scholarly journals A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Hirva Mamdani ◽  
Bryan Schneider ◽  
Susan M. Perkins ◽  
Heather N. Burney ◽  
Pashtoon Murtaza Kasi ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Phase Ii ◽  
Residual Disease ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
M2 Macrophages ◽  
Activated T Cells ◽  
Trimodality Therapy ◽  
Surgical Specimen

BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

Phase II study of perioperative toripalimab in combination with FLOT in patients with locally advanced resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4050-4050
Author(s):  
Hongli Li ◽  
Jingyu Deng ◽  
Shaohua Ge ◽  
Fenglin Zang ◽  
Le Zhang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Death Receptor ◽  
Disease Free Survival ◽  
Complete Response ◽  
R0 Resection ◽  
Combination Regimen

4050 Background: FLOT is the standard perioperative treatment for resectable gastric /gastroesophageal junction (GEJ) adenocarcinoma. However, patient’s outcome is still poor. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in various cancers. This trial evaluates the addition of Toripalimab to FLOT for resectable patients. Methods: This is a prospective, single-arm, investigator-initiated phase II trial. Patients with histologically confirmed, resectable, gastric and GEJ adenocarcinoma (≥cT2 or cN+) were enrolled to receive 4 pre-and post-operative cycles of toripalimab (240mg, q2w) plus FLOT (docetaxel 50 mg/m2; oxaliplatin 85 mg/m2; leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2w). The primary endpoint was pathological complete response rate (pCR). The secondary endpoints included major pathological (complete and nearly complete) response (MPR), and R0-resection rate, 3-year disease-free survival rate, overall survival, and adverse events. Results: In total, of 36 patients were enrolled from June 2019 through Dec 2020. Male, 66.7%; median age, 60y; cT3 8.3%, T4, 83.3%; cN+ 88.9%; GEJ 47%; MSI-H, 5.6%, Her-2neu-positive, 5.6%, EBER-positive, 5.6%). Two patients refused surgery, six patients have not yet completely neoadjuvant treatment. 100% of patients completed the 4 pre-cycle. Patients who had received gastrectomy after neoadjuvant treatment (n=28) were included in this analysis. 6 (21%) patients had operations involving a thoracic approach (oesophagogastrectomy with two field lymphadenectomy), 21 (75%) gastrectomy with D2 lymphadenectomy. 8 (29%) evaluable patients had Clavien-Dindo grade II post-operative complications and 2 (7%) grade IIIA complications; one patient had an anastomotic leakage that was treated endoscopically. There were no emergency re-operations. All 28 patients achieved R0-resection and were discharged home after a median of 12 days (range:7-63) in hospital. 7 （25%）patients achieved pCR (TRG1a) and 12 (42.9%) patients achieved major pathologic response (MPR, TRG1a/b). Treatment-related adverse events (TRAEs) to any drug were reported in 30 (94%) patients. Mostly TRAEs were grade 1-2, the grade 3 or 4 TRAEs included neutropenia (34%), neutropenia (25%), lymphopenia (3%), Alanine aminotransferase increased (3%), hypokalemia (3%) and anaemia (3%). Conclusions: Perioperative toripalimab in combination with FLOT showed promising efficacy with high pCR and MPR rate and well tolerated safety profile in patients with resectable gastric/GEJ adenocarcinoma. This combination regimen might present a new option for patients with locally advanced, resectable gastric/GEJ adenocarcinoma. Clinical trial information: NCT04354662.

Safety and efficacy of durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Two-year follow-up results from Big Ten Cancer Research Consortium study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 404-404 ◽  
Author(s):  
Hirva Mamdani ◽  
Bryan J. Schneider ◽  
Pashtoon Murtaza Kasi ◽  
Laith I. Abushahin ◽  
Thomas J. Birdas ◽  
...  
Keyword(s):  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
R0 Resection ◽  
Trimodality Therapy ◽  
Surgical Specimen ◽  
Safety And Efficacy ◽  
Grade 3

