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Speech-recognition tests are a routine component of the clinical hearing evaluation. The most common type of test uses recorded monosyllabic words presented in quiet. The interpretation of test scores relies on an understanding of the variance of repeated tests. Confidence intervals are useful for determining if two scores are significantly different or if the difference is due to the variability of test scores. Because the response to each test item is binary, either correct or incorrect, the binomial distribution has been used to estimate confidence intervals. This method requires that test scores be independent. If the scores are not independent, the binomial distribution will not accurately estimate the variance of repeated scores. A previously published dataset with repeated scores from normal-hearing and hearing-impaired listeners was used to derive confidence intervals from actual test scores in contrast to the predicted confidence intervals in earlier reports. This analysis indicates that confidence intervals predicted by the binomial distribution substantially overestimate the variance of repeated scores resulting in erroneously broad confidence intervals. High correlations were found for repeated scores, indicating that scores are not independent. The interdependence of repeated scores invalidates confidence intervals predicted by the binomial distribution. Confidence intervals and confidence levels for repeated measures were determined empirically from measured test scores to assist in interpreting differences between repeat scores.

The role of microenvironment-derived ligands in regulating EphA2 expression levels.

Supplementary Figure 1. Study flowchart

Revised supplemental figures and tables

Purpose: In an attempt to identify genes that are involved in resistance to SN38, the active metabolite of irinotecan (also known as CPT-11), we carried out DNA microarray profiling of matched HCT116 human colon cancer parental cell lines and SN38-resistant cell lines following treatment with SN38 over time.Experimental Design: Data analysis identified a list of genes that were acutely altered in the parental cells following SN38 treatment as well as constitutively altered in the SN38-resistant cells.Results: Independent validation of 20% of these genes by quantitative reverse transcription-PCR revealed a strong correlation with the microarray results: Pearson's correlation was 0.781 (r2 = 0.61, P < 0.000001) for those genes that were acutely altered in the parental setting following SN38 treatment and 0.795 (r2 = 0.63, P < 0.000002) for those genes that were constitutively altered in the SN38-resistant cells. We then assessed the ability of our in vitro-derived gene list to predict clinical response to 5-fluorouracil/irinotecan using pretreatment metastatic biopsies from responding and nonresponding colorectal cancer patients using both unsupervised and supervised approaches. When principal components analysis was used with our in vitro classifier gene list, a good separation between responding and nonresponding patients was obtained, with only one nonresponding and two responding patients separating with the incorrect groups. Supervised class prediction using support vector machines algorithm identified a 16-gene classifier with 75% overall accuracy, 81.8% sensitivity, and 66.6% specificity.Conclusions: These results suggest that in vitro-derived gene lists can be used to predict clinical response to chemotherapy in colorectal cancer.

Supplementary table 1. Main characteristics of patients receiving different dose levels

Supplementary Data from Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models

Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED).Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual.Results: Twenty-five patients received 17-DMAG (range 2.5–106 mg/m2). At 106 mg/m2 of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m2. Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m2 or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥20 mg/m2) and sustained for 96 hours (≥40 mg/m2). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively).Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m2 weekly i.v. Clin Cancer Res; 17(6); 1561–70. ©2011 AACR.

Supplementary table 1. Clinical-pathological features of the resection-only and chemotherapy/resection stage II/III colorectal cancer patient cohorts with mature survival data in the Singapore dataset. Supplementary table 2. EphA2 and clinical-pathological correlates in CRC. Correlation between EphA2 and CD44, LGR5, CD133, Ki-67 and AXL in 509 stage I-IV CRC cases of the Singapore dataset. Supplementary table 3. Statistical associations between pairs of factors in the surgery only (A) and surgery/chemotherapy (B) stage II/III groups in the Singapore dataset. Supplementary table 4. A. Univariate and multivariate analysis (Cox proportional hazards regression) of resection-chemotherapy stage II/III patient group. B. Final multivariate model (Cox proportional hazards regression) of resection-chemotherapy stage II/III patient group. Supplementary table 5. Statistical association between expression levels of TGF-α and EphA2 using Spearman's Rank Correlation in GSE17536, GSE39582, GSE14333 and The Cancer Genome Atlas (TCGA). Within each dataset the value of Rho and associated p-value is reported.

Purpose:Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response.Patients and Methods:Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level.Results:Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs.Conclusions:In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Supplementary table 3. Multivariate model for Overall Survival (Cytotoxic Agents)

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). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

Supplementary table 2. Multivariate model for overall survival (Molecularly Targeted Agents).

