Analysis Of Clinical Endpoints Research Articles

Abstract CT084: Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following Induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC) - phase III trial interim analysis

Abstract Background: Treatment of locally advanced pancreatic cancer (LAPC) remains a clinical challenge with a median survival of 16-18 months1. Control of local disease, beyond systemic therapy, is part of the treatment paradigm being investigated in this patient population. Double balloon mediated local delivery of intra-arterial gemcitabine (IAG) into the tumor has been demonstrated to be safe in this patient population2. TIGeR-PaC is an ongoing Phase III clinical trial comparing the efficacy of this approach compared to standard of care IV gemcitabine/nab-paclitaxel (GN) for patients with LAPC. Methods: The trial is designed with an induction phase for all patients of upfront systemic chemotherapy and radiation prior to randomization to IAG or continuation of GN. ECOG 0-1 LAPC patients receive 3 cycles of GN and 1 cycle of radiation (SBRT, 33 Gy in 5 fractions). Following induction, patients with non-progressive disease are randomized to receive IAG (8 treatments bi-weekly for 16 weeks) or continuation of GN for 4 cycles over 16 weeks. After the 16 weeks of randomized therapy, patients with non-progressive disease receive continuation systemic therapy of GN or low-dose oral capecitabine, per investigator’s preference until disease progression and are followed for survival only. The primary endpoint is the overall survival (OS), and the study is powered at an 80% power to detect a hazard ratio of 0.6 between the two arms. It is assumed that the hazard functions are proportional only during the randomized treatment period, after which the two hazard functions become approximately identical during the continuing treatment period. The primary endpoint of OS for the two treatment arms will be compared using a 2-sided Wilcoxon test. The first interim analysis of the trial for the ITT population is performed after the 26th out of an expected 86 events have occurred in the trial (30%). Clinical Endpoint Analysis: The first interim analysis of the primary endpoint of OS was conducted on Feb 2nd, 2023. This was based on a data lock on survival status of all patients after the sponsor became aware that the 26th event in the trial occurred on Dec. 21st, 2022. As of that date, 45 patients had been randomized in the trial and the survival status of all 45 subjects was used as of the date for analysis. Of the 45 patients randomized, 23 were randomized to IAG and 22 to continuation of IV GN. There were equal number of primary events, 13, in each arm. The median survival in the control arm is 10 months, versus 16 months in the IAG arm. The p-values based on Wilcoxson non-proportional hazard ratio is 0.051 between the 2 arms. The study continues to accrue patients with a second interim analysis (after 52 events) expected at end of 2024. 1. Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. JAMA. 2016;315(17):1844. 2. Rosemurgy AS, Ross SB, Vitulli PL, et al. Safety Study of Targeted and Localized Intra-Arterial Delivery of Gemcitabine in Patients with Locally Advanced Pancreatic Adenocarcinoma. J Pancreat Cancer. 2017;3(1):58-65. Citation Format: Michael Pishvaian, Amer Zureikat, Charles Lopez, Kenneth Meredith, Emmanuel Zervos, Hassan Hatoum, Ki Chung, Daniel J. Berg, Antonio Ucar, Ripal Gandhi, Reza Nazemzadeh, Parikh Nainesh, Paula Novelli, Brian Kouri, Christopher Laing, Brian Boone, Thor Johnson, Susan Bates, Karyn Goodman, Ramtin Agah. Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following Induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC) - phase III trial interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT084.

Abstract 9330: Machine Learning Can Enable the Automation of Clinical Endpoint Adjudication

Introduction: Clinical Endpoint Adjudication is a critical component of Cardiovascular (CV) clinical outcome trials and relies on manual decision making to adjudicate clinical events, including CV death. This process is resource intensive and subject to human-driven variance. As part of a broader initiative to automate data collection and analysis of clinical endpoints, we evaluated whether machine learning (ML) algorithms could replicate the outcomes of expert adjudication for CV death. Algorithms were trained on data from THEMIS (NCT01991795), a large, randomized trial comparing ticagrelor to placebo in patients with Type 2 Diabetes Mellitus. Methods: We deployed a deep learning, biomedical named entity (NE) extraction model called BERN to extract relevant NE’s from clinical text of THEMIS events. NE’s were transformed into a sparse, numerical matrix and concatenated with event-level structured features to form a data set of 962 events. Expert adjudicator consensus for CV death was used as ground truth. We trained models using grid search and cross validation, experimenting with XGBoost, Random Forest, Logistic Regression, and Naïve Bayes. Performance was assessed on a 25% (240 of 962) validation subset of the data excluded from training. Metrics used to evaluate performance were Precision, Recall, Accuracy and Area Under the Receiver Operating Characteristic Curve (AUC). Results: Best performance was observed on models trained using Naïve Bayes (>97% ROC AUC on validation data), see Table. Top ranked features for classifying CV death included site investigator decision, sex, and NE’s associated with diagnoses or symptoms, such as “edema” and “chest pain.” Conclusion: With high consistency between automated and expert adjudication, our models demonstrate that machine learning may augment or even replace clinician adjudication in CV outcome trials. Subsequent research will focus on pursuing ML approaches to adjudicate other outcome events.

Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.

5507 Background: The CLIO trial (NCT02822157) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m2 q 4 wks; Topotecan 1.25 mg/m2 day 1—5 q 3 wks; Paclitaxel 80 mg/m2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT02822157.

The Use of Stromal Vascular Fraction in the Treatment of Male Sexual Dysfunction: A Review of Preclinical and Clinical Studies.

Stem cell therapy using stromal vascular fraction (SVF) is a promising treatment modality. SVF is comprised of a mixture of adipose-derived stem cells, endothelial precursor cells, and immune modulatory cells that act synergistically to facilitate angiogenesis and epithelial cell differentiation. This makes SVF an attractive option for men's sexual disorders that require reconstitution of vasculature and endothelial lining, namely erectile dysfunction (ED) and Peyronie's disease (PD). The objective of this study was to compare and contrast the available literature regarding the use of SVF in the treatment of male sexual dysfunction. A literature review was performed in PubMed with the keywords "stromal vascular fraction" and/or "erectile dysfunction" and/or "Peyronie's disease" and/or "sexual dysfunction." The main outcome measure for preclinical studies was erectile function, as measured by changes in intracavernous pressures, and results of histopathologic analysis of corporal tissue. Clinical endpoint analysis in humans included various patient questionnaires. For ED, there were 5 preclinical studies included in the analysis, with 1 Phase 1 clinical trial in humans. Major limitations of both the preclinical and clinical studies included the absence of SVF component analysis, and short duration of follow-up. Despite a paucity of preclinical studies, there was a single clinical study assessing the efficacy of combination SVF and shock wave therapy in the treatment of PD. Limitations of this study included an absence of a control group and the use of subjective data. Preclinical and clinical data in the use of SVF for the treatment of male sexual dysfunction is deficient. Even though multiple medicinal disciplines are studying the use of SVF on a myriad of pathologies, further investigative work elucidating the mechanism and potential adverse effects of SVF need to be performed before clinical trials are undertaken. Haney NM, Gabrielson A, Kohn TP, Hellstrom WJG. The Use of Stromal Vascular Fraction in the Treatment of Male Sexual Dysfunction: A Review of Preclinical and Clinical Studies. Sex Med Rev 2019;7:313-320.

Analysis of Clinical End Points of Randomised Trials Including Bevacizumab and Chemotherapy versus Chemotherapy as First-line Treatment of Metastatic Colorectal Cancer

AimsProgression-free survival is recognised as an appropriate end point for randomised clinical trials of chemotherapy of patients with metastatic colorectal cancer, although it is not clear if it is reliable after chemotherapy plus bevacizumab. Materials and methodsA literature search of randomised trials of systemic treatment including chemotherapy plus bevacizumab versus chemotherapy in patients with metastatic colorectal cancer was undertaken. For each trial the differences in overall survival and in either time-to-event or response-related end points were calculated. A Spearman test was carried out between the difference in each end point and the difference in survival. For the end points with the higher relationships with overall survival a regression analysis was carried out and R2 (proportion of variability explained) was reported. ResultsProgression-free survival is closely related to overall survival (r=0.817; R2=0.706) and this relationship does not seem to be changed by the discontinuation of bevacizumab. The response-related end points have a better overall performance than the other time-to-event end points, even when only phase III trials are considered. In phase III trials, the disease control rate seems to be strongly related to overall survival (r=0.975; R2=0.889) and the overall response rate reports a good performance (r=0.866; R2=0.484). An open-label design and the timing of disease radiological evaluation do not seem to interfere with the correlation of differences of progression-free survival and overall survival. ConclusionsA validation of the disease control rate and the overall response rate as a surrogate end point of survival at a patient level and a standardised definition of the timing for their measurement are strongly recommended in trials of chemotherapy plus bevacizumab.