404 Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. No adjuvant tx has been shown to improve survival in these pts. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulate PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who have residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: 24 pts were enrolled from 4/2016-1/2018(median age: 60yrs (range, 43-70). 18 received carbo/paclitaxel and 6 received cis/5-FU concurrently with radiation. Staging at diagnosis: T2N0(n = 3, 12.5%), T2N2(n = 3, 12.5%),T3N0(n = 6, 25%), T3N1(n = 6, 25%), T3N2(n = 4, 17%), T3N3(n = 1, 4%), T3Nx(n = 1, 4%).19 pts(79%) had positive lymph nodes(LNs) at the time of surgery following CRT. 12 pts completed 1yr of tx, 12 came off tx because of relapse(6), AEs(5), and consent withdrawal(1). Most common AEs were fatigue(n = 8, 33.3%) and nausea(n = 6, 25%). 3pts (12.5%) developed grade 3 irAEs: pneumonitis(1), hepatitis(1), colitis(1). At median follow up of 21.9mo(range, 1.7-23.9mo), 11 pts have relapsed: 9 distant and 2 locoregional. Two of 3 pts with grade 3 irAEs are alive and disease free at 17 and 23 mo respectively. 1-yr RFS and OS were 79.2% and 95.5%, respectively. RFS at 26 mo was 20.6%. Overall mOS and mOS after relapse were 28.1mo(range, 22.9-28.1) and 11.1 mo(range, 0.1-11.3mo) respectively. The study was expanded to enroll 14 additional pts who are currently undergoing tx. Conclusions: Adjuvant durvalumab following trimodality therapy for LA-EAC and GEJ adenocarcinoma is safe with improvement in 1-yr RFS to 79.2% compared to historical rate of 50%. RFS was 20.6% at 26 months. Evaluation of predictive biomarkers of RFS with durva is underway. Clinical trial information: NCT02639065.

scholarly journals TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2839
Author(s):  
Alessandra Raimondi ◽  
Federica Palermo ◽  
Michele Prisciandaro ◽  
Massimo Aglietta ◽  
Lorenzo Antonuzzo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Operative Management ◽  
High Rate ◽  
High Status ◽  
Gastroesophageal Junction Cancer ◽  
Neoadjuvant Immunotherapy ◽  
Non Operative Management

In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

Phase II trial of preoperative (POP) irinotecan (I) + cisplatin (C) and radiotherapy for esophageal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4056-4056
Author(s):  
A. L. Visbal ◽  
G. Darling ◽  
R. Wong ◽  
M. Guindi ◽  
J. Hornby ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Perioperative Complications ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
R0 Resection ◽  
Thoracic Esophagus

4056 Background: Esophagectomy (E) for locally advanced esophageal cancer (LAEC) yields limited survival; this phase II trial assess feasibility and efficacy of induction chemo-radiotherapy followed by E. Methods: Patients (pts) with LAEC of the thoracic esophagus (TE) or gastroesophageal junction (GEJ), ECOG PS ≤ 2 and surgical candidates underwent POP I (65mg/m2) + C (30mg/m2) on weeks 1,2,4,5,7,8 + concurrent conformal radiotherapy (40Gy/20 fractions (F) during wk 4–7) and external beam boost (10Gy/5F on wk 8); E was performed on wk 12–16 after restaging. Pts receiving 75% of POP chemotherapy were eligible for pathologic (p) evaluation; planned sample size 36 nonM1A pts. Results: 52 pts enrolled from 11/02 to 12/05, mean age 60 yr (33–79), male:40, GEJ:TE/15:37; 37 adenocarcinoma, 13 SCC, 2 other; 13 pts were stage IIA, 7 IIB, 22 III, and 10 IVA. Toxicity during POP treatment included ANC (G3/4:36%), febrile neutropenia (9%), diarrhea (G3:9%), nausea (G3:6%), esophagitis (G3:2%) and anorexia (G3/4:15%); 3 pts stopped treatment due to toxicity, 2 withdrew, 2 progressed becoming non-operable, 1 died of a stroke and 1 from central line sepsis. Clinical response by RECIST was CR:2%, PR:30%, SD:62% and PD in 6%. Dysphagia improved or resolved in 34/47 pts (72%) during POP treatment. Of 43 evaluable pts, 41 underwent E, achieving R0 resection in 98% (1 refused E, 1 pending). Perioperative complications included anastomotic leak (23%), Afib (21%), pneumonia (21%), delirium (10%) and aspiration (10%); 1 pt died from aspiration. 7 pts (17%) achieved pCR, 2 of whom were pretreatment clinical stage IIA, 1 IIb and 4 III; downstaging occurred in 3/7 pts; 15 pts (36.6%) achieved minimal residual disease, 15 (36.6%) pPR, and 4 (9.8%) pSD. At a median (med) follow-up of 15.2 months (1.3–34.5m), 16/52 patients died (med & 2yr overall survival (OS) of 29 m & 66%). Of 41 resected pts, 17 recurred (med & 2yr disease free survival (DFS) of 20m & 46%) of whom 10 died of progression (med & 2-yr OS of 29m & 68.4%). 2yr DFS & OS was 83% & 86% in pCR vs 41% & 76% in non-pCR. Conclusion: In LAEC, induction I/C and radiotherapy followed by E is associated with 72% dysphagia improvement, a significant but manageable toxicity profile, and encouraging survival compared to historical controls. [Table: see text]

