bluuebunny/crossref_metadata_2025_split huggingface dataset:
GOBLET: A phase 1/2 multiple-indication biomarker, safety, and efficacy study in advanced or metastatic gastrointestinal cancers exploring treatment combinations with pelareorep and atezolizumab.
Authors: Arnold Dirk , Collienne Maike , Wilkinson Grey A , Loghmani Houra , Heineman Thomas Charles 
Published: January 2022

TPS216 Background: Checkpoint blockade therapy only benefits a small subset of GI cancer patients (approximately 4%) with microsatellite instability-high (MSI-H) tumors, which are characterized as immunologically ‘hot’ (Bonneville et al., 2017). Most GI cancers, however, have microsatellite stable (MSS) tumors, which have an immunologically “cold” phenotype with fewer genetic mutations, reduced immune cell infiltration, and downregulated immune checkpoint proteins. These attributes make MSS tumors resistant to conventional immunotherapy including checkpoint blockade therapy (Ooki et al., 2021). Pelareorep is a naturally occurring, non-genetically modified reovirus. Upon intravenous administration, pelareorep selectively kills tumor cells and promotes several immunologic effects that prime tumors to respond to checkpoint blockade. These include the stimulation of tumor-directed innate and adaptive immune responses, increased T cell infiltration, expansion of new T cell clones, and increased PD-L1 expression in tumors (Samson et al., 2018, Manso et al. 2021 AACR). Given its expected synergy with checkpoint blockade, as well as its encouraging efficacy in prior GI cancer studies (Mahalingam et al. 2020), the GOBLET study is designed to evaluate pelareorep plus atezolizumab in multiple GI cancer indications. Methods: GOBLET is an open-label, non-randomized, multiple-cohort, phase 1/2 study in patients with advanced or metastatic GI cancers. This study employs a Simon two-stage design. Stage 1 comprises four treatment groups: Cohort 1 – First-line pancreatic cancer treated with pelareorep plus atezolizumab and chemotherapy (gemcitabine and nab-paclitaxel) (N = 12); Cohort 2 – First-line MSI-H colorectal cancer (CRC) treated with pelareorep plus atezolizumab (N = 19); Cohort 3 – Third-line CRC treated with pelareorep plus atezolizumab and chemotherapy (trifluridine/tipiracil) (N = 14); and Cohort 4 – Second-line or later squamous cell carcinoma of the anal canal treated with pelareorep plus atezolizumab (N = 10). The first 3-6 patients enrolled into the chemotherapy-containing cohorts (Cohorts 1 and 3) comprise a safety run-in that must be successfully concluded prior to enrolling additional patients into these cohorts. The primary objectives are safety and efficacy based on objective response rate (ORR) at week 16. Any cohort showing a promising ORR in Stage 1, based on pre-specified criteria, may be advanced to Stage 2 and enroll additional patients. Clinical trial information: 2020-003996-16.
A phase 1b/2 study of VS-6766 in combination cetuximab in patients (pts) with advanced KRAS mt colorectal cancer (CRC).
Authors: Shergill Ardaman , Liao Chih-Yi , Kindler Hedy L. , Polite Blase N. , Catenacci Daniel V.T. 
