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.

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.

Efficacy and safety of liposomal mitoxantrone (Lipo-MIT) in advanced breast cancer (ABC): A randomized, open label, active-controlled, single-center, phase II clinical trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1093-1093
Author(s):  
Leiping Wang ◽  
Yannan Zhao ◽  
Ting Li ◽  
Jun Cao ◽  
Yiqun Du ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Lower Incidence ◽  
Troponin T ◽  
Objective Response ◽  
Phase Ii Clinical Trial ◽  
Efficacy And Safety ◽  
Single Center ◽  
Open Label

1093 Background: Anthracyclines are associated with cardiotoxicity and myelosuppression in breast cancer (BC) patients. A new drug delivery system, liposomal preparation has shown higher anti-cancer effect and lower toxicity due to modified drug release and particle shape. This trial aimed to evaluate the efficacy and safety of Lipo-MIT in ABC. Methods: This is a randomized, open label, active-controlled, single-center, phase II clinical trial. Eligible patients were randomized in a ratio of 1:1 to receive Lipo-MIT or mitoxantrone hydrochloride injection (MIT) intravenously. The dosage was 20 mg/m2 for Lipo-MIT and 14 mg/m2 for MIT, once every four weeks (i.e., one treatment cycle). The primary endpoint was objective response rate(ORR). The secondary endpoints were progression free survival (PFS) and safety. Results: From Oct 2015 through Jul 2017, 60 patients were randomized to Lipo-MIT group (n = 30) or MIT group (n = 30). The Median (Q1,Q3) age was 56.0 (41.0,62.0) years in Lipo-MIT group and 54.5 (44.0,62.0) years in MIT group. Nineteen patients in Lipo-MIT group and 23 in MIT group received < 4 cycles of treatment, 11 patients in Lipo-MIT group and 7 in MIT group were treated for 4 or more cycles. When Lipo-MIT group was compared with MIT group, ORR was 13.3% (4/30) and 6.7% (2/30), disease control rate (PR+SD) was 50% (15/30) and 30% (9/30), median PFS was 2.30 (95% CI: 1.74-3.91) and 1.86 (95% CI: 1.74-2.40) months ( P> 0.05). Lipo-MIT showed significantly lower incidence of all-grade white blood cell decreased (86.7% vs 96.7%), neutrophil count decreased (80.0% vs 96.7%), conjugated bilirubin increased (53.3% vs 56.7%), aspartate aminotransferase increased (40.0% vs 53.3%), and troponin T increased (3.3% vs 36.7%) than MIT, but higher incidence of anemia (76.7% vs 46.7%), skin hyperpigmentation (66.7% vs 3.3%), and platelet count decreased (56.7% vs 53.3%) than MIT. Conclusions: Lipo-MIT provided numerically better ORR, DCR, and PFS than MIT in ABC. Lower incidence of troponin T increased might suggest lower cardiotoxicity of Lipo-MIT. It is worthwhile to further explore the clinical utility of Lipo-MIT in ABC. Clinical trial information: NCT02596373 .

PD1 inhibition in soft-tissue sarcomas with tertiary lymphoid structures: A multicenter phase II trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11507-11507
Author(s):  
Antoine Italiano ◽  
Alban Bessede ◽  
Emmanuelle Bompas ◽  
Sophie Piperno-Neumann ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Soft Tissue ◽  
Phase Ii ◽  
Progressive Disease ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Progression Rate ◽  
Multicenter Phase ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

