. Conclusions: IDO1 inhibition with epacadostat increased the eradication rate of anti-PD-1 therapy in an orthotopic syngeneic GBM model and long term survivors rejected tumor following orthotopic re-challenge. Further combinatorial studies incorporating IDO inhibitor therapy for GBM, including mechanistic studies, are warranted. Citation Format: David A. Reardon, Prafulla C. Gokhale, Sarah R. Klein, Kristen L. Jones, Paul T. Kirschmeier, Maria Speranza, Holly Koblish, Peggy Scherle, Lance Leopold, Robert Newton, Gordon J. Freeman. Inhibition of IDO1 with epacadostat enhances anti-tumor efficacy of PD-1 blockade in a syngeneic glioblastoma (GBM) model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 572. doi:10.1158/1538-7445.AM2017-572

To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons.An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR]1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR2.7 at all time-points). Kendall's τ was 0.50 (P0.001) in the setting of docetaxel-based therapy and 0.34 (P0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review.Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.

Background Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts

What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted.• Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC.• A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). • Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. • Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. • Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms.• C-reactive protein was independently prognostic for OS and PFS (P ≤ 0.002) after adjusting for all modeled risk estimates and classifiers. • C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. • A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. • Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone.• Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. • Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted.

Background AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC. Patients and methods Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1 : 1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1–3. The primary end point was overall survival (OS). Results Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel–prednisone (ADP) and placebo–DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72–1.55, P = 0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo–DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n = 34), outcomes appeared to favor ADP (median OS 19 versus 14 months). Conclusions AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Introduction: AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. Methods: An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Results: Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m 2 days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort ( n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort ( n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. Conclusions: AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m 2 . The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.

Purpose: AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC). Experimental Design: Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy. Results: Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed ≥50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed. Conclusion: AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.

Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-XL, and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC50 for AT-101 is between 1 and 10 μM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (ΔΨm) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.

8558 Background: Efficacy of treatment options for pts with r/r cHL is limited. Evidence suggests blocking the PI3K or JAK-STAT pathways may be efficacious in cHL directly and through modulation of...

This paper discusses background information and the body of clinical data that has been accumulated to demonstrate the efficacy and safety of gemtuzumab ozogamicin (Mylotarg, Wyeth Pharmaceuticals, Philadelphia, PA). Based on these data, gemtuzumab ozogamicin was approved by the United States Food and Drug Administration for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. The recommended dosage of gemtuzumab ozogamicin is 9 mg/m2, administered as a 2-hour intravenous infusion for a total of 2 doses with 14 days between doses.

Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells that express CD33 by means of a humanized anti-CD33 monoclonal antibody conjugated to a modified antitumor antibiotic, calicheamicin. The effects of gemtuzumab ozogamicin (given intravenously at a dose of 9 mg/m2 for 2 doses separated by 2 weeks) have been evaluated in 3 phase II studies involving patients (n = 188) with acute myeloid leukemia (AML) in first relapse. Interim analysis has revealed that 30% of patients achieved remission, characterized byor = 5% blasts in the marrow, neutrophil countor = 1500/microL, hemoglobinor = 9 g/dL, and independence from red blood cell and platelet transfusion. Grade 3/4 acute toxicities included nausea or vomiting (11%); elevated serum aminotransferase enzyme (16%) and bilirubin (26%) levels; and infusion-related chills (9%), fever (6%), and hypotension (5%). As predicted with CD33-targeted therapy, most patients had neutropenia (98%) and thrombocytopenia (99%). However, the incidence of grade 3/4 bleeding events (14%) and infection rates (pneumonia, 7%; sepsis, 15%) was low. No patients were reported to have treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Veno-occlusive disease (VOD) after gemtuzumab ozogamicin treatment (but prior to other therapies) occurred in 2% of patients (4/188), and the VOD-related death rate was1% (1/188). Prior hematopoietic stem cell transplant may be a risk factor for VOD (P = 0.002, univariate analysis). Gemtuzumab ozogamicin is a safe and effective treatment in carefully selected patients with AML in first relapse.

3010 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that is overexpressed in cancers and induces immune tolerance by suppressing T-cell responses. INCB024360, ...

4000 Background: Local and systemic inflammation (INFL) are hallmarks of cancer, including PC, that adversely impact prognosis. Given the role of JAK-STAT signaling in cancer INFL, the efficacy and...

Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is characterized by elevated hematocrit requiring phlebotomy, splenomegaly, a variety of symptoms and increased thrombotic risk. Ruxolitinib, a JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses in a phase 2 study of patients (pts) with PV who were resistant to or intolerant of hydroxyurea (HU). Pts experienced phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) counts, platelet (PLT) counts, and disease-related symptoms. Here, we describe the baseline (BL) characteristics and symptom burden of pts in a phase 3 study of ruxolitinib in pts with PV who are resistant to or intolerant of HU. Methods RESPONSE is a randomized (1:1), open-label, phase 3 study (NCT01243944) comparing the efficacy and safety of ruxolitinib with best available therapy (BAT) in pts with PV who are resistant to or intolerant of HU (modified European LeukemiaNet criteria), have splenomegaly, and require phlebotomy for inadequate hematocrit (Hct) control. Fourteen disease-related symptoms were assessed on a scale of 0 (absent) to 10 (worst imaginable) using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Blinded data are presented here. Results BL demographic data are available for the 222 enrolled pts (Table). Apart from HU, other common prior medications for PV included interferons (15%), PLT aggregation inhibitors (10%), alkylating agents (3.6%), alkyl sulfonates (3.2%), pyrimidine analogues (1.8%), and nitrosoureas (1.4%). The majority of pts (54.5%) had 1 phlebotomy within 12 weeks prior to screening; 23.9% had 2 and 17.1% had 3 or more phlebotomies. RESPONSE BL demographics are generally similar in terms of age (60 years vs 57-67); sex (66% male vs 58%-68%); Hct (44% vs 45%-48%); and platelets (419 x 109/L vs 320-429 x 109/L) to other PV studies including trials of givinostat (Finazzi BJH 2013) and AOP2014 (Gisslinger ASH 2012) and the ECLAP-PV (Marchioli JCO 2005) and CYTO-PV studies (Marchioli NEJM 2012). At the time of writing, BL symptom data from the MPN-SAF were available for 164 pts (Table). Pts in this study reported a similar symptom burden as PV pts from a large study of pts with MPNs (Emanuel JCO 2012; N = 1425; PV, n = 538), including similar mean scores for early satiety, abdominal discomfort, concentration problems, night sweats, itching, and tiredness/fatigue. In addition, prior therapy may have adversely affected BL symptom burden, as many of these symptoms (concentration problems, night sweats, fatigue) have been shown to be worsened by the use of conventional therapy to strictly control Hct (< 45%) and cardiovascular risk (Emanuel EHA 2013). BL MPN-SAF symptom data for all 222 pts will be presented. In addition, correlations between BL EORTC QLQ-C30 and MPN-SAF scores will be presented. Summary/Conclusions Demographic and BL symptom data from the RESPONSE study demonstrated that pts with HU refractory or intolerant PV have a significant disease burden that includes a variety of symptoms. These findings are consistent with those of Emanuel (JCO 2012), which showed that pts with PV have a significant symptom burden and a reduced quality of life. Pts with PV in the RESPONSE study are representative of those who have been studied in other clinical trials for the treatment of PV. Disclosures: Vannucchi: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF and by the European Commission and Health Canada for the treatment of disease-related splenomegaly or symptoms in adult patients with MF. Here, we describe the baseline (BL) characteristics and symptom burden of patients in a phase 3 study of ruxolitinib in patients with PV who are resistant to or intolerant of HU. Kiladjian:Novartis: Honoraria; Shire: Honoraria. Durrant:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pane:Novartis: Consultancy, Honoraria; Shire: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; SBio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. He:Incyte: Employment. Leopold:Incyte: Employment, Stock options Other. Li:Novartis: Employment, Equity Ownership. Pirron:Novartis: Employment, Equity Ownership. Lawniczek:Novartis: Employment. Verstovsek:Incyte: Research Funding.

