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Supplementary Figure 1. Occurence of infection during treatment with single agent PI3K-AKT-mTOR inhibitors

Supplementary figure 1. Plot of resminostat concentration versus degree of HDAC enzyme inhibition at 2 hour post-dose on day 1 for all dose levels using the Hill model.

Purpose: Novel antitumor therapies against the PI3K–AKT–mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown.Experimental Design: In this retrospective case–control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K–AKT–mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K–AKT–mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K–AKT–mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K–AKT–mTOR inhibitors and cytotoxic chemotherapies.Results: The incidence of all grade infection was significantly higher with all single-agent PI3K–AKT–mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9–9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K–AKT–mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1–12.4; P = 0.02). Also, the combination of PI3K–AKT–mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0–11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0–7.6; P = 0.03) infection when compared with single-agent PI3K–AKT–mTOR inhibitors.Conclusions: Inhibitors of the PI3K–AKT–mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K–AKT–mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K–AKT–mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents. Clin Cancer Res; 21(8); 1869–76. ©2015 AACR.

Purpose: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors.Experimental Design: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed.Results: Nineteen patients (median age 58 years, range 39–70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions.Conclusions: Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days. Clin Cancer Res; 19(19); 5494–504. ©2013 AACR.

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.Merck SharpDohme Corp, a subsidiary of MerckCo, Inc.

In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC).To evaluate health-related quality of life (HRQoL) in KEYNOTE-426.A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib.HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease-Related Symptoms (FKSI-DRS) questionnaires.Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (-0.79% improvement vs sunitinib; 95% confidence interval [CI] -7.2 to 5.6), QLQ-C30 (7.5% improvement vs sunitinib; 95% CI 1.0-14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2-17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82-1.3; TTfD HR 0.82; 95% CI 0.69-0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87-1.3; TTfD HR 0.98; 95% CI 0.83-1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95-1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1-1.7). Patients were assessed during the off-treatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL.Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS.Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups.

Aims Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. Methods This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment. Results Thirty-one patients received >= 1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56)vsthose with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22)vsthose with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. Conclusion Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.

Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.

BACKGROUND: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.METHODS: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.RESULTS: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml(-1) min(-1). Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.CONCLUSIONS: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).British Journal of Cancer advance online publication 21 February 2017; doi:10.1038/bjc.2017.36 www.bjcancer.com.

BackgroundBAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.MethodsThis two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).ResultsSeventy-three patients received BAL101553 at doses of 15–80 mg/m2(phase 1,n = 24; phase 2a,n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population.ConclusionsThe RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties.Clinical trial registrationEudraCT: 2010-024237-23.

4500 Background: In the first interim analysis of the randomized, multicenter, open-label, phase 3 KEYNOTE-426 study (NCT02853331), treatment with pembro + axi significantly improved OS, PFS, and ORR vs sunitinib monotherapy in treatment-naive advanced ccRCC. Extended follow-up (median, 30.6 mo) continued to demonstrate the superior efficacy of pembro + axi vs sunitinib monotherapy in this patient population. Here, we present the results of the prespecified final analysis with 42.8-mo median follow-up. Methods: Treatment-naive patients (pts) with advanced ccRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, intolerable toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs Rest of World). Dual primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR, and safety. The protocol-specified final analysis was based on a target of 404 OS events. No formal hypothesis testing was performed because all efficacy endpoints were met previously at the first interim analysis; nominal P values are reported. Results: Overall, 861 pts were randomly assigned to receive pembro + axi (n=432) or sunitinib (n=429). Median duration of follow-up, defined as time from randomization to the database cutoff date, was 42.8 mo (range, 35.6-50.6). At data cutoff, 418 pts had died: 193 (44.7%) of 432 pts in the pembro + axi arm vs 225 (52.4%) of 429 pts in the sunitinib arm. Compared with sunitinib, pembro + axi improved OS (median: 45.7 vs 40.1 mo; HR, 0.73 [95% CI, 0.60-0.88]; P

327 Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .

Introduction: The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours. Methods: During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1–5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10–13, 20 mg qd days 14–26; cohort 2, anastrozole 1 mg qd days 10–19; cohort 3, letrozole 2.5 mg qd days 10–38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B. Results: Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0–τ decreased by 20% (90% CI 0.71–0.90) and 27% (0.63–0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0–τ increased by 13% (1.06–1.22) and 16% (1.11–1.21), respectively]; however, the 90% CI fell within the 0.7–1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable. Conclusions: The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified. Funding: AstraZeneca. Clinical Trial Registration: NCT02093351.

Background:\ud \ud This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours.\ud Methods:\ud \ud Eligible patients with ECOG PS 0–1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF.\ud Results:\ud \ud Totally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses.\ud Conclusions:\ud \ud Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed.

// Saeed Rafii 1 , Charlie Gourley 2 , Rajiv Kumar 1 , Elena Geuna 1 , Joo Ern Ang 1 , Tzyvia Rye 2 , Lee-May Chen 3 , Ronnie Shapira-Frommer 4 , Michael Friedlander 5 , Ursula Matulonis 6 , Jacques De Greve 7 , Amit M. Oza 8 , Susana Banerjee 9 , L. Rhoda Molife 1 , Martin E. Gore 9 , Stan B. Kaye 1 and Timothy A. Yap 1 1 Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK 2 University of Edinburgh Cancer Research UK Centre, Edinburgh, UK 3 University of California San Francisco, San Francisco, CA, USA 4 Sheba Medical Centre, Ramat Gan, Israel 5 Prince of Wales Cancer Centre, Randwick, Australia 6 Dana-Farber Cancer Institute, Boston, MA, USA 7 Oncologisch Centrum UZ Brussel, Brussels, Belgium 8 Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 9 Gynae-Oncology Unit, Royal Marsden Hospital, London, UK Correspondence to: Timothy A. Yap, email: tyap@mdanderson.org Keywords: PARP inhibitor, olaparib, BRCA, ovarian cancer, predictive biomarkers Received: October 25, 2016 Accepted: February 22, 2017 Published: April 10, 2017 ABSTRACT Background: The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib. Results: 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p

Purpose: Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron. Experimental Design: Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a “3+3” design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose (MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort. Results: Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased γ-glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence >10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85–237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration–time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD. Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation. Clin Cancer Res; 20(24); 6284–94. ©2014 AACR.

ABSTRACT Aims: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients. Patients & methods: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks. Results: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy. Conclusion: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.

Conventional therapeutic options for patients with advanced upper gastrointestinal cancers (UGIC) are limited. Following first-line treatments, some patients are offered experimental therapies, including participation in Phase I trials. This study aims to describe the experience of UGIC patients treated in a dedicated Phase I unit.Patient, tumour and treatment characteristics, and clinical outcomes of UGIC patients treated consecutively at the Drug Development Unit, Royal Marsden Hospital, between 2005 and 2009, were recorded.Ninety-six patients who previously received a median of 2 (range 1-4) lines of chemotherapies were treated in 30 Phase I trials. Of 81 evaluable patients, 9 achieved RECIST-objective response (11 %) with a 6-month clinical benefit rate of 14 %. Median progression free and overall survival were 7.7 weeks [95 %CI 7.7 (6.4-9.0)] and 19.1 weeks (95 %CI 17.5-20.8), respectively. Grade 3 or 4 toxicities were observed in 37 patients (39 %) and led to trial discontinuation in 9 (9 %); no toxicity-related death was recorded. In the multivariate analysis, serum albumin (35 g/dl, HR2.0, p = 0.002) and lactate dehydrogenase (192 μmol/l, HR1.7, p = 0.016) were prognostic of overall survival.Phase I clinical trials can be considered a reasonable option in selected patients with relapsed UGIC. The use of objective prognosticators may improve selection and risk/benefit profile of patients.