Background There is an increasing need to administer hearing tests outside of sound-attenuating rooms. Maximum permissible ambient noise levels (MPANLs) from published in standards (Occupational Health and Safety Administration [OSHA] 1983; American National Standards Institute [ANSI] S3.1–1999 (R2018)) can be modified to account for the additional attenuation provided by circumaural earphones (relative to supra-aural earphones) that are used for pure-tone audiometry. Ambient noise can influence the results of pure-tone audiometry by elevating thresholds by direct masking and by producing distractions that affect the accuracy of the test. The effects of these distractions have not been studied in relation to pure-tone audiometry in adult listeners. Purpose In Part I MPANLs provided by ANSI and OSHA standards are extended to account for the greater attenuation provided by circumaural earphones. Rules (“alerts”) were developed taking into account the listeners' thresholds. In Part II effects of distracting noise on pure-tone thresholds are reported. Methods and Results In Part I MPANLs two standards were modified for circumaural earphones by adding the additional attenuation provided by three circumaural earphones (relative to supra-aural earphones). A set of rules (“alerts”) is provided for identifying masking effects from ambient noise in a variety of conditions (earphone type, threshold elevation, uncovered ear). In Part II the distracting effects of an industrial noise sample on thresholds obtained from five listeners with normal hearing are described. Pure-tone thresholds were measured in quiet and in distracting noise presented at various levels. The effects of the distracting noise on the following variables were measured: time per trial, number of trials required to measure threshold, threshold shift, and perceived distractibility of the noise. Time per trial was unaffected by distracting noise. Number of trials required for threshold, threshold shift, and perceived distractibility increased with distracting noise level. Conclusion Part I: The modified MPANLs provide more relevant determinations of the potential effects of ambient noise on pure-tone thresholds than the values in the standards. Part II: Distracting noise affects pure-tone threshold measurements in a manner that is different from direct masking. The potential contaminating effect of distracting noise can be measured and reported.

PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

Clinical trials for MET inhibitors have demonstrated limited success for their use in colon cancer (CC). However, clinical efficacy may be obscured by a lack of standardisation in MET assessment for patient stratification. In this study, we aimed to determine the molecular context in which MET is deregulated in CC using a series of genomic and proteomic tests to define MET expression and identify patient subgroups that should be considered in future studies with MET‐targeted agents. To this aim, orthogonal expression analysis of MET was conducted in a population‐representative cohort of stage II/III CC patients (n = 240) diagnosed in Northern Ireland from 2004 to 2008. Targeted sequencing was used to determine the relative incidence of MET R970C and MET T992I mutations within the cohort. MET amplification was assessed using dual‐colour dual‐hapten brightfield in situ hybridisation (DDISH). Expression of transcribed MET and c‐MET protein within the cohort was assessed using digital image analysis on MET RNA in situ hybridisation (ISH) and c‐MET immunohistochemistry (IHC) stained slides. We found that less than 2% of the stage II/III CC patient population assessed demonstrated a genetic MET aberration. Determination of a high MET RNA‐ISH/low c‐MET IHC protein subgroup was found to be associated with poor 5‐year cancer‐specific outcomes compared to patients with concordant MET RNA‐ISH and c‐MET IHC protein expression (HR 2.12 [95%CI: 1.27–3.68]). The MET RNA‐ISH/c‐MET IHC protein biomarker paradigm identified in this study demonstrates that subtyping of MET expression may be required to identify MET‐addicted malignancies in CC patients who will truly benefit from MET inhibition., A population representative study looking at the molecular context in which MET is deregulated in colon cancer using a series of genomic and proteomic tests. This study demonstrates the limited number of genetic MET aberrations present in a Northern Irish colon cancer cohort and identifies a cancer‐specific poor prognosis MET RNA/c‐MET protein subgroup that may be amenable to targeted therapy.

Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide. Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours. Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease. Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporation into DNA. Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by fluoropyrimidines or anthracyclines represents an effective strategy to induce cell lethality. dUTPase inhibition significantly sensitised TNBC cell lines to fluoropyrimidines and anthracyclines through imbalanced nucleotide pools and increased DNA damage leading to decreased proliferation and increased cell death. These results suggest that repair of treatment-mediated DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a promising strategy to enhance the efficacy of TNBC chemotherapy.

A method for testing auditory processing of non-linguistic speech-like stimuli was developed and evaluated.Monosyllabic words were temporally reversed and distorted. Stimuli were matched for spectrum and level. Listeners discriminated between distorted and undistorted stimuli.Three groups were tested. The Normal group was comprised of 12 normal-hearing participants. The Senior group was comprised of 12 seniors. The Hearing Loss group was comprised of 12 participants with thresholds of at least 35 dB HL at one or more frequencies.The Senior group scored lower than the Normal group, and the Hearing Loss group scored lower than the Senior group. Scores for forward compressed speech were slightly higher than backward compressed speech but the difference was not statistically significant. Retest scores were slightly higher than scores on the first test, but the difference was not statistically significant.Large differences in discrimination of distorted speech were observed among the three groups. Age and hearing loss separately affected performance. The depressed performance of the Senior group may be a result of "hidden hearing loss" that is attributed to cochlear synaptopathy. The backward-distorted speech task may be a useful non-linguistic test of speech processing that is language independent.