Phase II clinical trial using anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) for HER2-negative (0-2+) metastatic breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1080-1080
Author(s):  
Lawrence G. Lum ◽  
Archana Thakur ◽  
Zaid S. Al-Kadhimi ◽  
Abhinav Deol ◽  
Michael S. Simon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Tumor Markers ◽  
Phase Ii ◽  
Bispecific Antibody ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Activated T Cells ◽  
Her2 Breast Cancer

1080 Background: This study presents a phase II cell therapy trial in 32 women with metastatic or locally advanced HER2- breast cancer (BrCa) who received infusions of anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (BATs). This phase II study (NCT 01022138) was conducted to determine if BATs infusions could improve time to progression (TTP) and overall survival (OS), as well as to confirm the toxicity profile of BATs. Methods: The phase II included 32 patients with a median of 4 lines of therapy (7 TNBC and 25 HR/PR+ HER2- patients) with an average age of 52.5 years (range 28-75 years). Twenty-one patients had ≥3 lines of prior therapy and 11 patients had 1-2 lines. Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD3 antibody and expanded in IL-2, armed with HER2Bi, and aliquoted for the clinical trial. Patients received oncologist’s choice of chemotherapy (4 cycles/4 months) followed by 3 infusions of BATs given once per week for 3 weeks and a boost given 12 weeks after the 3rd infusion. Results: Fifteen of 32 (ORR of 46.8%) who had received any cells had stable disease (SD) at 1 month after the last infusion, and 8 of 15 (25%) had SD > 4 months. For patients who completed 3 or 4 infusions (17-83 x 109 BATs), 8 of 31 patients had TTP > 4 months. One patient completed 2 infusions (17 x 109 BATs). There were no dose limiting toxicities (DLTs). Tumor markers decreased in 13 of 23 (56.5%) patients with evaluable markers. The median OS was 13.8, 16.5, and 12.4 months for all, ER/PR+, and TNBC, respectively. OS for all patients with chemosensitive (chemoS) and chemoresistant (chemoR) disease was 14.6 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in HER2- ER/PR+ patients was 16.5 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in TNBC patients was 12.4 and 22.6 months, respectively (NS). The median TTP for all, HER2- ER/PR+, and TNBC patients was 2.7, 2.9, and 1.4 months, respectively. Increases in serum IL-2 and IL-12 were associated with BATs infusions. Conclusions: Targeting HER2- tumors was safe. There were trends toward improved survival in patients who were HER2-/ER/PR+ TNBC, patients who were chemoS, was associated with increased TTP and OS in all groups, and was associated with decreased tumor markers in those who received 4 infusions. Immune studies showed evidence for induction of adaptive immunity directed at breast cancer antigens. Targeting metastatic HER2- BrCa with BATs shows promise. Clinical trial information: NCT 01022138.