Published: January 2022

TPS219 Background: KRAS mutations (mts) are present in about 45% of CRC and predict lack of response to anti-EGFR therapy like cetuximab. Limited therapy options exist for pts after prior 5-FU based regimens. Regorafenib or TAS-102 is commonly used however, the modest clinical benefit, and toxicity limit their use. Novel therapies are needed for pts at this point in their disease course. KRAS G12D and G12V mts occur in 11-12% and 9-10% of CRC, respectively, whereas G12C mts occur in 3-4% of CRCs . KRAS G12C mts occur in 3-4% of CRCs. Recently, results of phase 1/2 KRYSTAL-1 study were reported. Adagrasib (a KRAS G12C inhibitor) was used with/without cetuximab in heavily pretreated CRC pts harboring KRAS G12C mts. The objective response rate (ORR) and disease control rate (DCR) was 43% and 100% (resp.) in pts receiving cetuximab and adagrasib (28 evaluable pts), and 22% and 87%, resp., in those receiving adagrasib alone (42 evaluable pts). Phase 1b CodeBreaK101 study evaluating sotorasib ( KRAS G12C inhibitor) and panitumumab (anti-EGFR) combination in KRAS G12C mt CRC showed 15.4% confirmed ORR and 26.9% unconfirmed ORR. These data are encouraging, suggesting EGFR inhibition in combination with downstream KRAS inhibition may represent important therapeutic strategy for this disease. KRAS mts lead to constitutive activation of the MAPK pathway signaling and cell activation. VS-6766 is a novel dual RAF/MEK inhibitor which has shown activity in KRAS mutated tumors. Combination of EGFR inhibition and VS-6766 may overcome resistance of KRAS mt CRC cancers to EGFR inhibition alone. Preclinically, VS-6766 and EGFR inhibition showed synergy in KRAS mt CRC cell lines, including cell lines harboring KRAS G12D and G12V mts, and CRC PDX of KRAS G12V mt CRC showed tumor regression with this combination. These data support the development of VS-6766 with anti-EGFR therapy in KRAS mt CRC warranting this phase 1 study to evaluate safety and efficacy of this combination in clinical settings. Methods: This is an open label, single arm study evaluating VS-6766 with cetuximab in pts with KRAS mt advanced CRC. Phase 1b primary endpoints include safety and tolerability, and maximum tolerated dose and recommended phase 2 dose determination. ORR is the primary endpoint of the Phase 2 study. Secondary endpoints include OS and PFS. There will be upto 4 dose levels tested. Three de-escalation doses to find the optimal cetuximab dose, and one dose escalation of VS-6766, are planned. Eligible pts include those with metastatic CRC and progression after 5-FU, oxaliplatin, irinotecan and VEGFi therapy. Based on prior studies, dermatologic, gastrointestinal, ocular and CPK elevation have been the main toxicities noted with VS-6766. The study is funded by research grants from Verastem Oncology. Cetuximab will be supplied by Eli Lilly.
KEYNOTE-B79 phase 1b trial to evaluate the allogeneic CAR T-cells CYAD-101 and pembrolizumab in refractory metastatic colorectal cancer patients.
Authors: Kim Richard D. , Prenen Hans , Rottey Sylvie , Kim Dae Won , Flament Anne , Lehmann Frederic , Van Cutsem Eric 
Published: January 2022

TPS227 Background: The allogeneic chimeric antigen receptor (CAR) T-cell treatment CYAD-101 utilizes the NKG2D receptor that targets eight ligands expressed on tumor cells and also on stromal and immunosuppressive immune cells of the tumor microenvironment. CYAD-101 co-expresses a T-cell receptor (TCR) inhibitory peptide with the aim to eliminate the potential of graft versus host disease (GvHD), the main safety risk associated with engineered cells of allogeneic origin. In the previous alloSHRINK trial (NCT03692429), CYAD-101 was administered post FOLFOX preconditioning chemotherapy to 15 patients with progressive metastatic colorectal cancer (mCRC) who were previously treated with FOLFOX. Overall, the treatment was well tolerated with no evidence of GvHD. The disease control rate was 73.3% with two patients presenting a confirmed partial response per RECIST’s criteria (4 months and 8 months of duration from first CYAD-101 infusion) and nine had stable disease with a median duration of 4.6 months. Evidence of increase in the TCR repertoire and modulation of the cytokine profile post-treatment with CYAD-101 were observed implying that CYAD-101 may also be modulating the immune suppressive environment in patients mirroring what was demonstrated in pre-clinical models. We considered that a sequential therapy with the anti-PD1 monoclonal antibody pembrolizumab to further release the anti-tumor potential of this expanded T-cell population may drive deeper, more durable and new clinical responses beyond that currently demonstrated with the CAR T-cells alone. Methods: The phase 1b KEYNOTE-B79 trial (NCT04991948) will evaluate, according to a Simon’s two stage study design, the safety and clinical activity of three consecutive infusions of CYAD-101 (1x109 cells per infusion) post FOLFOX preconditioning chemotherapy with two-week interval between cycles, followed by pembrolizumab treatment (200 mg administered every three weeks for up to two years) in microsatellite stable/mismatch-repair proficient mCRC patients with recurrent/progressing disease after at least one metastatic line of therapy, which must include FOLFOX chemotherapy. The pembrolizumab treatment will be initiated 3 weeks after the last CYAD-101 infusion to fall outside the classical time window of potential CAR T-cell toxicities (e.g., cytokine release syndrome). The co-primary endpoints of the trial are the occurrence of dose-limiting toxicities (DLTs) at any time from the first FOLFOX preconditioning treatment up to 3 weeks after the first pembrolizumab treatment and the objective response rate (ORR) at the tumor assessment planned 6 weeks after the first pembrolizumab treatment administration. The KEYNOTE-B79 study will be initiated in Q4-2021 in five sites in USA and Europe. Clinical trial information: NCT04991948.