BackgroundClinical cancer research trials may offer little or no direct clinical benefit to participants where a cure is no longer possible. As such, the decision-making and consent process for patient participation is often challenging.AimTo gain understanding of how patients make decisions regarding clinical trial participation, from the perspective of both the patient and healthcare professionals involved.MethodsIn-depth, face to face interviews using a grounded theory approach. This study was conducted in a regional Cancer Centre in the United Kingdom. Of the 36 interviews, 16 were conducted with patients with cancer that had non-curative intent and 18 with healthcare professionals involved in the consent process.Results‘Nothing to lose’ was identified as the core category that underpinned all other data within the study. This highlighted the desperation articulated by participants, who asserted trial participation was the ‘only hope in the room’. The decision regarding participation was taken within a ‘trusting relationship’ that was important to both patients and professionals. Both were united in their ‘fight against cancer’. These two categories are critical in understanding the decision-making/consent process and are supported by other themes presented in the theoretical model.ConclusionThis study presents an important insight into the complex and ethically contentious situation of consent in clinical trials that have non-curative intent. It confirms that patients with limited options trust their doctor and frequently hold unrealistic hopes for personal benefit. It highlights a need for further research to develop a more robust and context appropriate consent process.

Purpose This project was undertaken to develop automated tests of speech recognition, including speech-recognition threshold (SRT) and word-recognition test, using forced-choice responses and computerized scoring of responses. Specific aims were (1) to develop an automated method for measuring SRT for spondaic words that produces scores that are in close agreement with average pure-tone thresholds and (2) to develop an automated test of word recognition that distinguishes listeners with normal hearing from those with sensorineural hearing loss and which informs the hearing aid evaluation process. Method An automated SRT protocol was designed to converge on the lowest level at which the listener responds correctly to two out of two spondees presented monaurally. A word-recognition test was conducted with monosyllabic words (female speaker) presented monaurally at a fixed level. For each word, there were three rhyming foils, displayed on a touchscreen with the test word. The listeners touched the word they thought they heard. Participants were young listeners with normal hearing and listeners with sensorineural hearing loss. Words were also presented with nonrhyming foils and in an open-set paradigm. The open-set responses were scored by a graduate student research assistant. Results The SRT results agreed closely with the pure-tone average (PTA) obtained by automated audiometry. The agreement was similar to results obtained with the conventional SRT scoring method. Word-recognition scores were highest for the closed-set, nonrhyming lists and lowest for open-set responses. For the hearing loss participants, the scores varied widely. There was a moderate correlation between word-recognition scores and pure-tone thresholds which increased as more high frequencies were brought into the PTA. Based on the findings of this study, a clinical protocol was designed that determines if a listener's performance was in the normal range and if the listener benefited from increasing the level of the stimuli. Conclusion SRTs obtained using the automated procedure are comparable to the results obtained by the conventional clinical method that is in common use. The automated closed-set word-recognition test results show clear differentiation between scores for the normal and hearing loss groups. These procedures provide clinical test results that are not dependent on the availability of an audiologist to perform the tests.