3025 Background: INCB024360 is a potent, selective inhibitor of IDO1. As the catabolism of tryptophan (Trp) to kynurenine (Kyn) by IDO1 inhibits immune responses and IDO1 expression is elevated in many human cancers, IDO1 inhibition may potentiate effective antitumor immune responses. Methods: This dose-escalation study in adult pts with advanced malignancies used a 3+3 design to determine MTD, toxicity, PK, PD, and tumor response rate. Daily doses of INCB024360 were evaluated in 28-day cycles in 8 cohorts (50 mg once daily; 50 mg, 100 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg BID). Treatment continued until disease progression or unacceptable toxicity. PK and PD samples were drawn on days 1 and 15. Results: 52 pts have been treated. Tumor types included colorectal (56%), melanoma (12%), and other (33%). The most common adverse events (≥20%) were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. The most common grade 3 or 4 adverse events were abdominal pain, hypokalemia, and fatigue (9.6% each). One DLT each was observed at 300 mg BID (grade 3 radiation pneumonitis) and 400 mg BID (grade 3 fatigue); no DLTs were observed in the 18 pts treated with 600 mg or 700 mg BID. There were no objective responses. At 56 days, stable disease was seen in 15 patients and lasted ≥112 days in 7 patients. Significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected at all doses and in all pts. Maximal effects were observed at doses ≥300 mg BID. With repeat dosing, 700 mg BID provided an average plasma concentration ~5-fold the projected IC90. Overall, doses ≥300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. Conclusions: INCB024360 was generally well tolerated at doses of up to 700 mg BID and there appears to be no correlation of dose with toxicity. Doses ≥300 mg BID were capable of >90% inhibition of IDO1 activity and found to effectively normalize plasma Kyn levels. The recommended dose as monotherapy is 600 mg BID. Clinical trial information: NCT01195311.

Abstract 2940 Background: The ubiquitin-proteasome pathway has been validated as a therapeutic target for multiple myeloma by the incorporation of proteasome inhibitors such as bortezomib and carfilzomib into our standards of care against this disease. A minority of patients achieve complete remission with single-agent therapy, however, and proteasome inhibitors may induce on- and off-target anti-apoptotic effects and clinical toxicities that limit their utility. Unlike proteasome inhibitors, which have a broad impact on intracellular proteolysis, E3 ligases are responsible for ubiquitination of only a small subset of proteins. Our hypothesis proposed that inhibition of the Human double minute (HDM)-2 E3 ligase, which in part is responsible for p53 ubiquitination, could be a more rational therapeutic target for myeloma, where p53 mutations are less common than is the case in solid tumors. Methods: We used Nutlin-3a and MI-63, which bind to the p53 binding pocket of HDM-2, as prototypic agents, and studied their activity against both wild-type (wt) and mutant (mut) p53 cell line models of multiple myeloma. These studies were supported by the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: Inhibition of HDM-2 in wt p53 (MM1.S, H929, MOLP-8) cells with Nutlin-3a or MI-63 reduced viability, with a median inhibitory concentration (IC50) in the 0.5–2 μM range. In wt cells, genomic and proteomic studies showed that MI-63 induced transcription of downstream gene targets including p21, PUMA and Bax, and promoted accumulation of p53, p21, p27, and Bax. This was accompanied by cell cycle arrest at G1, and induction of apoptosis as demonstrated by Annexin V staining and caspase activation. Interestingly, these agents also showed activity against mut p53 cells such as RPMI 8226 and U266, though with higher IC50's of 30–40 μM. Knockdown of HDM-2 sensitized mut p53 myeloma cells to MI-63, suggesting that this agent was inducing cell death in an on-target manner. In p53 mutant cells, MI-63 induced both type I cell death and type II, autophagic cell death, as determined by conversion of microtubule-associated protein 1 light chain 3, and activation of transcription of autophagy (ATG) genes ATG3 and 5. Since autophagy can be a mechanism of cell survival or cell death, we tested the impact of the autophagy inhibitors chloroquine and 3-methyladenine, and found that they reduced the impact of MI-63 on viability. Moreover, knockdown of ATG5 helped rescue cells as well, supporting the possibility that autophagic activation was a mechanism of cell death in these myeloma models. Synergistic anti-myeloma effects were seen when MI-63 was combined with the BH3 mimetic ABT-737, with decreased viability and enhanced apoptosis, accompanied by increased Bax activation and caspase cleavage. Notably, ABT-737 also enhanced the effects of MI-63 on mut p53 myeloma models, where increased levels of both type I and II programmed cell death were seen. Conclusions: Together, our findings support the possibility that HDM-2 is a promising therapeutic target for multiple myeloma, and also provide a rationale for translation of HDM-2 inhibitors alone, and in combination with ABT-737, to the clinic. Disclosures: Leopold: Ascenta Therapeutics: Employment, Equity Ownership.