Afatinib is an irreversible ErbB family blocker currently under evaluation in late-stage clinical trials. This study primarily assessed the cardiac safety, pharmacokinetics and antitumor activity of afatinib in cancer patients. In this multicenter, Phase II, open-label, single-arm trial, 60 patients with solid tumors who were expected to express epidermal growth factor receptor-1 and HER2 received oral afatinib 50 mg daily. QTcF intervals (QT interval corrected by the Fridericia formula) were evaluated based on electrocardiogram recordings time-matched with pharmacokinetic blood samples after single (Day 1) and continuous (Day 14; steady state) administration. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0; antitumor activity was assessed using RECIST 1.0. There was a nonsignificant decrease of 0.3 ms (90 % confidence interval −2.8, 2.3; N = 49) in the mean of the average time-matched QTcF interval from baseline to steady state. The maximum plasma concentration for afatinib was seen at median t max 3 h after both single dose and at steady state. No relationship between afatinib plasma concentrations and time-matched QTcF, QT and heart rate change was found. The overall adverse event profile was consistent with the known safety profile of afatinib. One patient demonstrated a partial response (PR) and two patients unconfirmed PRs. Afatinib had no impact on cardiac repolarization, had a manageable safety profile and demonstrated antitumor activity in this uncontrolled study.

PARP inhibitors (PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases. These secondary mutations restored full-length BRCA2 protein, and most likely cause olaparib resistance by re-establishing BRCA2 function in the tumour cells.

We have previously reported a prognostic score for patients in phase I trials in the Drug Development Unit, treated at the Royal Marsden Hospital (RPS). The RPS is an objective tool used in patient selection for phase I trials based on albumin, number of disease sites and LDH. Patients with mesothelioma are often selected for phase I trials as the disease remains localised for long periods of time. We have now reviewed the clinical outcomes of patients with relapsed malignant mesothelioma (MM) and propose a specific mesothelioma prognostic score (m-RPS) that can help identify patients who are most likely to benefit from early referral.Patients who participated in 38 phase I trials between September 2003 and November 2015 were included in the analysis. Efficacy was assessed by response rate, median overall survival (OS) and progression-free survival (PFS). Univariate (UVA) and multivariate analyses (MVA) were carried out to develop the m-RPS.A total of 65 patients with advanced MM were included in this retrospective study. The PFS was 2.5 months (95% confidence interval [CI] 2.0-3.1 months) and OS was 8 months (95% CI 5.6-9.8 months). A total of four (6%) patients had RECIST partial responses, whereas 26 (40%) patients had RECIST stable disease3 months. The m-RPS was developed comprising of three different prognostic factors: a neutrophil: lymphocyte ratio greater than 3, the presence of more than two disease sites (including lymph nodes as a single site of disease) and albumin levels less than 35 from the MVA. Patients each received a score of 1 for the presence of each factor. Patients in group A (m-RPS 0-1; n = 35) had a median OS of 13.4 months (95% CI 8.5-21.6), whereas those in group B (m-RPS 2-3; n = 30) had a median OS of 4.0 months (95% CI 2.9-7.1, P 0.0001). A total of 56 (86%) patients experienced G1-2 toxicities, whereas reversible G3-4 toxicities were observed in 18 (28%) patients. Only 10 (15%) patients discontinued phase I trials due to toxicity.Phase I clinical trial therapies were well tolerated with early signals of antitumour activity in advanced MM patients. The m-RPS is a useful tool to assess MM patient suitability for phase I trials and should now be prospectively validated.

Item does not contain fulltext PURPOSE: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was 50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). FINDINGS: In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t(1/2) was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and Vz/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t(1/2) was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. IMPLICATIONS: Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).

Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disappointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early-phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies. Clin Cancer Res; 18(14); 3750–61. ©2012 AACR.

The fibroblast growth factor (FGF) signaling pathway is implicated as a key driver of tumor progression and growth via the dysregulation of cell proliferation, differentiation, survival, and angiogenesis in multiple tumor types. In addition, it may serve as a mechanism of resistance to antivascular endothelial growth factor targeted therapy. As such this pathway has emerged as a relevant therapeutic target, and several agents that can inhibit or modulate its signaling are in various stages of development. This review will summarize the current clinical status of agents targeting FGF receptors. In addition, strategies to accelerate the clinical development of these targeted agents will be presented.

