Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer.

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.

Baseline Results of the West London lung cancer screening pilot study - Impact of mobile scanners and dual risk model utilisation.

OBJECTIVES: The West London lung screening pilot aimed to identify early-stage lung cancer by targeting low-dose CT (LDCT) to high risk participants. Successful implementation of screening requires maximising participant uptake and identifying those at highest risk. As well as reporting pre-specified baseline screening metrics, additional objectives were to 1) compare participant uptake between a mobile and hospital-based CT scanner and 2) evaluate the impact on cancer detection using two lung cancer risk models. METHODS: From primary care records, ever-smokers aged 60-75 were invited to a lung health check at a hospital or mobile site. Participants with PLCOM2012 6-yr risk ≥1.51 % and/or LLPv2 5-yr risk ≥2.0 % were offered a LDCT. Lung cancer detection rate, stage, and recall rates are reported. Participant uptake was compared at both sites (chi-squared test). LDCT eligibility and cancer detection rate were compared between those recruited under each risk model. RESULTS: Of 8366 potential participants invited, 1047/5135 (20.4 %) invitees responded to an invitation to the hospital site, and 702/3231 (21.7 %) to the mobile site (p = 0.14). The median distance travelled to the hospital site was less than to the mobile site (3.3 km vs 6.4 km, p < 0.01). Of 1159 participants eligible for a scan, 451/1159 (38.9 %) had a LLPv2 ≥2.0 % only, 71/1159 (6.1 %) had a PLCOM2012 ≥1.5 % only; 637/1159 (55.0 %) met both risk thresholds. Recall rate was 15.9 %. Lung cancer was detected in 29/1145 (2.5 %) participants scanned (stage 1, 58.6 %); 5/29 participants with lung cancer did not meet a PLCOM2012 threshold of ≥1.51 %; all had a LLPv2 ≥2.0 %. CONCLUSION: Targeted screening is effective in detecting early-stage lung cancer. Similar levels of participant uptake at a mobile and fixed site scanner were demonstrated, indicating that uptake was driven by factors in addition to scanner location. The LLPv2 model was more permissive; recruitment with PLCOM2012 alone would have missed several cancers.

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours.

BACKGROUND: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). PATIENTS AND METHODS: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. RESULTS: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11). CONCLUSION: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.

Multidisciplinary interventions in a specialist Drug Development Unit to improve family history documentation and onward referral of patients with advanced cancer to cancer genetics services.

BACKGROUND: Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU). METHODS: Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) 'traffic light' system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review. RESULTS: Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%). CONCLUSION: Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity.

Clinical outcomes of adolescents and young adults with advanced solid tumours participating in phase I trials.

BACKGROUND: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. AIM: To study the outcome of AYA patients in phase I clinical trials. METHODS: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. RESULTS: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. CONCLUSION: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.

The role of genomic profiling in adolescents and young adults (AYAs) with advanced cancer participating in phase I clinical trials.

INTRODUCTION: Adolescents and young adults (AYAs) diagnosed with cancer between ages 15-39 years may harbour germline variants associated with cancer predisposition. Such variants represent putative therapeutic targets, as may somatic variants in the tumour. Germline and tumour molecular profiling is increasingly utilised to facilitate personalisation of cancer treatment in such individuals. AIM: Considering AYAs with advanced solid tumours managed in a specialist drug development unit (DDU), the aims of this study were to investigate the use and impact of: 1. Germline genetic assessment. 2. Tumour molecular profiling. METHODS: AYAs treated in the DDU at the Royal Marsden Hospital between 2002 and 2016 were identified from departmental databases. Data regarding clinicopathological features, clinical assessments and germline and tumour genetic testing were retrieved by chart review. RESULTS: The study cohort included 219 AYAs. Common cancer types included sarcoma (41, 19%); cervical (27, 12%); breast (25, 11%); ovarian (23, 11%) and colorectal (21, 10%) cancers. Germline testing was undertaken in 34 (16%) patients, 22 of whom carried a pathogenic variant. Using current testing criteria, an additional 32 (15%) would be eligible for germline testing based on their personal history of cancer alone. Tumour testing was undertaken in 46 (21%) individuals. Somatic mutations were commonly identified in TP53 13 (28%); PIK3CA (8, 18%); KRAS (4, 9%) and MET 5 (11%). DISCUSSION: A significant proportion of AYAs with advanced cancer have targetable somatic or germline mutations. Consideration of familial risk factors and inclusion of germline testing wherever appropriate can complement tumour testing to optimise patient management and inform management of at-risk relatives.

