Growth in eligibility criteria content and failure to accrue among National Cancer Institute (NCI)-affiliated clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1515-1515
Author(s):  
John Stuart Peterson ◽  
Deborah Plana ◽  
Danielle Sara Bitterman ◽  
Skyler B Johnson ◽  
Benjamin Harris Kann
Keyword(s):  
Multivariable Analysis ◽  
Phase Iii ◽  
Word Count ◽  
Eligibility Criteria ◽  
Support Unit ◽  
National Priority ◽  
Clinical Trial Accrual ◽  
Unique Word ◽  
Cancer Trials ◽  
The Impact

1515 Background: Cancer clinical trial accrual across diverse socioeconomic and demographic groups is a national priority, yet up to 20% of trials fail due to poor accrual. Eligibility criteria content may contribute to poor accrual, but effects are challenging to measure. We sought to evaluate growth of eligibility criteria within NCI-affiliated cancer trials and the impact on trial accrual over the past decade. Methods: We conducted a retrospective study with the Aggregate Analysis of ClinicalTrials.gov (AACT) (abstracted: 02/02/2021). We included NCI-affiliated, interventional Phase II or III trials that initiated between 01/01/2008 and 12/13/2018. We excluded active and recruiting trials that lacked accrual data on the Cancer Trials Support Unit website. Trials whose status was “Withdrawn”, “Terminated”, or “Suspended” due to low accrual, or had less than 50% target accrual after two years active were deemed accrual failures. Eligibility criteria were extracted from inclusion and exclusion criteria and complexity was estimated by the number of unique content words, calculated by removing duplicates and stop words from the word count. Association of unique word count with accrual failure was evaluated by univariable and multivariable logistic regressions, adjusting for other predictors of low accrual identified in earlier research. Results: Of 1197 trials included, 231 (19.3%) failed due to low accrual. Eligibility criteria increased in length from a median of 214 (IQR [23, 282]) unique content words in 2008 to 417 (IQR [289, 514]) in 2018. The rate of trial accrual failure increased with unique word count decile from 11.8% in the first decile (12 to 112 words) to 29.4% in the tenth decile (445 to 750 words) (P = 0.004). On multivariable analysis, unique word count remained independently associated with low accrual (OR: 1.07 per decile, 95%CI [1.01-1.13], P = 0.02), as did Phase III and metastatic disease settings (Table). Conclusions: Eligibility criteria content has increased dramatically in the last decade in NCI-affiliated trials. Increasing eligibility criteria content associates strongly with accrual failure, even after adjusting for multiple known predictors of accrual. These findings underscore the need for efforts to simplify eligibility criteria to improve trial accrual. Further investigation is ongoing to determine specific criteria qualities that portend accrual failure.[Table: see text]

Validation of the decipher genomic classifier (GC) in SAKK 09/10: A phase III randomized trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy (RP).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5010-5010
Author(s):  
Alan Dal Pra ◽  
Pirus Ghadjar ◽  
Stefanie Hayoz ◽  
Daniel Eidelberg Spratt ◽  
Vinnie YT Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Controlled Trial ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Phase Iii ◽  
Clinical Progression ◽  
Clinical Value ◽  
Prognostic Utility ◽  
The Impact