Gene Expression Analysis in Ovarian Cancer – Faults and Hints from DNA Microarray Study

The introduction of microarray techniques to cancer research brought great expectations for finding biomarkers that would improve patients’ treatment; however, the results of such studies are poorly reproducible and critical analyses of these methods are rare. In this study, we examined global gene expression in 97 ovarian cancer samples. Also, validation of results by quantitative RT-PCR was performed on 30 additional ovarian cancer samples. We carried out a number of systematic analyses in relation to several defined clinicopathological features. The main goal of our study was to delineate the molecular background of ovarian cancer chemoresistance and find biomarkers suitable for prediction of patients’ prognosis. We found that histological tumor type was the major source of variability in genes expression, except for serous and undifferentiated tumors that showed nearly identical profiles. Analysis of clinical endpoints [tumor response to chemotherapy, overall survival, disease-free survival (DFS)] brought results that were not confirmed by validation either on the same group or on the independent group of patients. CLASP1 was the only gene that was found to be important for DFS in the independent group, whereas in the preceding experiments it showed associations with other clinical endpoints and with BRCA1 gene mutation; thus, it may be worthy of further testing. Our results confirm that histological tumor type may be a strong confounding factor and we conclude that gene expression studies of ovarian carcinomas should be performed on histologically homogeneous groups. Among the reasons of poor reproducibility of statistical results may be the fact that despite relatively large patients’ group, in some analyses one has to compare small and unequal classes of samples. In addition, arbitrarily performed division of samples into classes compared may not always reflect their true biological diversity. And finally, we think that clinical endpoints of the tumor probably depend on subtle changes in many and, possibly, alternative molecular pathways, and such changes may be difficult to demonstrate.

Feature extraction via composite scoring and voting in breast cancer

Identification and characterization of tumor subtypes using gene expression profiles of triple negative breast cancer patients. Microarray data of four breast cancer studies were pooled and evaluated. Molecular subtype classification was performed using random forest and a novel algorithm for feature extraction via composite scoring and voting. Biological and clinical properties were evaluated via GSEA, functional annotation clustering and clinical endpoint analysis. The subtype signatures are highly predictive for distant metastasis free survival of tamoxifen-treated patients. Consensus clustering and the novel algorithm proposed three triple negative subtypes. One subtype shows low E2F4 gene expression and is predictive for survival of ER negative breast cancer patients. The other two subtypes share commonalities with luminal B tumors. Classification of breast cancer expression profiles may reveal novel tumor subtypes, possessing clinical impact. Furthermore, subtype characterizing gene signatures might hold potential for novel strategies in cancer therapy.

Immunosuppressive Cytokine Gene Polymorphisms and Outcome after Related and Unrelated Hematopoietic Cell Transplantation in a Chinese Population

Cytokine gene polymorphisms can affect the outcome of allogeneic hematopoietic stem cell transplantation. We analyzed 6 single nucleotide polymorphisms in 3 immunosuppressive cytokine genes, TGFβ1-509(C>T), +869(T>C), TGFβ1 receptor II (TGFβ1RII) +1167(C>T, codon389 AAC/AAT), and IL-10-1082(A>G), -819(T>C), -592(A>C), in a cohort of 138 pairs of recipients and their unrelated donors and a second cohort of 102 pairs of recipients and their HLA-identical sibling donors. TGFβ1-509 T/T genotype in the donors or T allele-positivity in the recipients was associated with a significant protective effect against acute graft-versus-host disease (aGVHD) and grades II-IV aGVHD in the unrelated transplantation cohort. In the combined cohort, multivariate analysis confirmed that donors with the TGFβ1-509 T/T genotype also conferred protection against the risk of aGVHD and grades II-IV aGVHD. In both the unrelated transplantation cohort and the sibling transplantation cohort, the IL-10-819 C/C and -592 C/C genotypes in either recipients or donors were significantly associated with a higher incidence of aGVHD. In the combined cohort, the IL-10 promoter haplotype polymorphisms at positions -1082, -819, and -592 influenced the occurrence of aGVHD and death in remission. Recipients without the A-T-A haplotype or those transplanted from donors without the A-T-A haplotype had a higher incidence of aGVHD than those who were A-T-A homozygotes or heterozygotes. Estimates for death in remission showed a clear advantage for recipients transplanted from donors with the A-T-A haplotype. In multivariate analysis, recipients without the A-T-A IL-10 haplotype had a higher risk of aGVHD (relative risk [RR] = 0.764; 95% confidence interval [CI]: 0.460-1.269; P = .096) and grades II-IV aGVHD (RR = 0.413; 95% CI: 0.245-0.697; P = .001). These results provide the first report of an association between TGFβ1, TGFβ1RII, and IL-10 polymorphic features and outcome of allo-HSCT in a Chinese population, and suggest an interaction between TGFβ1-509 genotypes and IL-10 promoter haplotype polymorphisms at positions -1082, -819, and -592 and the risk of aGVHD.