A prospective observational study to determine the feasibility of tumor response assessment by circulating tumor DNA (ctDNA) in patients with locally advanced rectal cancer (LARC) undergoing total neoadjuvant therapy (TNT).
Authors: Chakrabarti Sakti , McKenna Edward , Oxencis Carolyn , Peterson Carrie , Hall William A. , Ludwig Kirk A. , Ridolfi Timothy , Erickson Beth , Miller James , Banerjee Anjishnu , Thomas James P. 
Published: January 2022

TPS234 Background: Total neoadjuvant therapy (TNT) followed by total mesorectal excision (TME) is one of the standard treatment options for patients with locally advanced rectal cancer (LARC). A commonly employed TNT protocol consists of 8 biweekly cycles of oxaliplatin-based chemotherapy (CT) followed by radiation concurrent with fluoropyrimidine-based chemotherapy (CRT) for about 6 weeks. During the TNT, patients undergo tumor response assessments periodically with standard modalities (SM) consisting of pelvic magnetic resonance imaging (MRI) and proctoscopic/endoscopic examination. The objective of the current protocol is to evaluate the feasibility of tumor response assessment by ctDNA in patients with LARC undergoing TNT. The present feasibility study is designed to collect preliminary data to evaluate if a subsequent larger validation study is justified. If ctDNA-based response assessment is validated, ctDNA can potentially replace at least some components of the SM (for example, MRI) as tumor response assessment by SM is often time-consuming, expensive, and poses logistical challenges. Methods: Patients with LARC undergoing TNT will be enrolled. After obtaining informed consent, venous blood samples will be obtained for ctDNA level measurements at the following time points: baseline (within 1 week before the CT begins), after 4 cycles of CT within +/- 5 days of the MRI study, after 8 cycles of CT within +/- 5 days of the MRI study, and 1 to 14 days before TME. ctDNA levels will be measured by a commercially available ctDNA assay (Signatera by Natera), and ctDNA response is defined as >90% drop in the ctDNA level after treatment compared to the baseline level. Tumor response will be evaluated after 4 and 8 cycles of CT by SM. Primary endpoint: correlation between the response rate (RR) assessed by ctDNA and by SM after 4 cycles of CT. Secondary endpoints: 1) correlation between the RR assessed by ctDNA and by SM after 8 cycles of CT, and 2) correlation between the ctDNA defined RR and the complete pathological response (pCR) rate. The trial will enroll 30 patients. To evaluate the primary endpoint, differences in ctDNA levels between the baseline and 4-cycles post-CT will be computed. The differences will then be expressed as a proportion of each patient’s baseline level, D. This relative change, D, will be compared between the responder and non-responder groups using a two-sample Welch’s t-test. Similar methods will be applied for the secondary endpoints. All analyses will use the nominal type I error level of 0.05 and two-sided tests. Clinical trial information: NCT04670588.
Minimal residual disease assessment in colorectal cancer (MiRDA-C).
