scholarly journals Circulating tumor DNA as a novel tool to shape clinical trial designs with the potential to impact outcomes: a focus on PI3K inhibitors

2017 ◽  
Vol 28 (11) ◽  
pp. 2882-2887 ◽  
Author(s):  
D. Sellami ◽  
B. Dharan ◽  
C. Wilke ◽  
S.J. Scherer ◽  
S. Hirawat
Keyword(s):  
Clinical Trial ◽  
Circulating Tumor Dna ◽  
Pi3k Inhibitors ◽  
Clinical Trial Designs ◽  
Tumor Dna

Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3506-3506
Author(s):  
Andrea Sartore-Bianchi ◽  
Filippo Pietrantonio ◽  
Sara Lonardi ◽  
Benedetta Mussolin ◽  
Francesco Rua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Liquid Biopsy ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Type I ◽  
Tumor Dna

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

TiFFANY study: A multicenter phase II basket-type clinical trial to evaluate efficacy and safety of pan-FGFR inhibitor TAS-120 for advanced solid malignancies with FGFR alterations identified by circulating tumor DNA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3156-TPS3156
Author(s):  
Tomoko Jogo ◽  
Yoshiaki Nakamura ◽  
Yoshito Komatsu ◽  
Ken Kato ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Survival Duration ◽  
Efficacy And Safety ◽  
Multicenter Phase ◽  
Solid Malignancies ◽  
Ctdna Analysis ◽  
Tumor Dna

TPS3156 Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations ( FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.

scholarly journals Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

2021 ◽  
pp. 1166-1177
Author(s):  
Fotios Loupakis ◽  
Shruti Sharma ◽  
Madiha Derouazi ◽  
Sabina Murgioni ◽  
Paola Biason ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Systemic Therapy ◽  
Residual Disease ◽  
Prognostic Biomarker ◽  
Circulating Tumor Dna ◽  
Significant Prognostic Factor ◽  
Resection Of Metastases ◽  
Tumor Dna

PURPOSE More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD). PATIENTS AND METHODS We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician. RESULTS Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001). CONCLUSION This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.

scholarly journals Circulating tumor DNA and RNA as an exploratory biomarker to evaluate GT0918 in a phase I/II clinical trial in mCRPC patients

2018 ◽  
Vol 29 ◽  
pp. viii51-viii52
Author(s):  
M. Tan ◽  
S. Zhang ◽  
Z. Zhao ◽  
A. Wang ◽  
D. Cheung ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Circulating Tumor Dna ◽  
Dna And Rna ◽  
Tumor Dna

Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS886-TPS886
Author(s):  
Hiromichi Maeda ◽  
Naoki Nagata ◽  
Takeshi Nagasaka ◽  
Koji Oba ◽  
Hideyuki Mishima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Mutation Status ◽  
Line Therapy ◽  
Tumor Dna

TPS886 Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.

Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer:NRG-GI005 (COBRA).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS148-TPS148
Author(s):  
Van K. Morris ◽  
Greg Yothers ◽  
Scott Kopetz ◽  
Samuel A. Jacobs ◽  
Peter C. Lucas ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Phase Ii ◽  
Predictive Biomarkers ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Phase Iii ◽  
Tumor Dna

TPS148 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms:standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. The trial is actively accruing towards the phase II endpoint across all US and Canadian cooperative groups. Support:U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.

Genetic mutation analysis of plasma circulating tumor DNA by ultra-deep sequencing in breast benign lesions and cancers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14572-e14572
Author(s):  
Qian Wu ◽  
Wenjing Jian ◽  
Xumei Yao ◽  
Xintong Xie ◽  
Hanjie Fang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Cancer Patients ◽  
Tumor Tissue ◽  
Mutation Detection ◽  
Circulating Tumor Dna ◽  
Breast Diseases ◽  
Breast Lesions ◽  
Breast Cancer Patients ◽  
Tumor Dna

e14572 Background: Mammography screening for breast cancer results in large number of impalpable lesions without clear determination of the malignancy. Analysis of breast cancer related gene mutations in blood circulating tumor DNA (ctDNA) may provide clarification. This analysis aims to provide insights into the feasibility of the approach. Methods: The clinical trial was conducted at top tier teaching hospitals in China to recruit patients with breast diseases for surgery. Eligible patients were consented and the breast lesions were pathologically diagnosed. Peripheral blood was collected prior to surgical resection. For breast cancer patients, samples of resected tissue were also collected. The samples were analyzed using our proprietary NGS technique called systematic error correction sequencing (Sec-Seq) (detailed in Abstract ##e23057, ASCO 2018). Results: In total, 69 patients with breast lesions (57 malignant and 12 benign) were included in this analysis. Tumor gDNA and plasma ctDNA were analyzed by deep NGS sequencing using a panel of 62 breast cancer-associated genes. The average sequencing depth is 35000. After deduplication, the average number of unique reads is 1500. Detection limit for mutant allele frequency was set at 0.2% for ctDNA and 1% for tumor tissue. For ctDNA mutation detection, 2 out of 12 patients with benign diseases were found with mutations while 10 out of 55 breast cancer patients had no mutations, resulting in an overall sensitivity of 82% and specificity of 83%. By cancer stage, the two Stage 0 (carcinoma in situ) patients had no mutation, and the range of mutations detected is between 53% to 75% from Stage I to III. The tumor tissue samples have higher rate of mutations (only 2 cancer patients, 1 Stage 0 and 1 Stage 2, had no mutations). 15% patients have at least one common mutation detected in both the tumor tissue and ctDNA, and 27% patients have mutations in the same genes in the two matching samples. The concordance increases as the clinical stage advances. The most commonly mutated genes are previously reported breast cancer drivers of PIK3CA (79% of tumor and 18% of ctDNA samples), TP53 (56% and 39%), and BRCA1 (6% and 15%). Conclusions: In this hypothesis generating analysis, we showed the feasibility of plasma ctDNA sequencing for gene mutation detection in early stage breast cancer and differentiation from the benign breast diseases. Although with limited number of samples, the data encourage further improvement of the gene panel and the validation of ctDNA assay as a non-invasive approach to the cancer screening. Clinical trial information: ChiCTR1800017345.

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