High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy.

Despite impressive clinical activity in patients with germline BRCA1 and BRCA2 (BRCA1/2) mutant cancers, antitumor responses to poly(ADP-Ribose) polymerase (PARP) inhibitors are variable. We set out to assess the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors, its correlation with patient outcomes, and the identification of factors associated with RDR. We retrospectively reviewed all patients with advanced cancers from five early phase PARP inhibitor monotherapy trials. 113 patients (ovarian cancers 57.5%; breast cancers 23.9%) were included in this retrospective study; 46 (40.7%) patients developed RDR on PARP inhibitor monotherapy. We identified two patterns of RDR: early RDR (1st or 2nd on-treatment scans) in 69.6% of patients, and late RDR (penultimate or final scans) in 30.4% of patients. Early RDR was associated with shorter time to progression (TTP) (225 vs 367 days, HR:0.59, 95%CI 0.36-0.98; p=0.04) and overall survival (OS) (499 vs 857 days; HR:0.47, 95%CI 0.27-0.82, p=0.006). Seventy-nine (69.9%) patients had known germline BRCA1/2 mutations; 49.4% of these BRCA1/2 mutation carriers developed RDR versus 20.6% of patients with unknown or wildtype BRCA1/2 status. Harboring germline BRCA1/2 mutations was independently predictive for RDR (RR:2.93, 95% CI 1.08-7.90, p=0.03). Patients with germline BRCA1 mutations had worse TTP and OS than BRCA2 mutation carriers (212 vs 406 days, HR:0.58, 95% CI 0.36-0.94, p=0.023 and 515 vs 937 days; HR:0.49, 95% CI 0.29-0.83; p=0.007). RDR with PARP inhibitors are frequent, particularly in germline BRCA1/2 mutation carriers. These findings have clinical implications for patient outcomes and may reflect underlying intrapatient genomic heterogeneity.

Phase I clinical trials in patients with advanced non-small cell lung cancer treated within a Drug Development Unit: What have we learnt?

OBJECTIVES: Despite advances in novel drug development for patients with advanced non-small cell lung cancer (NSCLC), there are still only a limited number of approved treatments. We therefore evaluated the clinical outcomes of patients with advanced NSCLC referred to a dedicated phase I clinical trials unit assessed baseline clinical factors associated with successful enrollment onto phase I trials. MATERIAL AND METHODS: We conducted a retrospective study involving patients with advanced NSCLC referred to the Drug Development Unit at the RMH between January 2005 and December 2013. RESULTS: 257 patients with advanced NSCLC were referred for consideration of phase I trials, of which only 89 (35%) patients successfully commenced phase I trials. The commonest reasons for not entering study included poor ECOG performance status and rapid disease progression. A multivariate analysis identified that ECOG performance status (0-1) and RMH prognostic score (0-1) were associated with successful enrollment onto phase I trials (p<0.001). Single agent therapies included novel agents against the phosphatidylinositol-3 kinase pathway, insulin growth factor-1 receptor and pan-HER family tyrosine kinases. These trial therapies were well tolerated and mainly associated with grade 1-2 adverse events, with a minority experiencing grade 3 toxicities. Nine (10%) patients, 4 with known EGFR or KRAS mutations, achieved RECIST partial responses. Median time to progression was 2.6 months and median overall survival was 8.1 months for patients enrolled. CONCLUSIONS: Phase I trial therapies were generally well tolerated with potential antitumor benefit for patients with advanced NSCLC. Early referral to drug development units at time of disease progression should be considered to enhance the odds of patient participation in these studies.

Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

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<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib. METHODS: We conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib. CONCLUSION: PTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity.

Clinical factors of response in patients with advanced ovarian cancer participating in early phase clinical trials.

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.

Trabectedin as a chemotherapy option for patients with BRCA deficiency.

Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412-24. ©2016 AACR.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. METHODS: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. FINDINGS: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. INTERPRETATION: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. FUNDING: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.

A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.

BACKGROUND: The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted. METHODS: Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics. RESULTS: One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients. CONCLUSIONS: OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.

Venous thromboembolism at time of diagnosis of ovarian cancer: Survival differs in symptomatic and asymptomatic cases.

OBJECTIVES: To determine the impact on survival of symptomatic and asymptomatic venous thromboembolism (VTE) at time of diagnosis of primary ovarian malignancy. MATERIALS AND METHODS: The clinical records of 397 consecutive cases of primary ovarian malignancy were studied. Clinical, pathological and survival data were obtained. RESULTS AND CONCLUSIONS: Of 397 cases, 19 (4.8%) were found to have VTE at diagnosis, of which 63.2% (n=12) were asymptomatic. VTE was significantly associated with reduced overall median survival (28 vs. 45 months, p=0.004). Decreased survival was associated with symptomatic VTE compared to patients with asymptomatic VTE (21 vs. 36 months, p=0.02) whose survival was similar to that of patients without VTE. Decreased survival remained significant in symptomatic patients after controlling for stage of disease at diagnosis, cytoreductive status and adjuvant chemotherapy use. Overall these data suggest for the first time that symptomatic but not asymptomatic VTE prior to primary treatment of ovarian cancer is an independent adverse prognostic factor.

Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors.

PURPOSE: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. EXPERIMENTAL DESIGN: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study. RESULTS: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. CONCLUSION: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors.

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PURPOSE: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). PATIENTS AND METHODS: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. RESULTS: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·µmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. CONCLUSION: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.

Dose-response relationship in phase i clinical trials: a European Drug Development Network (EDDN) Collaboration Study.

INTRODUCTION: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. EXPERIMENTAL DESIGN: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. RESULTS: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). CONCLUSION: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD).

Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: results of a DLT-TARGETT international survey.

INTRODUCTION: It is increasingly clear that definitions of dose-limiting toxicity (DLT) established for phase 1 trials of cytotoxic agents are not suitable for molecularly targeted agents because of specific toxicity profiles. An international survey collected expertise on the definition of DLT, as part of an initiative aimed at presenting new guidelines for phase 1 trials of targeted agents. METHODS: A 15-question survey was sent to corresponding authors of phase 1 reports. Questions involved: duration of the DLT assessment period, incorporation of specific grade 1 (G1) or G2 toxicity and their minimum duration to qualify as DLT, exclusion of specific G3 and inclusion of dose modification/delay. RESULTS: Among the 400 investigators contacted, 93 replied of whom 65 completed the questionnaires. A total of 87% opted for an extended DLT assessment period beyond cycle 1, with the proviso not to delay patient accrual. Reanalysis at the end of the study of all safety data was proposed in order to recommend the phase 2 dose. Most respondents (92%) suggested including dose modification in the definition of DLT when dose intensity was decreased to 70%. Whilst moderate toxicity was deemed relevant by 70%, the G1/2 toxicities selected to define DLT however varied. CONCLUSION: The majority of experts favoured a longer DLT assessment period as well as incorporation of specific G2 toxicities into the DLT definition. However, no clear consensus existed on a re-definition of DLT. Therefore analyses of a large international data warehouse were also used to develop guidelines presented in a companion paper.