5010 Background: GC has been shown to independently prognosticate outcomes in prostate cancer. Herein, we validate the GC in a European randomized phase III trial of dose escalated SRT after RP. Methods: SAKK 09/10 (NCT01272050) randomized 350 patients with biochemical recurrence after RP to 64Gy vs 70Gy. No patients received androgen deprivation therapy (ADT) or pelvic nodal radiotherapy. A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. RP samples were centrally reviewed for the highest-grade tumor and those passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to obtain the GC score (0 to 1; < 0.45, 0.45-0.6, > 0.6 for low-, intermediate-, and high, respectively). The primary aim of this study was to validate the GC for the prediction of freedom from biochemical progression (FFBP) using Cox multivariable analysis (MVA) adjusting for age, T-category, Gleason score, persistent PSA after RP, PSA at randomization, and randomization arm. The secondary aims were to evaluate the association of GC with clinical progression-free survival (CPFS) and use of salvage ADT. Results: Of 233 patients with tissue available, 226 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 6.3 years (IQR 6.0-7.2). GC score (continuous per 0.1 unit, score 0-1) was independently associated with FFBP (HR 1.14 [95% CI 1.03-1.25], p = 0.009). Higher GC scores were independently associated with CPFS, use of salvage ADT, and rapid biochemical failure ( < 18 months after SRT). High- vs. low/intermediate-GC showed a HR of 2.22 ([95% CI 1.37-3.58], p = 0.001) for FFBP, 2.29 ([95% CI 1.32-3.98], p = 0.003) for CPFS, and 2.99 ([95% CI 1.50-5.95], p = 0.002) for use of salvage ADT. Patients with high-GC had 5-year FFBP of 45% [95% CI 32-59] vs 71% [95% CI 64-78] in low-intermediate GC. Similar estimates for GC risk groups were observed in the 64Gy vs 70Gy in GC high (5-year FFBP of 51% [95% CI 32-70] vs 39% [95% CI 20-59]) and in low-intermediate GC (75% [95% CI 65-84] vs 69% [95% CI 59-78]). Conclusions: This study represents the first contemporary randomized controlled trial in patients with recurrent prostate cancer treated with early SRT without ADT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and radiotherapy dose, patients with a high-GC were more than twice as likely than a lower GC score to experience biochemical and clinical progression and receive salvage ADT. This data confirms the clinical value of Decipher GC for tailoring treatment in the postoperative salvage setting.

Impact of single agent daily prednisone on survival and toxicities in post-docetaxel men with metastatic castration-resistant prostate cancer (mCRPC): An analysis of 2 phase III trials.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 213-213
Author(s):  
Guru Sonpavde ◽  
Gregory Russell Pond ◽  
Arnoud J. Templeton ◽  
Eugene D. Kwon ◽  
Johann S. De Bono
Keyword(s):  
Statistical Significance ◽  
Oral Prednisone ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Grade 3 ◽  
Combination Regimens ◽  
The Impact

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.

The influence of renal function on gemcitabine-based chemotherapy for advanced biliary tract cancer: An exploratory subgroup analysis of JCOG1113.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 368-368
Author(s):  
Makoto Ueno ◽  
Chigusa Morizane ◽  
Takuji Okusaka ◽  
Gakuto Ogawa ◽  
Yuya Sato ◽  
...  
Keyword(s):  
Renal Function ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Tract Cancer ◽  
Grade 3 ◽  
The Impact

368 Background: JCOG1113 is a randomized phase III trial to evaluate gemcitabine (GEM) plus S-1 (GS) versus GEM plus cisplatin (GC) regarding overall survival (OS) for advanced biliary tract cancer (BTC) (UMIN000001685) and the non-inferiority of GS was demonstrated. It is necessary to consider renal function using cisplatin or S-1 because cisplatin has renal toxicity, and the toxicity of S-1 is affected by renal function. Therefore, we evaluated the influence of renal function on the efficacy and safety of GC and GS in JCOG1113. Methods: All enrolled patients (pts) in JCOG1113 (n = 354) were analyzed. Eligibility criteria included chemotherapy-naïve pts with recurrent or unresectable biliary tract adenocarcinoma, ECOG-PS of 0–1, CCr > 50 ml/min, and adequate organ function. Renal function was classified into two groups by creatinine clearance (CCr) as calculated by the Cockcroft-Gault formula; high CCr (CCr ≥ 80 ml/min) or low CCr (80 > CCr ≥ 50 ml/min). The impact of renal function on OS and progression-free survival (PFS) were compared using the Cox regression model. The adverse events (AEs) were compared using Fisher’s exact test. Results: Eighty-eight pts on GC and 88 pts on GS were included in the high CCr group, and 87 pts on GC and 91 pts on GS were included in the low CCr group. There were no differences between the groups regarding, sex, PS, primary site, biliary drainage, operation, or recurrence, except for age. The hazard ratio (HR) of GS to GC for OS was 1.12 (95% CI 0.81–1.56) in the high CCr group and 0.80 (95% CI 0.58–1.11) in the low CCr group. The HR of GS to GC for PFS was 1.06 (95% CI 0.78–1.44) in the high CCr group and 0.69 (95% CI 0.50–0.94) in the low CCr group. Grade 3-4 AEs of white blood cell count decreased (35.3%/23.6%), anemia (29.4%/7.9%) and platelet count decreased (18.8%/10.1%) were more common in GC than GS in the low CCr group. In contrast, the incidence of all grade 3-4 non-hematological AEs was higher (36.0%/11.8%) in GS than GC in the low CCr group ( p = 0.0002). Conclusions: GS was better in terms of OS, PFS, and hematological toxicities than GC in the low CCr group. GS might be recommended for the population with lower renal function in the treatment for advanced BTC.