Authors: Dasari Arvind , Abdelrahim Maen , Acoba Jared David , Alluri Krishna Chaitanya , Dragovich Tomislav , Kazmi Syed Mohammad Ali , Musher Benjamin Leon , Sun Ryan , Wong Lucas , You Y. Nancy , Zaiden Robert Anthony , Kopetz Scott 
Published: January 2022

TPS236 Background: Detection of circulating tumor DNA (ctDNA) in the bloodstream is emerging as a novel marker for identifying of radiographically occult microscopic or minimal residual disease (MRD) in colorectal cancer (CRC) patients (pts) after curative intent treatments. Accumulating data suggest that ct-DNA defined MRD is a highly specific prognostic biomarker for future recurrences with a lead time of several months and prospective clinical trials are being conducted using ct-DNA defined MRD as an integral biomarker for improving risk stratification for adjuvant chemotherapy decision making. However, large scale, prospective data regarding kinetics of ctDNA-defined MRD with accurate pre-analytical methodology for plasma isolation and paired clinical data are limited. Methods: In this multi-center, prospective observational study, 1,000 pts with resectable CRC (stages II – IV) without other active malignancies undergoing therapy with curative intent will be enrolled any time from time of diagnosis up to start of adjuvant therapy (or ≤ 3 months post curative surgery, whichever is earlier). All therapeutic and surveillance visits decisions are at the discretion of the treating physicians. Serial biospecimens including blood (in Cell-Free DNA BCT tubes) to be processed to plasma and buffy coat in ≤ 2 days and formalin fixed tumor tissue will be collected at key time points until the time of radiographic recurrence or up to 5 years of surveillance. Blood draws will be at study entry, after each line of neoadjuvant therapy, post-surgery, during and after adjuvant therapy in addition to each surveillance visit. These blood draws will be coordinated with pts’ standard of care visits in order to minimize additional venipunctures. Relevant clinical data including demographics, cancer history, treatment details and outcomes, serum tumor markers and genomic data will be collected at each time point. Samples will be evaluated retrospectively with a primary objective of evaluating sensitivity and specificity of post-operative MRD for radiographic recurrences utilizing Guardant Health’s Reveal assay. Other key objectives include evaluating ctDNA kinetics with neoadjuvant and adjuvant therapies and to correlate with outcomes. The study is active, and enrollment is ongoing. Clinical trial information: NCT04739072.
PIONEER: A multicenter, open-label, randomized phase II trial of second-line apatinib plus chemotherapy versus chemotherapy alone in gastric and gastroesophageal junction adenocarcinoma (GA/GEA) refractory to or intolerant of prior anti-PD-1 therapy.
Authors: Yu Dandan , Liu Hongli , Hu Jianli , Ma Hong , Xue Jun , Liu Junli , Wang Jing , Lin Zhenyu , Jin Min , Yang Shengli , Zhao Lei , Zhang Tao 
Published: January 2022

TPS361 Background: Immunotherapy has revolutionized landscape of cancer treatment. Anti-PD-1 therapy provides significant clinical benefit and durable response in various types of cancers. However, clinical response rate to anti-PD-1 therapy has been reported to vary from 10%-40% in different cancers. And, a substantial number of patients who initially responded to anti-PD-1 therapy developed acquired resistance over time. Few effective treatment options are available for such patients. Previous studies indicated that prior anti-PD-1 exposure might increase tumor response to anti-VEGFR2 (ramucirumab) plus chemotherapy in patients with advanced/metastatic GA/GEA. Apatinib, a highly selective VEGFR2 inhibitor, has been demonstrated to be efficacious and well-tolerated for the treatment of chemotherapy-refractory advanced GA/GEA. The PIONEER study is designed to evaluate the efficacy and safety of second-line apatinib plus chemotherapy in GA/GEA patients after prior anti-PD-1 therapy. Methods: PIONEER (NCT05029453) is a multicenter, open label, randomized phase II trial of second-line apatinib plus chemotherapy versus chemotherapy alone in patients with histologically confirmed advanced GA/GEA refractory to or intolerant of prior anti-PD-1 therapy for no less than 2 months. Patients must be ≥18 years of age, with ECOG PS of 0 or 1, and have measurable disease per RECIST v1.1, adequate organ function, and expected survival time of ≥12 weeks. Patients who previously received antiangiogenic agents (such as apatinib or ramucirumab), had concurrent or previous tumor history within past 3 years, or underwent anti-tumor therapy within 4-week of recruitment will be excluded. Approximately 60 patients will be randomized (1:1) to receive apatinib (500 mg orally qd) plus chemotherapy (docetaxel 60/75 mg/m2, d1 q3w, and nab-paclitaxel 125 mg/m2 d1 & d8 q3w or 260 mg/m2 d1 q3w) or chemotherapy alone until disease progression, unacceptable toxicity, or death. The primary endpoint is progression-free survival (PFS). The secondary endpoints are overall response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and adverse events (AEs) per NCI CTCAE v5.0. Patient enrollment has just started and is expected to be completed in June 2022. Clinical trial information: NCT05029453.
