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International audience; BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell–derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment.METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire–6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]).RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P

Background Tralokinumab is an anti–interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2. Methods The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data. Results FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting tralokinumab efficacy. Discussion A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population. Trial registration STRATOS 1 and 2 are registered on ClinicalTrials.gov (NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014). Electronic supplementary material The online version of this article (10.1186/s12890-019-0889-4) contains supplementary material, which is available to authorized users.

Introduction and Objectives In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced annualized asthma exacerbation rates (AAER) by up to 71% versus placebo in adults with severe, uncontrolled asthma. We evaluated the effect of tezepelumab on exacerbations in patients from PATHWAY with low and high bronchodilator reversibility. Methods Adults with severe, uncontrolled asthma were randomized to receive tezepelumab (70 mg every 4 weeks [Q4W], 210 mg Q4W or 280 mg every 2 weeks) or placebo for 52 weeks. AAER and the rate of exacerbations resulting in hospitalization or emergency room (ER) visits were estimated for patients with low ( Results Of 550 randomized patients, 299 and 251 had low and high FEV1 reversibility, respectively. Tezepelumab 210 mg (phase 3 dose) reduced AAER over 52 weeks by 70% (95% confidence interval [CI]: 41, 85) and 72% (95% CI: 32, 88) versus placebo in patients with low and high FEV1 reversibility, respectively. For pooled tezepelumab doses, AAER was reduced by 69% (95% CI: 50, 81) and 60% (95% CI: 26, 78) in the low and high groups, respectively. Data were similar for 70 and 280 mg. Exacerbations resulting in hospitalizations or ER visits were reduced by 85% (95% CI: 21, 97) and 78% (95% CI: −32, 96) versus placebo in patients with low and high FEV1 reversibility, respectively, for tezepelumab 210 mg, and by 84% (95% CI: 51, 94) and 64% (95% CI: −18, 89) in the pooled tezepelumab group, respectively. Conclusions Tezepelumab treatment reduced AAER irrespective of baseline bronchodilator reversibility, further supporting its potential benefits in a broad population of patients with severe asthma.

Background Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study. Methods SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving Conclusions SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose. Trial registration NCT03406078 (ClinicalTrials.gov). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078

Background Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study. Methods CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants’ type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit. Discussion CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation. Trial registration NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.

Background Patients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline disease phenotype. This article reports the design and objectives of the pivotal phase 3 NAVIGATOR study. Methods NAVIGATOR (NCT03347279) is an ongoing randomized, double-blind, placebo-controlled trial in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma, who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids (N = 1061). The study population includes approximately equal proportions of patients with high (≥ 300 cells/μL) and low ( Discussion NAVIGATOR is evaluating the effect of tezepelumab in patients with a broad range of severe asthma phenotypes at baseline, including those with low blood eosinophil counts. The target sample size for NAVIGATOR (N = 1060) was achieved, and it is the largest clinical study of tezepelumab in severe, uncontrolled asthma to date. NAVIGATOR aims to further investigate the effect of tezepelumab on exacerbations and build on observations from the phase 2b PATHWAY study, and to demonstrate further the potential of tezepelumab to provide patients with severe, uncontrolled asthma with improvements in lung function, asthma control and health-related quality of life. Trial registration NCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.

Background Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies. Methods DESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated. Discussion DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma. Trial registration NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Background: In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced annualized asthma exacerbation rates (AAER) by up to 71% versus placebo in adults with severe, uncontrolled asthma. We evaluated the effect of tezepelumab on exacerbations in patients from PATHWAY with low and high bronchodilator reversibility. Methods: Adults with severe, uncontrolled asthma were randomized to receive tezepelumab (70mg every 4 weeks [Q4W], 210mg Q4W or 280mg every 2 weeks) or placebo for 52 weeks. AAER and the rate of exacerbations resulting in hospitalization or emergency room (ER) visits were estimated for patients with low ( Results: Of 550 randomized patients, 299 and 251 had low and high FEV1 reversibility, respectively. Tezepelumab 210mg (phase 3 dose) reduced AAER over 52 weeks by 70% (95% confidence interval [CI]: 41, 85) and 72% (95% CI: 32, 88) versus placebo in patients with low and high FEV1 reversibility, respectively. For pooled tezepelumab doses, AAER was reduced by 69% (95% CI: 50, 81) and 60% (95% CI: 26, 78) in the low and high groups, respectively. Data were similar for 70 and 280mg. Exacerbations resulting in hospitalizations or ER visits were reduced by 85% (95% CI: 21, 97) and 78% (95% CI: −32, 96) versus placebo in patients with low and high FEV1 reversibility, respectively, for tezepelumab 210mg, and by 84% (95% CI: 51, 94) and 64% (95% CI: −18, 89) in the pooled tezepelumab group, respectively. Conclusions: Tezepelumab treatment reduced AAER irrespective of baseline bronchodilator reversibility, further supporting its potential benefits in a broad population of patients with severe asthma.