6630 Background: Ruxolitinib (RUX) has demonstrated clinical benefit as therapy for MF. This study explores the safety and efficacy of RUX in pts with MF and low PC, where clinical data are limited. Methods: In this phase II study, pts with intermediate-1 to high-risk MF, and PC of 50–100x109/L started RUX at 5 mg BID. Doses could be increased in 5 mg QD increments every 4 weeks (wks) beginning at wk 4. Doses were decreased or held for PC 9/L and 9/L respectively. Assessments: Total Symptom Score (TSS, using the modified MF Symptom Assessment Form v2.0, and comprised of scores from 0=absent to 10=worst imaginable for night sweats, itching, bone/muscle pain, early satiety, abdominal discomfort and pain under left ribs); Patient Global Impression of Change (PGIC, a 7-point scale ranging from “very much improved” to “very much worse”); spleen size by palpation and by MRI (data not yet available); and safety. Results: At the time of analysis, 23 pts had completed ≥4 wks on study. At baseline: mean PC=72x109/L; high (4%), intermediate-2 (52%) and intermediate-1 (44%) risk group; mean spleen length=16.6 cm; mean TSS=25.5. At the time of analysis, 4%, 40%, 26%, 26% and 4% of pts were receiving RUX 5 mg QD, 5 mg BID, 5 mg AM/10 mg PM, 10 mg BID, and 10 mg AM/15 mg PM, respectively. At wk 4 (all pts on 5 mg BID), mean TSS improved 14%; 13% had ≥50% improvement. At wk 8 (52% on 5 mg AM/10 mg PM), mean TSS improved 23%; 30% had ≥50% improvement. Mean spleen length reduction of 22% (wk 4) and 27% (wk 8) was observed, and PGIC scores of “much improved” or “very much improved” were reported in 35% (wk 4) and 39% (wk 8) of pts. There were no Grade 4 PC, no dose holds for AEs and no discontinuations; 1 pRBC transfusion-dependent pt had Grade 4 anemia. Three pts experienced a total of 4 SAEs (fever; hypnagogic dreams; and spleen pain/pneumonitis) which resolved while on treatment. Conclusions: Effects on spleen size, PGIC, and TSS, even over the first weeks at low doses, are superior to those observed in the placebo group in the COMFORT-I study. These preliminary findings suggest a dosing strategy starting with 5 mg BID RUX with subsequent dose optimization may be efficacious and well tolerated in MF pts who have low platelets.

2500^ Background: The ineffectiveness of the immune system to control tumor growth is, in part, a result of immunosuppression imposed by negative regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme that catabolizes the first and rate-limiting step in the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been shown preclinically to play an important role in tumor-mediated immunosuppression. In cancer patients (pts), elevated IDO1 levels are associated with poor prognosis and shortened survival in a number of tumor types. Here we describe the pharmacodynamic (PD) assessment of INCB024360, a novel inhibitor of IDO1. Methods: Plasma samples were obtained from consented pts in study INCB 24360-101, a phase I dose-escalation study in patients with advanced malignancies. Trp and Kyn levels in plasma were determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells was also monitored. Results: Using anti-IDO1 specific antisera and archived tumor samples, we found IDO1 expression in various human tumors, including ovarian, colorectal, breast and prostate. Consistent with this result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were detected in archived plasma samples from pts, indicative of higher IDO1 activity in cancer pts. To date, 23 pts have been treated with the selective IDO1 inhibitor INCB024360. When plasma samples from patients were collected pre- and post-INCB024360 treatment, significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected. As an additional biomarker measurement, whole blood samples collected from pts at various times after dosing were stimulated ex vivo with interferon-γ and lipopolysaccharide to increase IDO1 activity and also showed dose-dependent decreases in IDO activity. With the current dose regimens and assays we have successfully achieved sustained inhibition of >90% at a well tolerated dose of INCB024360. Conclusions: This is the first demonstration of PD activity of an IDO1-specific inhibitor in cancer pts. Our study also confirms that IDO1 is frequently activated in cancer pts. The methods described will be used to establish a phase II dose.