11507 Background: PD1 inhibition has shown limited activity in all comers clinical trials including patients with advanced soft-tissue sarcomas (STS). In the PEMBROSARC study, objective response rate, progression-free (PFS) and overall survival (OS) were respectively 2.1%, 1.4 and 7.1 months respectively (Toulmonde et al. Jama Oncol 2017). We have recently shown that the presence of tertiary lymphoid structures (TLS) may represent a biomarker to select patients who are more likely to benefit from immunotherapy (PetitPrez et al., Nature 2020). We report here the first clinical trial investigating the efficacy of PD1 inhibition in TLS-positive STS. Methods: PEMBROSARC is an open-label multicenter phase II study of pembrolizumab in combination with low-dose cyclophosphamide in pts with STS selected based on the presence of TLS. TLS status has been assessed centrally has previously described (PetitPrez et al., Nature 2020). Eligible patients received pembrolizumab 200mg IV q21 days and cyclophosphamide 50 mg BID 1week on, 1 week off. All patients had confirmed progressive disease at inclusion based on central review of two imaging performed at less than 6 months interval. The primary efficacy endpoint was 6-month non-progression (as per RECIST evaluation criteria v1.1). Based on the following hypotheses: 15% 6-month non-progression rate (H0), 40% acceptable 6-month non-progression rate (H1), 5% type I error rate, 90% power, a total of 29 assessable patients were necessary and 8 patients or more had to be progression-free at 6 months to reach the first endpoint. Results: 240 patients were screened for TLS status between September 2018 and January 2020 in 7 centers of the French Sarcoma Group. Among them, 48 were found to be TLS+ as per central review and 35 were included in the study. The three most frequent histological subtypes were: well-differentiated/dedifferentiated liposarcoma (n = 13); UPS (n = 6), and leiomyosarcoma (n = 4). 30 patients were eligible for efficacy. Of those, as per central imaging review, 13 patients (43.3%) had tumor shrinkage resulting in partial response in 8 patients (26.7%) and stable disease in 5 cases (16.7%). 10 patients had progressive disease. Twelve patients were progression-free at 6 months (40.0% 95%CI = [22.7 – 59.4]).Median PFS and OS were 4.1 months (95%CI, 1.4-9.6) and 14.5 months (95%CI, 8.5- 18.3 months), respectively. Conclusions: With an objective response and a 6-month non-progression rates of 26.7% and 40% respectively versus 2.1% and 4.2% in all comers, the PEMBROSARC study confirms that selection based on TLS status is an efficient approach to tailor immunotherapy in STS patients. Clinical trial information: NCT02406781.

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.

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

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS261-TPS261
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 ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Phase Iii ◽  
Stage Ii Colon Cancer ◽  
Tumor Dna

TPS261 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. Trial accrual is anticipated across all US and Canadian cooperative groups.NCT#: 04068103. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: 04068103.

A phase II, multicenter, open-label study of [fam-] trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing gastric cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS180-TPS180 ◽  
Author(s):  
Kohei Shitara ◽  
Yung-Jue Bang ◽  
Hyun Cheol Chung ◽  
Hiroshi Yabusaki ◽  
Satoru Iwasa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Topoisomerase I ◽  
Objective Response ◽  
Survival Duration ◽  
Efficacy And Safety ◽  
Antibody Drug Conjugate ◽  
Primary Analysis ◽  
Her2 Positive ◽  
Open Label

TPS180 Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer (GC) who progressed on trastuzumab-based therapy. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, topoisomerase I inhibitor payload, cleavable peptide-based linker, and high drug-to-antibody ratio of approximately 8. In an ongoing phase I trial, [fam-] trastuzumab deruxtecan showed an acceptable safety profile and promising antitumor activity in salvage-line subjects with HER2+ GC who previously received trastuzumab (confirmed objective response rate [ORR] of 43.2% [19/44]; Iwata et al, ASCO 2018). Methods: The randomized, phase II, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in HER2-expressing GC. The primary cohort, HER2+ (IHC 3+ or IHC 2+/ISH+) GC subjects who progressed after ≥ 2 prior regimens and previously received trastuzumab, will be randomized (2:1) to [fam-] trastuzumab deruxtecan (6.4 mg/kg dose; once every 3 weeks) or physician’s choice (irinotecan or paclitaxel). Two nonrandomized exploratory cohorts will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in subjects with HER2-low GC (IHC 2+/ISH- and IHC 1+, respectively) who are treatment-naïve to HER2-targeted therapies. The primary endpoint is ORR assessed by an independent central review; secondary endpoints include overall survival (OS), progression-free survival, duration of response, disease control rate, pharmacokinetics, and safety (as shown in ClinicalTrials.gov). The primary analysis for ORR and interim OS analysis will occur after all subjects complete tumor assessments on week 18 and when approximately 108 OS events are observed, whichever comes later. The primary cohort will enroll 180 subjects; providing 92.9% power to detect a difference between the ORR of 40% for [fam-] trastuzumab deruxtecan vs 15% for physician’s choice. Each exploratory cohort will enroll a maximum of 20 subjects. Enrollment began in October 2017. As of Feb 13, 2018, 12 of 180 subjects have been enrolled. Clinical trial information: NCT03329690.

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