A 58-year-old woman presented with metastatic endometrioid endometrial adenocarcinoma after being previously treated with surgery and adjuvant radiotherapy for early-stage endometrial cancer. She had received several lines of chemotherapy for multiple relapses over 9 years and displayed a profound sensitivity to platinum-containing regimens.CT scans demonstrated progressing liver, lung and peritoneal metastases and MRI detected multiple intracerebral metastases.New brain metastases secondary to progressive endometrioid endometrial carcinoma.On the basis of her sensitivity to repeated platinum treatment she was treated with the oral poly(ADP)-ribose polymerase (PARP) 1 inhibitor olaparib as part of a phase I trial. Repeat MRI scan at week 10 of treatment showed a significant reduction in the size of the brain metastases without steroid treatment or radiotherapy and the patient reported subjective improvement in tumor-related symptoms. After 8 months of olaparib treatment the patient developed objective disease progression. The tumor biopsy was negative for somatic BRCA1 and BRCA2 mutations, but displayed loss of PTEN, which has been suggested to be another predictive marker for sensitivity to PARP inhibitors. The patient remained alive for 10 months after completing olaparib, having gone on to derive further clinical benefit from repeat exposure to platinum-based therapy.

Introduction: First-line treatment options utilizing chemotherapy and cytokine-based treatments for patients with metastatic melanoma (MM) are unsatisfactory. We analyzed the clinical outcomes of patients with MM treated in phase I trials of novel agents. We hypothesized that patients included in phase I clinical trials did not have worse outcomes than with the chemotherapy and cytokine-based first-line treatment. Methods: Data of patients with MM treated at The Drug Development Unit between 2004 and 2010 were collected. The response rate (RR) and time to progression (TTP) for first-line therapy were compared to those of phase I trial therapy. Patients acted as their own controls for statistical analyses. Results: Sixty-five patients were treated in 31 phase I trials. First-line treatment included dacarbazine or temozolomide in 58 (89%) cases and interferon-α in 5 patients (8%) and cisplatin-based treatment in 2 patients (3%). There was no significant difference in either the RR (11 vs. 14%, p = 0.87) or TTP (90 vs. 53 days, p = 0.15) in patients treated with first-line treatment versus phase I treatment, respectively. Conclusion: Phase I clinical trials of molecularly targeted agents show clinical activity that is not dissimilar to that of treatment with existing chemotherapy and cytokine-based treatment.

Summary Background Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases. Methods Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760. Findings 29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6·1, range 1–24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. Interpretation Figitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease. Funding Pfizer Global Research and Development.

The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery.Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design.Thirty-seven patients received ZK 304709 from 15 to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria.There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.

The cell cycle is regulated by kinases such as the cyclin-dependent kinases (CDKs) and non-CDKs, which include Aurora and polo-like kinases, as well as checkpoint proteins. Mitotic kinesins are involved in the establishment of the mitotic spindle formation and function, and also play a role in cell cycle control. The disruption of the cell cycle is a hallmark of malignancy. Genetic or epigenetic events result in the upregulation of these kinases and mitotic kinesins in a myriad of tumour types, suggesting that their inhibition could result in preferential targeting of malignant cells. Such findings make the development of these inhibitors a rational and attractive new area for cancer therapeutics. Although challenges of potency and non-specificity have hampered their progress through the clinic, several novel compounds are presently in various phases of clinical trial evaluation.

Item does not contain fulltext BACKGROUND: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. METHODS: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. RESULTS: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-infinity) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-infinity treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. CONCLUSIONS: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.

Background Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. Methods Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. Results MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months. Conclusion MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity. Trial registration ClinicalTrials.gov: NCT00848718.

Purpose: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. Experimental Design: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. Results: Nineteen patients (median age 58 years, range 39–70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. Conclusions: Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days. Clin Cancer Res; 19(19); 5494–504. ©2013 AACR.

Apoptosis, a physiological process of programmed cell death, is disrupted in various malignancies. It has been exploited as an anti-cancer strategy traditionally by inducing DNA damage with chemotherapy and radiotherapy. With an increased understanding of the intrinsic and extrinsic pathways of apoptosis in recent years, novel approaches of targeting the apoptotic pathways have been tested in pre-clinical and clinical models. There are several early phase clinical trials investigating the therapeutic role of pro-apoptotic agents, both as single agents and in combination. In this review, we examine such treatment strategies, detailing the various compounds currently under clinical investigation, their potential roles in cancer therapeutics, and discussing approaches to their optimal use in the clinic.

e14086Background: 2-OHOA, is a first-in-class, synthetic hydroxylated lipid that activates SGSM1 and modulates the lipid content of cancer cell membranes. 2-OHOA reduces tumor growth in numerous xe...