Genetic variants in R-Spondin/RNF43 complex and gene expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 190-190
Author(s):  
Francesca Battaglin ◽  
Yi Xiao ◽  
Joshua Millstein ◽  
Andreas Seeber ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Multivariable Analysis ◽  
Colorectal Carcinogenesis ◽  
Phase Iii ◽  
First Line ◽  
Tissue Samples ◽  
Expression Levels ◽  
The Impact ◽  
Gene Expression Levels

190 Background: Wnt signaling deregulation is a primary driver of colorectal carcinogenesis. RNF43 is a key suppressor of Wnt activation while R-Spodin inhibits RNF43 activity. RNF43 mutations are associated with the serrated neoplasia pathway, BRAF mutation and MSI. We hypothesized that genetic variants in the R-Spodin/RNF43 complex and corresponding genes expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 17 functional SNPs within RNF43/ ZNRF3, LGR4/5 and RSPO1/2/3 was analyzed in 129 pts treated with first-line FOLFIRI/cet and 107 pts treated with FOLFIRI/bevacizumab (bev). Gene expression levels were measured from tumor tissue samples from 102 pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. False discovery rate (FDR) for gene expression analysis was computed using the Benjamini-Hochberg approach (significant Q < 0.1). Results: In the cet cohort, pts with the C/C genotype of ZNRF3 rs132531 had significantly shorter overall survival compared to any T allele carriers (mOS: 20.3 vs 52 mo) in both univariable (HR 3.61, 95% CI 1.65-7.88, P < .001) and multivariable analysis (adjusted P = .01). Conversely, RSPO1 rs4652964 any G allele carriers showed increased tumor response (TR) rates compared to the A/A genotype (83 vs 66 %, P = .04). These associations were not observed in bev arm. Lower gene expression levels of RNF43 were associated with shorter PFS in pts with right-sided tumors receiving FOLFIRI/cet ( P = .006, Q < 0.1). RSPO1 expression levels were also associated with TR in the same subgroup (70 vs 10% in high vs low; P = .001, Q < .05). RNF43 expression was associated with TR in pts with left-sided tumors (82% in high vs 58% in low, P = .014, Q = 0.1). Conclusions: Our results provide the first evidence that germline polymorphisms and tumor gene expression levels of RNF43/ ZNRF3 and RSPO1 may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and contribute to modulate anti-EGFRs activity.

Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group Study.

1998 ◽  
Vol 16 (8) ◽  
pp. 2620-2624 ◽  
Author(s):  
M Markman ◽  
M F Brady ◽  
N M Spirtos ◽  
P Hanjani ◽  
S C Rubin
Keyword(s):  
Residual Disease ◽  
Treatment Plan ◽  
Gynecologic Oncology ◽  
Complete Response ◽  
Phase Iii ◽  
Maximum Diameter ◽  
Gynecologic Oncology Group ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
The Impact