We have identified two spiro-oxindole-based modulators -compounds A and B- of the MDM2-p53 protein-protein interaction that display suitable pharmacological properties for human clinical testing (1) and a high affinity to the N-terminal domain of human MDM2. For instance, in fluorescence polarization (FP) displacement assay using N-terminal domain of human MDM2 and a p53-based peptide (2), compounds A and B display Ki values of 5 and 5,9 nM, respectively, while Nutlin 3 shows a Ki value of 80,3 nM. The superior binding activity of the spiro-oxindole derivatives was confirmed by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). Having established their binding activities for the human target and in order to properly address potential on-target adverse effects in preclinical settings, we cloned MDM2 N-terminal domains of monkey, dog, rat and mouse. Sequencing analysis showed that, while the rat data from NCBI Reference Sequence database (3) is inaccurate, there is a high identity between human and monkey sequences. FP displacement assays were developed using MDM2 N-terminal domains of dog, rat and mouse which matched above-mentioned N-terminal domain of human MDM2. Ki value determinations revealed that the binding affinities of compounds A and B but not of Nutlin 3 significantly shifted to higher values by using both rodent MDM2 while, by using canine MDM2, they were similar to the ones determined with human MDM2. These findings were unexpected since MDM2 N-terminal domain sequences are conserved between rodent and non-rodent species. Cellular p53 activation data obtained with Nutlin 3, compounds A and B in a panel of monkey, dog, rat and mouse cell lines were consistent with the biochemical findings and confirmed that compounds A and B are modest p53 activators in rodent cells. In line with the results obtained in cellular settings, acute in vivo induction of p53-dependent transactivation by compounds A and B was significantly weaker in mouse spleen than in human xenografted tumor samples. In conclusion, these data demonstrate that compounds A and B both display high affinity against human MDM2 and that modulators of the MDM2-p53 protein-protein interaction can exhibit inter-species selectivity. These findings should be taken into consideration in the assessment of the tolerabily of MDM2-p53 antagonists in preclinical settings. 1. Wang S. et al., AACR, Orlando FL, 2011, Abstract LB-204 2. Ding K. et al, J. Am. Chem. Soc. 127, 10130-1, 2005. 3. http://www.ncbi.nlm.nih.gov/protein/NP_001101569.1 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4648. doi:1538-7445.AM2012-4648

Two spiro-oxindole-based modulators -compounds A and B - of the MDM2-p53 protein-protein interaction display suitable pharmacological properties and are currently under advanced preclinical development (1). In vitro, these compounds induce massive cell death in a subset of relevant tumor models such as MDM2-amplified SJSA-1, while they can significantly block cell proliferation without detectable cytotoxic effect in other human cell lines (e.g. HCT116). To better characterize in vivo the different tumor cell sensitivity of these novel MDM2 antagonists, quantitative and longitudinal pharmacodynamic effects have been determined in several preclinical settings: i) anti-tumor efficacy, ii) activation of p53-dependent molecular biomarkers such as p53 itself, p21, MDM2, PUMA, Noxa, Bax and MIC-1 and iii) downstream biological effects monitored by immuno-assays as well as by in vivo fluorescence tomography and PET imaging. The results obtained from these studies have revealed striking differences in the biological read-outs associated with the observed cytotoxic versus cytostatic effects and provide guidance for the use of certain biomarkers in the clinical development of this new generation of anti-cancer agents. 1. Wang S. et al., AACR, Orlando FL, 2011, Abstract LB-204 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4731. doi:1538-7445.AM2012-4731

204 Background: The efficacy of docetaxel following exposure to androgen synthesis inhibitors such as KC or abiraterone acetate (AA) is unknown. Given the emerging use of pre-docetaxel AA and docetaxel’s inhibition of androgen signaling, we retrospectively evaluated the efficacy of every 3 week docetaxel with prednisone (DP) in mCRPC previously exposed to KC as compared to KC-naïve patients. Methods: A randomized phase II trial of men with mCRPC treated with DP+AT-101 (bcl-2 inhibitor) vs. DP+placebo was analyzed (stratified for pain and performance status). Both arms were combined for analysis as no significant differences were seen. Overall survival [OS], progression-free survival [PFS], objective response [ORR], pain and PSA response rates were estimated with and without prior KC. Results: Of 220 evaluable men, 40 (18.2%) received prior KC (median duration=2.0 months, maximum=31.1 months). These 40 men had less visceral disease (15% vs 28%), more prior radiotherapy (70% vs 51%), and increased prior radiological (38% vs 21%) or bone scan progression (55% vs 41%). Efficacy outcomes were not statistically different (table). After adjusting for baseline stratum and treatment group, prior KC did not appear to significantly change OS with DP-based therapy (HR 1.34, 95%CI: 0.86–2.09, p=0.20). Conclusions: Similar outcomes were observed in mCRPC treated with DP-based therapy with or without prior KC. Given the marginally inferior survival with prior KC, evaluation of docetaxel outcomes following AA is of clinical importance, given its more potent CYP17 inhibition. [Table: see text]