2525Background: BAL101553 (prodrug of BAL27862) is a small molecule TCC that binds microtubules and promotes tumor cell death through activation of the mitotic checkpoint. Antiproliferative effects...

2043Background: Malignant primary CNS tumors constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment (tx) options at relapse are limited. First-in-human solid tumor stud...

PARP inhibitors (PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases. These secondary mutations restored full-length BRCA2 protein, and most likely cause olaparib resistance by re-establishing BRCA2 function in the tumour cells.

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.

Histone deacetylase (HDAC) inhibitors have recently emerged as a novel and active class of anticancer agents. Belinostat is one member of the class that has been tested as a single agent and in combination with other chemotherapies and biological agents in the treatment of solid tumors and lymphoma.A literature search of pre-clinical and clinical studies of belinostat was performed. The data from these studies were analysed to summarise the progress of belinostat from Phase I to a current pivotal trial in peripheral T-cell lymphoma. The parallel development of appropriate biomarker analysis is also discussed.Belinostat has demonstrated significant clinical activity in T-cell lymphomas. Although its activity as a single agent in solid tumors has been less compelling, the emerging results from combination trials are promising. However, the basis for the activity of belinostat, like that of other HDAC inhibitors, remains to be truly defined and the identification of predictive and prognostic biomarkers of activity should be established to further progress the development of this compound.

Unplanned hospital admissions (UHAs) in the context of oncology Phase I trials are important, yet rarely reported.All patients admitted to the Royal Marsden Hospital Phase I clinical trials unit during February and March of 2005-2007 were included. The patient-, admission- and trial-related variables were collected. Correlations were sought between the occurrence of UHAs and the baseline patient/trial-related characteristics.Of the 308 admissions involving 177 patients, UHAs constituted 21% of all the admissions and 38% of the total bed occupancy. The majority of UHAs were cancer related (78%) and their occurrence was associated with a significant early patient attrition. Using multivariate analysis, the factors significantly associated with UHAs included age60 years (RR 2.32, confidence interval (CI)-95% 1.12-4.81), ≥3 metastatic sites (RR 3.26, CI-95% 1.54-6.90) and LDHULN (RR 2.18, CI-95% 1.06-4.46), with albumin35 g/dL trending to significance (p=0.052). The trials that contained cytotoxic chemotherapy incurred disproportionately higher rates of admissions (69.5%) than the trials that did not.UHAs constitute a substantial workload and impact on the speed and cost of, as well as resource allocation in Phase I oncology trials. The majority of UHAs are cancer rather than treatment related. The risk stratification to guide patient selection may help reduce the incidence of UHAs.

Purpose The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC). Patients and Methods In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of ≥ 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of ≥ 30% and ≥ 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration. Results Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of ≥ 30%, ≥ 50% and ≥ 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study ≥ 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a ≥ 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated. Conclusion Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.

The development of anticancer drugs remains slow and costly. Use of predictive biomarkers has been postulated to not only accelerate this process but also increase the odds of drug approval ([1][1]). Despite concerns about the validation of the insulin-like growth factor receptor type I (IGF-IR) as

Purpose It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis. Patients and Methods This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of ≥ 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; α = .05; β = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued. Results A decline in PSA of ≥ 50% was observed in 28 (67%) of 42 phase II patients, and declines of ≥ 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of ≥ 50% PSA decline and TTPP on abiraterone acetate and dexamethasone. Conclusion CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.

Eukaryotic organisms depend on the cell cycle for their survival though a cyclical biochemical process consisting of tightly controlled, enzymatically driven reactions that result in cell division and the generation of new cells. The cell cycle is regulated by kinases such as cyclin-dependent kinases (CDKs), and non-CDKs, which include the Aurora and Polo-like kinases, as well as checkpoint proteins and mitotic kinesins. The CDK family of serine-theronine kinases is a common target for genetic or epigenetic events, resulting in the amplification or overexpression of these kinases in a myriad of tumor types. Such findings make CDKs rational and attractive targets for cancer therapeutics as their inhibition could potentially result in preferential targeting of malignant cells. However, several cyclin-CDK complexes have been found to be dispensable for cell proliferation owing to functional redundancy, promiscuity, and compensatory mechanisms. Although these issues have hampered their progress into the clinic, several novel compounds are currently in various phases of clinical trial development. This chapter will introduce the role of CDKs in facilitating the cell cycle, their aberrations in malignant progression and pharmacological strategies targeting them.