Background The amplitude and temporal asymmetry of the speech waveform are mostly associated with voiced speech utterances and are obvious in recent graphic depictions in the literature. The asymmetries are attributed to the presence and interactions of the major formants characteristic of voicing with possible contributions from the unidirectional air flow that accompanies speaking. Purpose This study investigated the amplitude symmetry/asymmetry characteristics (polarity) of speech waveforms that to our knowledge have not been quantified. Study Sample Thirty-six spondaic words spoken by two male speakers and two female speakers were selected because they were multisyllabic words providing a reasonable sampling of speech sounds and four recordings were available that were not related to the topic under study. Research Design Collectively, the words were segmented into phonemes (vowels [130], diphthongs [77], voiced consonants [258], voiceless consonants [219]), syllables (82), and blends (6). For each segment the following were analyzed separately for the positive and negative datum points: peak amplitude, the percent of the total segment datum points, the root-mean-square (rms) amplitude, and the crest factor. Data Collection and Analyses The digitized words (44,100 samples/s; 16-bit) were parsed into 144 files (36 words × 4 speakers), edited, transcribed to numeric values (±1), and stored in a spread sheet in which all analyses were performed with in-house routines. Overall approximately 85% of each waveform was analyzed, which excluded portions of silent intervals, transitions, and diminished waveform endings. Results The vowel, diphthong, and syllable segments had durations (180–220 ms) that were about twice as long as the consonant durations (∼90 ms) and peak and rms amplitudes that were 6 to 12 dB higher than the consonant peak and rms amplitudes. Vowel, diphthong, and syllable segments had 10% more positive datum points (55%) than negative points (45%), which suggested temporal asymmetries within the segments. With voiced consonants, the distribution of positive and negative datum points dropped to 52 and 48% and essentially was equal with the voiceless consonants (50.3 and 49.6%). The mean rms amplitudes of the negative datum points were higher than the rms amplitudes for the positive points by 2 dB (vowels, diphthongs, and syllables), 1 dB (voiced consonants), and 0.1 dB (voiceless consonants). The 144 waveforms and segmentations are illustrated in the Supplementary Material along with the tabularized positive and negative segment characteristics. Conclusions The temporal and amplitude waveform asymmetries were by far most notable in segments that had a voicing component, which included the voiced consonants. These asymmetries were characterized by larger envelopes and more energy in the negative side of the waveform segment than in the positive side. Interestingly, these segments had more positive datum points than negative points, which indicated temporal asymmetry. All aspects of the voiceless consonants were equally divided between the positive and negative domains. There were female/male differences but with these limited samples such differences should not be generalized beyond the speakers in this study. The influence of the temporal and amplitude asymmetries on monaural word-recognition performance is thought to be negligible.

Outcomes inPatients with newly diagnosed mCRC were registered into FOCUS4 and tested forFOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) wereIn this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for

We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease.Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

The Auditec of St. Louis and the Department of Veterans Affairs (VA) recorded versions of the Northwestern University Auditory Test No. 6 (NU-6) are in common usage. Data on young adults with normal hearing for pure tones (YNH) demonstrate equal recognition performances on the two versions when the VA version is presented 5 dB higher but similar data on older listeners with sensorineural hearing loss (OHL) are lacking.To compare word-recognition performances on the Auditec and VA versions of NU-6 presented at six presentation levels with YNH and OHL listeners.A quasi-experimental, repeated-measures design was used.Twelve YNH (M = 24.0 years; PTA = 9.9-dB HL) and 36 OHL listeners (M = 71.6 years; PTA = 26.7-dB HL) participated in three, one-hour sessions.Each listener received 100 stimulus words that were randomized by 6 presentation levels for each of two speakers (YNH, −2 to 28-dB SL; OHL, −2 to 38-dB SL). The sessions were limited to 25 practice and 400 experimental words. Digital versions of the 16, 25-word tracks for each session were alternated between speakers.Each of the 48 listeners had higher recognition performances on the Auditec version of NU-6 than on the VA version. The respective overall recognition performances on the Auditec and VA versions were 71.4% and 64.1% (YNH) and 68.7% and 58.2% (OHL). At the highest presentation levels, recognition performances on the two versions differed by only 0.5% (YNH) and 3.3% (OHL). At the 50% correct point, performances on the Auditec version were 3.2 dB (YNH) and 6.1 dB (OHL) better than those on the VA version. The slopes at the 50% points on the mean functions for both speakers were about 4.9%/dB (YNH) and 3.0%/dB (OHL); however, the slopes evaluated from the individual listener data were steeper, 5.2 to 5.3%/dB (YNH) and 3.3 to 3.5%/dB (OHL). When the individual data were transformed from dB SL to dB HL, the differences between the two listener groups were emphasized. The four functions (2 speakers by 2 listener groups) were plotted for each of the 48 participants and each of the 200 words, which revealed the gamut of relations among the datasets. Examination of the data for each speaker across test sessions, in the traditional 50-word lists, and in the typically used 25-word lists of Randomization A revealed no differences of clinical concern. Finally, introspective reports from the listeners revealed that 91.7% and 83.3% of the YNH and OHL listeners, respectively, thought the Auditec speaker was easier to understand than the VA speaker. Recognition performances on each participant and on each word are presented.