Background Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. Patients and methods Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. Results A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. Conclusion The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. Trial identifier Clinicaltrials.gov NCT01750281.

Introduction Le tezepelumab est un anticorps monoclonal humain bloquant l’activite de la lymphopoietine stromale thymique. Dans l’etude de phase IIb PATHWAY ( NCT02054130 ), le tezepelumab a significativement reduit les taux annualises d’exacerbations de l’asthme (AAER) de 71 % par rapport au placebo, et a ameliore la fonction pulmonaire, le controle de l’asthme et la qualite de vie chez des adultes asthmatiques severes non-controles. Cette analyse post-hoc a evalue l’effet du tezepelumab chez des patients ayant un asthme allergique qui etaient eligibles a l’omalizumab (OMA). Methodes Les patients adultes ayant un asthme severe ont ete randomises entre tezepelumab (70 mg ou 210 mg SC toutes les 4 semaines Q4S, ou 280 mg SC toutes les 2 semaines Q2S) ou un placebo Q2S pendant 52 semaines. Les patients OMA-eligibles prenaient des corticoides inhales a fortes doses, avaient un resultat positif (> 0,35 unites) aux tests immuno-enzymatiques en fluorescence concernant les aero-allergenes perennes classiques, un taux serique initial total d’immunoglobulines (Ig) E ≥ 30–≤ 1500 UI/mL, et une association d’IgE et de poids corporel le rendant eligible a l’OMA. L’AAER et le volume expiratoire maximal par seconde (VEMS) ont ete determines pour les patients eligibles et ineligibles a OMA. Resultats Sur 550 patients randomises, respectivement 92 et 453 patients ont ete eligibles et ineligibles pour le traitement par OMA (5 inconnus). Les patients OMA-eligibles avaient des taux seriques totaux initiaux d’IgE et des taux de fraction expiree du monoxyde d’azote superieurs a ceux des patients OMA-ineligibles. Comparativement au placebo, le tezepelumab 210 mg a diminue l’AAER en 52 semaines de 79% (intervalle de confiance [IC] a 95 % : 37–93) et 69 % (IC95 % : 42–83) chez les patients OMA-eligibles et OMA-ineligibles ( Fig. 1 ). Concernant le tezepelumab toutes doses confondues, l’AAER a ete reduit de 76 % (IC95 % : 46–90) et 64 % (IC95 % : 45–77) respectivement chez les patients OMA-eligibles et OMA-ineligibles. Des ameliorations du VEMS ont ete observees dans les deux groupes d’eligibilite mais les estimations ponctuelles ont ete superieures chez les patients OMA-eligibles. Conclusion Le tezepelumab a diminue les exacerbations et ameliore le VEMS comparativement au placebo chez des patients ayant un asthme allergique ou non-allergique, ce qui corrobore encore ses effets benefiques dans une large population de patients atteints d’asthme severe.

Tralokinumab, a fully human IgG4 monoclonal antibody, specifically neutralizes IL-13. The ATMOSPHERE clinical development program comprised four randomized, placebo-controlled clinical trials and an open-label study that aimed to assess the efficacy and safety of tralokinumab for the treatment of severe, uncontrolled asthma. The two pivotal trials (STRATOS 1 and STRATOS 2; NCT02161757 and NCT02194699) evaluated the efficacy and safety of tralokinumab, with STRATOS 1 identifying a subgroup most likely to demonstrate enhanced response to treatment. Further trials have assessed the ability of tralokinumab to reduce oral corticosteroid use (TROPOS; NCT02281357) and determined its mechanistic effects (MESOS; NCT02449473). An open-label study in Japanese individuals (NCT02902809) assessed the long-term safety and tolerability of tralokinumab in this population.