PURPOSE To determine the response rate of intraperitoneal (i.p.) paclitaxel in patients with small-volume residual carcinomas of the ovary, fallopian tube, or peritoneum. PATIENTS AND METHODS Eligibility criteria included patients with one of the cancers noted above, with the largest residual disease 0.5 cm or less in maximum diameter at the end of second-look surgery, and prior treatment with systemic paclitaxel was permitted. The treatment plan was paclitaxel 60 mg/m2 i.p. weekly for 16 weeks, followed by surgical evaluation in patients without evidence of disease progression. RESULTS Of 80 patients entered onto the study, 76 were eligible, of whom 86% were considered to be potentially cisplatin-sensitive. Although five patients (7%) did not complete the first course of therapy because of catheter leakage or blockade, 53 patients (70%) received all 16 planned courses. Only 14 patients (18%) received fewer than 11 courses. Treatment was well tolerated, which included only moderate abdominal pain (grade 2, 12 patients; grade 3, one patient) and minimal neutropenia (grade 2, three patients; grade 3, one patient). Of 28 assessable patients with microscopic disease at the start of i.p. therapy, 17 patients (61%) achieved a surgically defined complete response (CR). Only one of 31 patients (3%) with any macroscopic disease achieved a CR. Of the eligible patients, 18 of 76 (24%) achieved a CR. CONCLUSION Salvage i.p. paclitaxel is tolerable and active in patients with microscopic residual disease. The impact of this treatment strategy on survival remains to be assessed in a phase III trial.

Genetic variants in the lipopolysaccharide (LPS) receptor complex and TLR4 expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 564-564
Author(s):  
Francesca Battaglin ◽  
Alberto Puccini ◽  
Shu Cao ◽  
Joshua Millstein ◽  
Ryuma Tokunaga ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Receptor Complex ◽  
Tlr4 Expression ◽  
First Line ◽  
Expression Levels ◽  
Ras Status ◽  
In Fire ◽  
The Impact

564 Background: Large metagenomic studies associate disrupted gut microbiome signatures, comprising more prevalently gram-negative bacteria, with CRC carcinogenesis. TLR4, the LPS receptor, has been involved in microbiota-mediated tumorigenesis. High TLR4 expression is associated with poor prognosis in CRC and TLR4 can activate EGFR through ligands epiregulin and amphiregulin. Hence, we hypothesized that genetic variants in the LPS receptor complex and TLR4 expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 5 functional SNPs within TLR4, MD2 and CD14 was analyzed in 129 pts treated with first-line FOLFIRI/cet (discovery, mPFS/OS: 12.8/49.8 mo) and 107 pts treated with FOLFIRI/bevacizumab (bev) (mPFS/OS: 11.5/31.4 mo). Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the discovery cohort, pts carrying the C/T variant of TLR4 rs4986791 had significantly shorter mPFS and OS compared to the C/C genotype in both uni- and multivariable analysis (PFS: 5.4 vs 13.3 mo, adjusted P[ Padj] = .01; OS: 21.7 vs 40.7 mo, Padj= .03). Conversely, C/C carriers of rs12377632 had a longer mPFS compared to any T in uni- and multivariable analysis (15.8 vs 12.2 mo, Padj< .001). Any A allele carriers of MD2 rs12546552 and any G allele carriers of CD14 rs2569190 showed shorter mPFS in multivariable analyses. These associations were not observed in bev arm. Significant interaction was found between TLR4 rs12377632 and RAS status ( P= .015). High TLR4 expression (log2 > 10.93) was associated with worse mPFS (7.2 vs 11 mo, P= .003) and OS (19.1 vs 29.8 mo, P< .001) in FIRE-3 cet arm. Conclusions: Our results provide the first evidence that polymorphisms in the LPS receptor complex and TLR4 expression levels may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and, overall, contribute to resistance to anti-EGFRs.