3540 Background: The relevance of individual RAS (KRAS and NRAS) and TP53 mutations in CRC is well described, but the impact of the combination of both mutations together is less understood. RAS/TP53-mutant (mut) patients (pts) were selected in FOCUS 4-C for treatment with Adavosertib (Wee1 inhibitor) due to hypothesised sensitivity due to replication stress and loss of cell cycle checkpoint control. Initial analyses in CRC suggest that RAS/TP53-mut pts may be prognostically distinct from either mutation alone. Here we examine the impact of RAS/TP53-mut status in both early stage and metastatic CRC (mCRC). Methods: RAS and TP53 mutational status were assessed by whole gene targeted NGS or PCR in hotspot regions. Pts with RAS/TP53 status in the following studies were included after exclusion of BRAF-V600E mutants and MSI-H cases: for early-stage, QUASAR2 trial (N = 408) and an Australian community cohort (N = 654); for mCRC, FOCUS (N = 373) and FOCUS4 (N = 721). Biomarker prevalence, clinical characteristics and outcome data in the RAS/TP53-mut group were compared to pts not showing dual RAS/TP53-mut. Results: The prevalence of RAS/TP53-mut was greater in mCRC compared to early CRC (43.9% vs 25.4% respectively, p < 0.001). In early-stage (II & III) cohorts combined, RAS/TP53-mut pts were more likely to be female, have a right-sided primary tumour, and involved lymph nodes. In early CRC RAS/TP53-mut pts had worse outcome: DFS HR = 1.49[1.19-1.88], p = 0.001, and OS HR = 1.48[1.16-1.89], p = 0.001. In FOCUS, RAS/TP53-mut mCRC pts had inferior PFS with 1st line chemotherapy than not dual RAS/TP53-mut: 6.9 vs 8.6 months (HR = 1.44[1.17-1.79], p = 0.001), and also shorter post-progression survival (HR = 1.49, p = 0.001), and overall survival (14.9 vs 18.9 mths [HR = 1.60, p < 0.0005]). Consistently, during 16 weeks of induction chemotherapy for mCRC pts in FOCUS4, 27.4% of RAS/TP53-mut pts had progressive disease, compared with 18.4% in not dual RAS/TP53-mut; PFS from study registration was reduced in RAS/TP53-mut (5.3 vs 6.1 mths;HR = 1.53[1.22-1.94],p < 0.001), but no statistically significant difference in OS (13.6 vs 17.6 mths;HR = 1.27,p = 0.23). Outcomes by each of the four biomarker groups (RAS/TP53 dual mut; RASwt/TP53mut; RASmut/TP53 wt; RAS/TP53 dual wt) will be presented but in all cases the dual mut subgroup had the worst outcomes compared to the other three groups, marginally better than BRAF-V600E CRC. Conclusions: RAS/TP53 dual mutation status provides useful and readily available prognostic information in both early and mCRC, independent of MSI and BRAF status. It is associated with increased risk of recurrence in early CRC, and a higher risk of chemotherapy resistance and inferior outcomes in mCRC. Evaluation of treatment strategies in this sizeable patient group and further understanding of the underlying mechanism of poor outcomes are urgently required.

TPS3645 Background: The prognostic advantage of early stage deficient-MMR/MSI-High CRC is lost after relapse, so there is a pressing clinical need to maximize the chance of cure in the early stages where prevalence of dMMR is higher comprising approximately 12% of Stage 3 and 20% of Stage 2 CRC. The efficacy of adjuvant checkpoint inhibition in this patient group has yet to be demonstrated in the context of micrometastatic disease without a supporting immune-competent microenvironment. Longitudinal studies especially in the neoadjuvant setting would optimally interrogate post-immunotherapy changes both in time and space. The NEOPRISM-CRC (NEOadjuvant PembRolizumab In Stratified Medicine – ColoReCtal) study is a Phase II Trial to determine whether neoadjuvant Pembrolizumab stratified to tumour mutation burden (TMB) is efficacious and safe. It will also be a platform to explore the relationships between possible predictive novel biomarkers and response to Pembrolizumab in blood, tumour tissue and microbiome. Methods: The study population consists of subjects with newly diagnosed operable dMMR/MSI-H CRC. Patients must be fit and eligible for planned curative surgery based on a) radiological node positive T1-4 CRC or b) high risk T3 defined as EITHER ≥ 5mm of extramural depth of invasion or unequivocal EMVI on imaging (regardless of depth), or T4 disease. They will receive one of two pre-operative regimens depending upon their TMB based on the FoundationOne®CDx test (FM1CDx). All patients will have one 21 day cycle of Pembrolizumab 200 mg IV. Prior to cycle 2 and with the result of the FM1CDx test, patients will continue their treatment as follows: A) TMB-high (defined as ≥20 mutations per Mb) or TMB-medium (defined as 6-19 mutations per Mb), or MSI-H on PCR if FM1CDx test is not evaluable: A further 2 cycles of Pembrolizumab 200 mg IV every 21 days. B) TMB-low (defined as ≤5 mutations per Mb), or if FM1CDx and PCR tests are not evaluable: No further Pembrolizumab given. Surgery to remove the CRC will be performed 4-6 weeks after the last dose of Pembrolizumab in both arms. Following resection patients may receive adjuvant chemotherapy in accordance with local institutional guidelines. The primary end point is pathological complete response rate (pCR). Secondary endpoints include 3 year RFS, OS, safety and health-related quality of life. Up to 32 patients will be registered over a 18-24 month period assuming that the pCR with 3 cycles of Pembrolizumab will be ≥ 33% for patients with high or medium TMB based on the FM1CDx profile, and intend to rule out a percentage ≤10%. To reach 80% power with 5% statistical significance, 19 patients are required in the high/medium TMB arm. The trial will be considered a success if at least 5/19 patients have a pCR after 3 cycles of Pembrolizumab. Enrolment will commence in March 2022. Clinical trial information: NCT05197322.