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

Background: The programmed death receptor 1 (PD-1) pathway is implicated in evasion of the antitumor immune response. Pembrolizumab is a potent, highly selective humanized monoclonal antibody against PD-1 designed to block interaction with its ligands, PD-L1 and PD-L2, thus removing inhibition of T-cell activation against cancer. PD-L1 is overexpressed in malignant pleural mesothelioma (MPM) and associated with poor prognosis. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1-positive MPM. Methods: KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab for PD-L1-positive advanced solid tumors. Key eligibility criteria for the MPM cohort were measurable disease, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1-positive bands in stroma as determined by a prototype immunohistochemistry assay at a central laboratory, failure of standard therapy, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, adequate organ function, and no autoimmune disease or interstitial lung disease. Pembrolizumab 10 mg/kg was given every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points are safety, tolerability, and preliminary efficacy. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Results: Of the 84 patients with MPM who were screened, 38 (45%) had PD-L1-positive tumors. Between March 2014 and December 2014, 25 patients with MPM were treated (68% men; median age, 65 years; 64% ECOG PS 1). 36% of patients had epithelioid histology. 88% of patients received ≥1 prior therapy (28% ≥2); 80% received a platinum and pemetrexed. Fifteen patients (60%) experienced a drug-related adverse event (DRAE); only 3 (12%) had grade ≥3 DRAEs. DRAEs with incidence >25% were nausea (40%), fatigue (32%), and decreased appetite (28%). Four patients (16%) experienced immune-related AEs, but only 2 patients required dose interruption (1 because of ALT increased, 1 because of uveitis). There was no treatment-related mortality, and no patients discontinued because of DRAEs. Preliminary overall response rate (confirmed and unconfirmed) was 24% (n = 6); 13 patients (52%) had stable disease, resulting in a disease control rate of 76%. Four patients (16%) had progressive disease, and 2 patients had no assessment at the time of analysis. 16 patients (64%), including all responders, remain on treatment (duration 8+ to 24+ weeks). Conclusion: Pembrolizumab is generally well tolerated and provides robust antitumor activity in patients with advanced PD-L1+ MPM. The 76% disease control rate in this previously treated MPM population is unprecedented and warrants further study. Citation Format: Evan W. Alley, L. Rhoda Molife, Armando Santoro, Kim Beckey, Sammy Yuan, Jonathan D. Cheng, Bilal Piperdi, Johannes H.M. Schellens. Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT103. doi:10.1158/1538-7445.AM2015-CT103