Eligibility criteria requirements and adherence in advanced prostate cancer trials.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 245-245
Author(s):  
Sarah Wong ◽  
Christopher Sweeney ◽  
Srikala S. Sridhar
Keyword(s):  
Prostate Cancer ◽  
General Population ◽  
Advanced Prostate Cancer ◽  
Performance Status ◽  
Locally Advanced ◽  
Phase Iii ◽  
Failure Rates ◽  
Eligibility Criteria ◽  
Screen Failure ◽  
Cancer Trials

245 Background: Eligibility criteria for advanced (metastatic and locally advanced) prostate cancer trials vary between trials and are specific to the therapy evaluated, and may not represent the general population. This reduces comparability between studies, generalizability of results, and may contribute to high screen failure rates (~25%). In this study, we aimed to better understand the eligibility criteria across trials and adherence to eligibility criteria. Methods: We compared eligibility criteria between trials and collected baseline demographics to assess for adherence to criteria for 13 phase III advanced prostate cancer trials published from 1999-2016. Results: Disease characteristics, age, performance status, tumor markers, and most hepatic, renal, and hematological criteria were consistent across trials. However, discrepancies in hemoglobin, absolute neutrophil count, glomerular filtration rate (GFR) and bilirubin criteria were observed (Table). Overall, 8/13 trials included patients that did not meet criteria but were analyzed by intent-to-treat. Criteria that were not followed included: hemoglobin and albumin (lower than permitted); while testosterone, serum creatinine, pain scores, and ECOG performance status were higher (more unwell) than permitted. Conclusions: Specific eligibility criteria vary across the trials, and a number of trials accrued ineligible patients. After accounting for drug-specific criteria, greater standardization of and consideration of general population for eligibility criteria is needed to improve homogeneity of trial populations across studies, generalizability of results, and possibly reduce screen failure rates in prostate cancer trials. [Table: see text]

Gene expression and genetic variants in Parkinson's disease (PD) genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3 phase III trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3595-3595
Author(s):  
Francesca Battaglin ◽  
Shu Cao ◽  
Alberto Puccini ◽  
Ryuma Tokunaga ◽  
Madiha Naseem ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Methylation Status ◽  
Multivariable Analysis ◽  
Epidemiological Studies ◽  
Tumor Location ◽  
Phase Iii ◽  
First Line ◽  
Age Related ◽  
The Impact

3595 Background: PD is one of the most common age-related neurodegenerative disorders. Large epidemiological studies have consistently reported a reduced risk of CRC in PD patients (pts), but the biology behind this evidence is unclear. The methylation status of SNCA, one of the causal PD genes, has been identified as a tool for CRC screening and early diagnosis when detected in stool samples, and alterations in core PD genes are prevalent across human malignancies including CRC. Methods: The impact on outcome of 13 SNPs within 6 core PD genes ( SNCA, PRKN, UCHL1, PINK1, DJ-1, LRRK2) was analyzed in pts enrolled in the randomized FIRE-3 trial. Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the cet cohort, pts carrying the G/G variants of SNCA rs356165 and rs2736990 had significantly shorter mOS (30 vs 41.1 mo) compared to any A genotype in both uni- and multivariable analysis (adjusted P[ Padj] = .047 and .042, respectively). LRKK2 rs3761863 T/T allele carriers showed shorter mPFS (9.5 vs 13.3 mo, Padj = .01), while rs11564148 any A carriers had longer mPFS (14.2 vs 10.2 mo, Padj = .01) compared to reference genotypes. LRKK2 rs11564148 any A carriers also showed longer mOS in multivariable analysis (43.7 vs 33.2 mo, Padj = .044). Any C allele carriers of PINK1 rs1043424 showed longer mPFS in uni- and multivariable analysis ( Padj < .001). No significant interaction was found with gender, tumor location and RAS status. These associations were not observed in bev arm. High SNCA expression was associated with worse mPFS (log2 > 7.89, 5.9 vs 11.2 mo) and mOS (log2 > 7.68, 17.9 vs 31.1 mo) in FIRE-3 cet arm ( P < .05). Conclusions: We provide the first evidence that gene expression and genetic variants in PD genes may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment. Our findings open new perspectives on the role of PD genes in CRC biology warranting further investigation.