3103 Background: CDC7, a protein with key roles in regulating cell-cycle progression is often over-expressed in malignant cells, particularly those with TP53 mutations. LY3143921, an orally administered ATP-competitive CDC7 inhibitor, demonstrated favorable pre-clinical anti-cancer activity in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC), particularly in TP53 mutant models. Methods: Phase Ia (dose escalation) recruited patients (pts) with advanced solid tumors enriched for malignancies associated with TP53 mutation. Pts received LY3143921 OD or BD continuously on a 21-day schedule, using an accelerated 3+3 escalation design, starting at 30 mg OD. Phase Ib recruited pts with CRC or sqNSCLC treated continuously at RP2D, or pts with other advanced tumors treated at RP2D on days 1-3 every 7 days. Radiological assessment was performed every 2 cycles initially. Pts in phase Ib could consent to pre- and on-treatment skin +/- tumor biopsies. Primary objectives: assess safety/tolerability and determine MTD and RP2D of LY3143921. Secondary objectives: evaluate preliminary efficacy and pharmacokinetic (PK) profile of LY3143921. Exploratory objective: correlate efficacy to baseline molecular/genetic alterations, including TP53 mutation and measure markers including pMCM2 in pre- and on- treatment tumor and skin samples. Results: 68 pts were recruited and 67 treated (38 phase Ia, 29 phase Ib). Most frequent drug-related CTCAEs (all grades): nausea (75%), orthostatic hypotension (50%), vomiting (47%), fatigue (45%) & diarrhea (44%). Grade 3-4 LY3143921 related AEs occurred in 17 pts. In phase Ia 8 DLTs occurred in 5 pts (G3 nausea, vomiting, fatigue & hyponatraemia and G2 diarrhea, anorexia & lethargy). RP2D was 360 mg BD (continuous non-fasted dosing schedule). 37 pts were evaluable for radiological response with no complete or partial responses seen, and stable disease (SD) was observed in 24 pts (65%). In phase Ia 3 pts achieved long term SD of 1, 2.5 and 3+ years duration. For evaluable pts treated in phase Ib, SD was seen in 8/12 CRC pts, 1/2 sqNSCLC pts and 2/2 pts treated with the intermittent schedule (median duration 15 weeks, range 6-18+). 2 pts remain on-study. Recruitment ceased due to lack of radiological response according to RECIST. Dose-dependent increases in LY3143921 exposure (Cmax & AUC0-24) were seen. IHC analyses of skin biopsies demonstrated reductions in pMCM2, indicating on-target activity of LY3143921. Pre-clinical testing of combination with standard of care agents is ongoing. Additional PD and PK data will be presented. Conclusions: LY3143921 is well tolerated, exhibits dose-dependent increases in plasma exposure and demonstrates evidence of target inhibition. Significant monotherapy clinical activity was not observed; further analyses should investigate potential predictive response biomarkers and rational combination approaches. Clinical trial information: NCT03096054.