Background: There is an urgent need for better trial designs to assess targeted drug combinations. We proposed a novel intrapatient (intrapt) dose escalation trial design to optimize drug exposures, minimize pharmacokinetic (PK) variability and reduce patient (pt) numbers needed (Yap et al, JCO 2013). In vivo synergy between PARP and PI3K pathway inhibition was seen in BRCA1-related and sporadic cancers (Juvekar et al; Ibrahim et al, Cancer Discov 2012), providing rationale for this study. Methods: Two-stage investigator initiated phase I trial: a) Intrapt dose escalation; b) Recommended phase II combination dose (RP2CD) expansion. Advanced cancer pts received escalating doses of AZD5363 (AZD) BID in 2 parallel arms (4 days on 3 days off [4/7 arm] at 320, 400, 480mg; 2 days on 5 days off [2/7 arm] at 480, 560, 640mg) with Olaparib (Ola) at 300mg BID in 3 weekly cycles. AZD was escalated after each cycle in each pt if drug related toxicities were ≤CTCAE G2. Dose limiting toxicities (DLT) were assessed during the 1st cycle of each dose level (DL). ≥6 evaluable pts were required at each DL. RECIST assessment was done every 3 cycles. Prior PARP or PI3K/AKT inhibitor use was allowed. PK and pharmacodynamics (PD) were assessed in tumor and normal tissue. Targeted +/- whole exome next generation sequencing was assessed in tumor and serial plasma DNA samples in all pts for predictive biomarkers of response. Results: Dose escalation was completed in 7.5 months (m) in 20 pts in 1 center; ≥6 evaluable pts were treated at each of the 3 DLs in both arms. Common (>15%) G1-2 toxicities were nausea, vomiting, fatigue, diarrhea and anemia. A DLT of G3 rash was seen at 480mg BID 4/7 AZD + 300mg BID Ola. Non DLT G3 anemia (n = 2), diarrhea (n = 2), fatigue (n = 1) and vomiting (n = 1) were seen in 4/7 arm; G3 hyperglycemia (n = 1), transaminitis (n = 1) and fatigue (n = 2) in 2/7 arm. No significant PK interactions were seen between Ola and AZD. Intrapt dose escalation of AZD showed dose dependent increases in PK exposures. Platelet-rich plasma PD showed significant decreases in pSer9 GSK3β post-therapy at all DLs (mean ≥55% [p Conclusion: This novel trial design led to rapid completion of dose escalation. RP2CD expansion (n = 40) is ongoing in: a) germline BRCA mut cancers; b) sporadic cancers with relevant somatic mutations. Citation Format: Vasiliki Michalarea, David Lorente, Juanita Lopez, Suzanne Carreira, Hasina Hassam, Mona Parmar, Nitharsan Sathiyayogan, Alison Turner, Emma Hall, Sonia Serrano Fandos, Satyanarayana Seeramreddi, Shaun Decordova, Karen Swales, Ruth Ruddle, Florence Raynaud, Nina Tunariu, Gerhardt Attard, L. Rhoda Molife, Udai Banerji, Ruth Plummer, Johann S. de Bono, Timothy A. Yap. Accelerated phase I trial of two schedules of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363 using a novel intrapatient dose escalation design in advanced cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT323. doi:10.1158/1538-7445.AM2015-CT323

Background: The PARPi olaparib (Ola) was recently granted FDA accelerated approval in advanced BMOC. Despite impressive clinical activity in BMOC, the impact of baseline pt factors remains unclear. We hypothesized that the platinum chemotherapy (Plt chemo) to PARPi interval (PTPI) can be used to refine the conventional prediction of response to PARPi based on the clinical categorization of pts into Plt sensitive (Plt-S) and Plt resistant (Plt-R). Methods: Retrospective study of pt with advanced BMOC treated in relapsed setting with ≥ 200 mg bid Ola between 4/2006 – 8/2013 in multiple centers. Pearson Chi2, odds ratios (OR) and Fisher’s exact probability tests were used for statistical analyses. Results: 108 advanced BMOC pts were assessed; median age 55y (range 38-79); 83 (77%) pts had high grade serous carcinoma. BRCA1:BRCA2 mutations ratio 71:29. Median prior lines of chemo: 3 (range 1-10). 41 (38%) pts had prior breast cancer (BC). 64% had Plt-S disease and 36% had Plt-R disease prior to Ola. Median PTPI was 53 weeks (w) (range 4-244). Median PTPI was 68.7w for Plt-S pts versus (vs) 25.9w for Plt-R pts (p < 0.0001). RECIST complete or partial responses (CR/PR) were observed in 23/65 (35%) Plt-S pts vs 5/38 (13%) Plt-R pts (p < 0.02). Pts with > 52w PTPI had higher CR/PR rates than those with < 52w PTPI independent of their Plt status (37% vs 18%, respectively, p = 0.053). Pts who had only 1 prior line of chemo had higher CR/PR rates vs pts who had > 1 prior line (p < 0.005). No differences in CR/PR rates were noted between pts with BRCA1 vs pts with BRCA2 mutations, pts with prior BC vs pts without, or use of chemo for BC vs none. Median progression-free survival was 70w for pts with PR/CR vs 28w for pts without (log-rank, p = 0.0004). Median survival was 161w for pts with CR/PR and 64w for pts without (log-rank, p = 0.0005). Conclusions: These data suggest that prediction of response to PARPi in advanced BMOC based on conventional Plt-S/Plt-R categorization may be refined by PTPI. Treatment of Plt-R BMOC pts with a non-Plt agent prior to Ola in order to prolong PTPI may be an appropriate clinical strategy. These findings should be validated prospectively in a larger data set.