Purpose Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) –associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. Patients and Methods This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. Results A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). Conclusion Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.

Long-term oral corticosteroid (OCS) use in patients with severe asthma is associated with significant adverse effects.This 40-week, randomised, double-blind trial evaluated the OCS-sparing potential of tralokinumab in patients with severe, uncontrolled asthma requiring maintenance OCS treatment plus inhaled corticosteroids/long-acting β2-agonists. Overall, 140 patients were randomised to tralokinumab 300 mg or placebo (n=70 in each group) administered subcutaneously every 2 weeks. The primary end-point was percentage change from baseline in average OCS dose at week 40, while maintaining asthma control. Secondary end-points included proportion of patients with a prescribed maintenance OCS dose of ≤5 mg, those with a ≥50% reduction in prescribed maintenance OCS dose and asthma exacerbation rate. Safety was also assessed.At week 40, the percentage reduction from baseline in the final daily average OCS dose was not significantly different between tralokinumab and placebo (37.62% versus 29.85%; p=0.271). There were no significant between-treatment differences for any secondary end-point. Overall, reporting of adverse events and serious adverse events were similar for the tralokinumab and placebo groups. Although a greater proportion of tralokinumab-treated patients reported upper respiratory tract infections (35.7% versus 14.3%), there were no reported cases of pneumonia.Overall, tralokinumab did not demonstrate an OCS-sparing effect in patients with severe asthma.

2579 Background: This three-center phase I study evaluated the PARP1/2 inhibitor olaparib (O) in combination with carboplatin (C), paclitaxel (Pa) or both (CPa) in patients (pts) with advanced solid tumors refractory to standard therapies (NCT00516724). Methods: This ongoing study consists of multiple parts (P) in which escalating doses of O capsule and tablet formulations were studied. Capsule formulation data are presented; continuous O with C (P1; 21 day cycle), CPa (P2a; 21 day cycle) and weekly Pa (P2b; 28 day cycle) or intermittent O with CPa (P3; 21 day cycle). Primary and secondary objectives were safety/tolerability and antitumor activity (RECIST), respectively. Results: This analysis (non validated data) included 87 enrolled pts (P1 [n=25] P2a [n=20] P2b [n=12] and P3 [n=30]). Most common tumor types were breast (26%), melanoma (10%) and ovarian (7%). 12 pts had known gBRCA1/2 mutations. A tolerable continuous dosing schedule of O with CPa was not determined. Most common AEs (all grades) were myelosuppression (71%) notably neutropenia (54%) and thrombocytopenia (26%), and fatigue (77%). Excessive treatment cycle delays due to hematologic toxicity occurred with continuous O combined with standard doses of C or CPa. Two doses were identified as tolerable: continuous O 100 mg bd with weekly Pa 80 mg/m2 and intermittent O 200 mg bd (d1–10) with CPa AUC4/175 mg/m2 q 3 weeks. 14/87 pts (16%) had an objective response (complete response [CR] 5%; partial response [PR] 11%); 28% had stable disease for ≥4 months. Activity appeared greater in pts with BRCA1/2 mutations (CR 17%; PR 33%). Conclusions: Continuous O in combination with CPa exacerbated hematologic toxicities leading to schedule delays. Tolerability improved with intermittent O. Antitumor activity was highest in pts with a BRCA1/2 mutation. This study identified two tolerable O capsule treatment schedules for further development. Clinical trial information: NCT00516724. [Table: see text]

11024 Background: The oral PARP inhibitor olaparib has shown antitumor activity as monotherapy in patients (pts) with breast and ovarian cancer with gBRCA1/2 mutations. This multicenter non-comparative study evaluated whether tumors in gBRCA1/2 mutation carriers are responsive to olaparib regardless of tumor type (NCT01078662). Methods: Heavily pretreated pts with advanced cancer refractory to standard therapy (98% of breast cancer pts had ≥3 lines of prior chemotherapy for metastatic disease) and with a gBRCA1/2 mutation, received olaparib 400 mg bid (capsule) until disease progression. Primary objective: tumor response by RECIST 1.1. Secondary objectives: PFS, OS and safety. Results: 298 pts received treatment and were evaluable. Enrollment is complete, 33 pts remain on study. Median duration of treatment in this heavily pretreated population was 5.5 months (range