Polymorphisms in the telomerase complex to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE-3 phase III trials.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 566-566
Author(s):  
Francesca Battaglin ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Shu Cao ◽  
Alberto Puccini ◽  
...  
Keyword(s):  
Multivariable Analysis ◽  
Phase Iii ◽  
First Line ◽  
Discovery Cohort ◽  
Mutational Status ◽  
Phase Iii Trials ◽  
Telomere Capping ◽  
Predictive And Prognostic Value ◽  
The Impact

566 Background: Telomere/telomerase interplay is involved in the regulation of genomic stability and cellular replicative potential. In CRC, shortening of telomeres promotes early steps of carcinogenesis but the prognostic role of telomere length is debated. High circulating levels of telomerase reverse transcriptase (TERT) appear to be a negative prognostic biomarker and polymorphisms in the telomerase RNA component (TERC) are associated with increased cancer risk. We hypothesized that genetic variants in the telomerase/telomere capping complex may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 21 selected SNPs within 13 genes ( TERT, TERC, CLPTM1L, TERF1/2, POT1, ACD, NOP10, NHP2, GAR1, STN1, CTC1) was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 451 pts enrolled in two independent randomized trials. TRIBE FOLFIRI/bevacizumab (bev) arm (n=215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n=107, mPFS/OS: 11.5/31.4 mo) as validation and FOLFIRI/cetuximab (cet) arm (n=129, mPFS/OS: 12.8/49.8 mo) as control. Results: In the discovery cohort, pts carrying any A allele of TERT rs2075786 showed longer mPFS (11.1 vs 9.3 mo, P= .021) and OS (33.5 vs 25 mo, P= .005) compared to the G/G genotype in multivariable analysis. Same results were observed for pts carrying any T allele of CLPTM1L rs401681 compared to the C/C genotype ( P= .022). Any C allele carriers of TERC rs2293607 also showed longer mOS in multivariable analysis ( P= .041) and the A/A genotype of ACD rs6979 was associated with longer mPFS in both uni- and multivariable analysis. Interestingly, the T/T genotype of CLPTM1L rs401681 was associated with shorter mPFS (7.8 vs 13.5 mo) in the cet cohort in uni- ( P= .003) and multivariable analysis ( P= .041). In subgroup analyses based on RAS mutational status several SNPs in additional genes were associated with PFS and/or OS in different cohorts. Conclusions: Our results suggest that SNPs in core telomerase/telomere capping complex genes may have a predictive and prognostic value in mCRC pts receiving targeted first-line treatments.

scholarly journals Extent of Exclusions for Chronic Conditions in Breast Cancer Trials

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Ian M Kronish ◽  
Kathleen Fenn ◽  
Laura Cohen ◽  
Dawn L Hershman ◽  
Paige Green ◽  
...  
Keyword(s):  
Breast Cancer ◽  
National Cancer Institute ◽  
Chronic Conditions ◽  
Chronic Condition ◽  
Randomized Clinical Trials ◽  
Performance Status ◽  
Phase Iii ◽  
Test Case ◽  
Eligibility Criteria ◽  
Cancer Trials

Abstract Experts have expressed concerns that patients with chronic conditions are being excessively excluded from cancer randomized clinical trials (RCTs), limiting generalizability. Accordingly, we queried clinicaltrials.gov to determine the extent to which patients with chronic conditions were excluded from phase III cancer trials, using National Cancer Institute-sponsored breast cancer RCTs as a test case. Two physicians independently coded for the presence of 19 prevalent chronic conditions within eligibility criteria. They also coded for exclusions based on performance status and vague criteria that could have broadly excluded patients with chronic conditions. The search identified 58 RCTs, initiated from 1993 to 2012. Overall, 88% of trials had at least one exclusion for a chronic condition, performance status, or vague criterion. The three most commonly excluded conditions were chronic kidney disease, heart failure, and ischemic heart disease. Our study demonstrated that patients with prevalent chronic conditions were commonly excluded from National Cancer Institute-sponsored RCTs.

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