Purpose: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Patients and Methods: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Results: Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. Conclusions: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Background English materials for speech audiometry are well established. In Spanish, speech-recognition materials are not standardized with monosyllables, bisyllables, and trisyllables used in word-recognition protocols.Purpose This study aimed to establish the psychometric characteristics of common Spanish monosyllabic, bisyllabic, and trisyllabic words for potential use in word-recognition procedures.Research Design Prospective descriptive study.Study Sample Eighteen adult Puerto Ricans (M = 25.6 years) with normal hearing [M = 7.8-dB hearing level (HL) pure-tone average] were recruited for two experiments.Data Collection and Analyses A digital recording of 575 Spanish words was created (139 monosyllables, 359 bisyllables, and 77 trisyllables), incorporating materials from a variety of Spanish word-recognition lists. Experiment 1 (n = 6) used 25 randomly selected words from each of the three syllabic categories to estimate the presentation level ranges needed to obtain recognition performances over the 10 to 90% range. In Experiment 2 (n = 12) the 575 words were presented over five 1-hour sessions using presentation levels from 0- to 30-dB HL in 5-dB steps (monosyllables), 0- to 25-dB HL in 5-dB steps (bisyllables), and −3- to 17-dB HL in 4-dB steps (trisyllables). The presentation order of both the words and the presentation levels were randomized for each listener. The functions for each listener and each word were fit with polynomial equations from which the 50% points and slopes at the 50% point were calculated.Results The mean 50% points and slopes at 50% were 8.9-dB HL, 4.0%/dB (monosyllables), 6.9-dB HL, 5.1%/dB (bisyllables), and 1.4-dB HL, 6.3%/dB (trisyllables). The Kruskal–Wallis test with Mann–Whitney U post-hoc analysis indicated that the mean 50% points and slopes at the 50% points of the individual word functions were significantly different among the syllabic categories. Although significant differences were observed among the syllabic categories, substantial overlap was noted in the individual word functions, indicating that the psychometric characteristics of the words were not dictated exclusively by the syllabic number. Influences associated with word difficulty, word familiarity, singular and plural form words, phonetic stress patterns, and gender word patterns also were evaluated.Conclusion The main finding was the direct relation between the number of syllables in a word and word-recognition performance. In general, words with more syllables were more easily recognized; there were, however, exceptions. The current data from young adults with normal hearing established the psychometric characteristics of the 575 Spanish words on which the formulation of word lists for both threshold and suprathreshold measures of word-recognition abilities in quiet and in noise and other word-recognition protocols can be based.

Background In the 1950s, with monitored live voice testing, the vu meter time constant and the short durations and amplitude modulation characteristics of monosyllabic words necessitated the use of the carrier phrase amplitude to monitor (indirectly) the presentation level of the words. This practice continues with recorded materials. To relieve the carrier phrase of this function, first the influence that the carrier phrase has on word recognition performance needs clarification, which is the topic of this study. Purpose Recordings of Northwestern University Auditory Test No. 6 by two female speakers were used to compare word recognition performances with and without the carrier phrases when the carrier phrase and test word were (1) in the same utterance stream with the words excised digitally from the carrier (VA-1 speaker) and (2) independent of one another (VA-2 speaker). The 50-msec segment of the vowel in the target word with the largest root mean square amplitude was used to equate the target word amplitudes. Research Design A quasi-experimental, repeated measures design was used. Study Sample Twenty-four young normal-hearing adults (YNH; M = 23.5 years; pure-tone average [PTA] = 1.3-dB HL) and 48 older hearing loss listeners (OHL; M = 71.4 years; PTA = 21.8-dB HL) participated in two, one-hour sessions. Data Collection and Analyses Each listener had 16 listening conditions (2 speakers × 2 carrier phrase conditions × 4 presentation levels) with 100 randomized words, 50 different words by each speaker. Each word was presented 8 times (2 carrier phrase conditions × 4 presentation levels [YNH, 0- to 24-dB SL; OHL, 6- to 30-dB SL]). The 200 recorded words for each condition were randomized as 8, 25-word tracks. In both test sessions, one practice track was followed by 16 tracks alternated between speakers and randomized by blocks of the four conditions. Central tendency and repeated measures analyses of variance statistics were used. Results With the VA-1 speaker, the overall mean recognition performances were 6.0% (YNH) and 8.3% (OHL) significantly better with the carrier phrase than without the carrier phrase. These differences were in part attributed to the distortion of some words caused by the excision of the words from the carrier phrases. With the VA-2 speaker, recognition performances on the with and without carrier phrase conditions by both listener groups were not significantly different, except for one condition (YNH listeners at 8-dB SL). The slopes of the mean functions were steeper for the YNH listeners (3.9%/dB to 4.8%/dB) than for the OHL listeners (2.4%/dB to 3.4%/dB) and were Conclusion The current data indicate that word recognition performances with and without the carrier phrase (1) were different when the carrier phrase and target word were produced in the same utterance with poorer performances when the target words were excised from their respective carrier phrases (VA-1 speaker), and (2) were the same when the carrier phrase and target word were produced as independent utterances (VA-2 speaker).