A single-arm phase II study of cabozantinib and atezolizumab in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC) who failed platinum-based chemotherapy.
Authors: Kuo Hung-Yang , Guo Jhe-Cyuan , Huang Ta-Chen , Lin Chia-Chi , Lee Jang-Ming , Yeh Kun-Huei , Hsu Chih-Hung 
Published: January 2022

TPS364 Background: Patients with R/M ESCC failing platinum-based chemotherapy have grave prognosis. Anti PD-1 immune-checkpoint inhibitors (ICIs), by demonstrating survival benefits over 2nd-line chemotherapy in multiple phase III trials, have emerged as a new standard-of-care for patients with platinum-refractory R/M ESCC. However, the efficacy of anti-PD-1 ICIs remains modest with an objective response rate (ORR) of 17-20%; and the median overall survivals (OS) for these patients range from 8.2 to 10 months. Cabozantinib, a multikinase inhibitor, in combination with atezolizumab has been investigated in the phase Ib COSMIC-021 trial, which includes multiple cohorts of various cancer types including gastroesophageal cancer and head-and-neck cancer. Promising preliminary results were reported in lung cancer and genitourinary cancer cohorts. To investigate the combination of cabozantinib plus atezolizumab in patients with ESCC, a subtype of esophageal cancer that may be under-represented in the gastroesophageal cancer cohort of COSMIC-021 trial, we thus proposed this phase II trial to verify the hypothesis whether adding cabozantinib to atezolizumab would improve the outcomes of R/M ESCC patients who have failed platinum-based chemotherapy. Methods: This single institution single-arm phase II study includes patients with histologically confirmed R/M ESCC who failed at least one platinum-based chemotherapy. Patients with prior exposure of any ICI or kinase inhibitor are excluded. Patients enrolled will receive cabozantinib 40mg once per day and atezolizumab 1200mg once every three weeks until disease progression or intolerable toxicities. The primary endpoint of this study is the ORR evaluated by RECIST 1.1; and the key secondary endpoints include progression-free survival, OS, and toxicity profile. We hypothesize that combination of cabozantinib plus atezolizumab will improve the ORR from 15% to 30%. With one-sided, 0.1 type I error (α), 0.2 type II error (β, corresponding power: 0.8), the sample size will be 37. The study, registered with clinical trial ID of NCT05007613, started patient enrollment in Jun 2021. As of Sep of 2021, 5 patients have been enrolled. Clinical trial information: NCT05007613.
An open-label phase 2 study of lenvatinib plus pembrolizumab in the neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma (EPOC2001).
Authors: Kawazoe Akihito , Wakabayashi Masashi , Furuya Hideki , Sato Akihiro , Sakamoto Naoya , Kuwata Takeshi , Kinoshita Takahiro , Shitara Kohei 
Published: January 2022

TPS372 Background: Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. A phase 2 study demonstrated remarkable clinical activity of lenvatinib plus pembrolizumab for advanced gastric cancer with objective response rate of 69% (Kawazoe A, et al. Lancet Oncol. 2020), leading to the global phase 3 LEAP-015 trial at first-line (NCT04662710). The objective of this study is to evaluate anti-tumor activity of lenvatinib with pembrolizumab as neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma. Methods: The study is an open-label, single-arm, single-center, phase 2 clinical trial. Eligible patients are with previously untreated gastric and gastroesophageal junction adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Patients will receive 3 cycles of 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks as the neoadjuvant treatment followed by surgery, and then 3 cycles of lenvatinib plus pembrolizumab followed by 11 cycles of pembrolizumab monotherapy as the adjuvant treatment. The primary endpoint is major pathological response rate, and the secondary endpoints are pathological complete response rate, tumor shrinkage effect on primary lesions, radical resection rate, treatment completion rate until surgery or adjuvant treatment, event-free survival, overall survival, and incidence of adverse events. We also investigate several biomarkers using pre- and post-treatment tumor and blood samples. First patient will be enrolled in November 2021. Clinical trial information: NCT04745988.