Background: Small bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic SBA beyond first-line FOLFOX/CAPOX. Later-line therapy has been extrapolated from colorectal cancer (CRC) studies, though SBA is biologically distinct with higher rates microsatellite instability (MSI-H) and intratumoral T-lymphocyte infiltration. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Methods: Previously treated advanced SBA patients received pembrolizumab 200 mg IV q3 weeks until disease progression (PD), toxicity, or to 35 dose maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary survival and safety endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Findings: 40 patients were treated for median duration of 4 cycles (range 1-35). MSI status was available for 36 patients (90%). All 40 patients are off study treatment due to: PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AE, 5%). Three confirmed partial responses (PR) (8%; 95% CI: 2-20) did not meet pre-defined success criteria. Median overall survival (OS) 7 . 1 mo (95% CI: 5 . 1-17 . 1) and median progression free survival (PFS) 2 . 8 mo (95% CI: 2 . 7-4 . 2) were similar across primary tumor sites. One confirmed PR was seen in 32 MSS/MSI-low patients (3%). MSS response correlated with high tumor mutation burden (TMB). Two of four MSI-H patients had a confirmed PR (50%) and remain alive without progression. 25 patients (63%) had grade ≥ 3 AEs, 11 pts (28%) had grade 4/5 AEs. Interpretation: In the largest study of SBA to date, and the first using immunotherapy, pembrolizumab did not achieve the hypothesized response rate; however, we did identify responses in certain biomarker-selected cohorts. Trial Registration: RU021502I (ACCRU), MISP #52192 (Merck), NCT02949219 (clinicaltrials.gov). Funding Statement: Primary study funding and investigational product was provided by the Merck Investigator Studies Program (MISP), and additional site-specific funding provided by the Kavanagh Family Foundation (MDACC) and Kevin T. Doner Memorial Fund (MDACC). Declaration of Interests: None to declare Ethics Approval Statement: Ethics board review and human research protections monitoring were performed at each institution. The trial was conducted according to ICH GCP.

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]

The aim of this study was to document cancer trial participation since establishment of the Northern Ireland Cancer Trials Network and investigate population and disease factors associated with trial participation. An independent cohort of over 51 000 cancer patients from the Northern Ireland Cancer Registry covering the same population (2007-2012) was linked to a database of 1316 interventional cancer trial participants in a UK region. The primary outcome measure was participation in an intervention clinical trial. Patients were followed up until 31 March 2013. Kaplan-Meier tests and Cox proportional hazard models using person days at risk to allow for death were used to investigate factors associated with trial participation. Multivariate analysis assessed the impact of age, cancer type and stage, distance from the cancer centre (radiotherapy), marital status, deprivation quintile and rurality. Participation was analysed separately for children (

BACKGROUNDSignet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.METHODSUsing test (n=26) and validation (n=18) cohorts, analysis of mutations, DNA methylation and transcriptome was carried out. Microsatellite instability (MSI) status was established and immunohistochemistry (IHC) was used to test for adaptive immunity (CD3) and the immune checkpoint PDL1.RESULTS DNA methylation data split the cohorts into hypermethylated (n=18, 41%) and hypomethylated groups (n=26, 59%). The hypermethylated group predominant in the proximal colon was enriched for CpG island methylator phenotype (CIMP), BRAF V600E mutation and MSI (PC) across both groups. No statistically significant difference in outcome was observed between the two groups.CONCLUSIONS Our data show that SRCCa phenotype comprises two distinct genotypes. The MSI(+)/CIMP(+)/BRAF V600E(+)/CD3(+)/PDL1(+) hypermethylated genotype is an ideal candidate for immune checkpoint inhibitor therapy. In addition, one fourth of SRCCa cases can potentially be targeted by KIT inhibitors.

Purpose: Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools. Experimental Design: Apoptosis competency of primary tumor samples from patients with stage III colorectal cancer (n = 120) was calculated by APOPTO-CELL from measured protein concentrations of Procaspase-3, Procaspase-9, SMAC, and XIAP. An enriched APOPTO-CELL signature (APOPTO-CELL-PC3) was synthesized to capture apoptosome-independent effects of Caspase-3. Furthermore, a machine learning Random Forest approach was applied to APOPTO-CELL-PC3 and available molecular and clinicopathologic data to identify a further enhanced signature. Association of the signature with prognosis was evaluated in an independent colon adenocarcinoma cohort (TCGA COAD, n = 136). Results: We identified 3 prognostic biomarkers (P = 0.04, P = 0.006, and P = 0.0004 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively) with increasing stratification accuracy for patients with stage III colorectal cancer. The APOPTO-CELL-PC3 signature ranked highest among all features. The prognostic value of the signatures was independently validated in stage III TCGA COAD patients (P = 0.01, P = 0.04, and P = 0.02 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively). The signatures provided further stratification for patients with CMS1-3 molecular subtype. Conclusions: The integration of a systems-biology–based biomarker for apoptosis competency with machine learning approaches is an appealing and innovative strategy toward refined patient stratification. The prognostic value of apoptosis competency is independent of other available clinicopathologic and molecular factors, with tangible potential of being introduced in the clinical management of patients with stage III colorectal cancer. Clin Cancer Res; 23(5); 1200–12. ©2016 AACR.

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.

Purpose:\ud \ud We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.\ud \ud Experimental design:\ud \ud Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.\ud \ud Results:\ud \ud Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.\ud \ud Conclusions:\ud WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.