Phase II trial of perioperative chemotherapy + avelumab in locally advanced gastroesophageal adenocarcinoma: Preliminary results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4046-4046
Author(s):  
Thierry Alcindor ◽  
Touhid Opu ◽  
Arielle Elkrief ◽  
Farzin Khosrow-Khavar ◽  
Carmen L. Mueller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Tumor Regression ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Daily Intake ◽  
Disease Free Survival ◽  
Type I ◽  
Perioperative Chemotherapy ◽  
Preliminary Results ◽  
Gastroesophageal Adenocarcinoma

4046 Background: Perioperative chemotherapy improves cure rate in locally advanced gastroesophageal adenocarcinoma (GEA), and immune checkpoint inhibitors are active at the metastatic stage. This trial tests the hypothesis that the addition of avelumab to perioperative chemotherapy will increase the major pathologic response (MPR) rate in comparison with historical controls. Methods: Phase II study of avelumab + chemotherapy (docetaxel, cisplatin and 5-FU or mDCF) given every 2 weeks for 4 cycles before and after surgery. Main inclusion criteria: GEA, cT3 and/or cN+, M0, WHO PS 0-1. Main exclusion criteria: use of immunosuppressants, serious autoimmune disease, daily intake >10 mg prednisone. Staging studies: CT, PET-CT, endoscopic ultrasound, diagnostic laparoscopy. Surgical resection: D2 lymphadenectomy, en-bloc esophagectomy for type I/II gastroesophageal junction (GEJ) tumors. Aim of the study: MPR as defined as tumor regression grades 0-1 (modified Ryan scheme); as per hypothesis, this experimental regimen will result in a 20% rate of MPR, compared with 7% with chemotherapy alone. Simon 2-stage design: if less than 2 MPR are seen in the first 16 patients, the study will be closed. The study hypothesis cannot be rejected if at least 6 MPR are seen in the first 50 patients. All adverse effects are prospectively recorded per CTCAE guidelines in patients who have received at least one treatment cycle. Survival rates are calculated with Kaplan-Meier method. Preliminary results are presented since the study has met its primary endpoint. Results: Feb 2018-Feb 2020: 28 patients enrolled (25 M/3 F, age 45-78). Location: GEJ (23), stomach (5). Staging: cT3 (25), cT4 (1), cN+ (20). Biomarkers expression: mismatch repair (MMR) protein loss (3/28); PD-L1(clone 73-10) expression in 1% (TPS) or more of tumor cells seen in 12/28 samples, and >10% in 6 patients. Grade 3 toxicity: stomatitis (2/28); nausea (2/28); vomiting (1/28); diarrhea (1/28); hypothyroidism (1/28); arthralgia (3/28); neutropenia (1/28). Grade 4 toxicity: pneumonia (1/28); neutropenia (2/28). Postoperative 30-day mortality: 0%. One patient was excluded from efficacy analyses for M1 staging; 27 patients underwent surgery, 26 with R0 (96%). Six cases (22%) show MPR: 3 grade 0 (11%) and 3 grade 1 (11%) tumor regressions. No correlation was seen between MMR proteins or PD-L1 expression and tumor regression. With a median follow-up of 1.5 years (range 0.4-2.5), the disease-free survival rate is projected to be 0.92 (95% CI 0.83-1.00) at 12 months and 0.77 (95% CI 0.58-1.00) at 24 months. Conclusions: The combination of mDCF chemotherapy with Avelumab demonstrates a promising safety and activity profile. Ongoing laboratory investigations are underway to correlate our findings with tumor molecular features before exposure to treatment. Clinical trial information: NCT03288350.

An open-label phase II study comparing two doses of MK-6482 for the treatment of advanced renal cell carcinoma (RCC) following progression on prior systemic therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS369-TPS369
Author(s):  
Michael B. Atkins ◽  
Yanfang Liu ◽  
Rodolfo F. Perini ◽  
Ananya Roy ◽  
John B. A. G. Haanen
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Survival Duration ◽  
Karnofsky Performance Scale ◽  
Open Label ◽  
Prior Systemic Therapy

TPS369 Background: Treatment options for RCC in the late-line setting after immunotherapy and vascular endothelial growth factor (VEGF)-targeted therapy are limited. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). The first-in-class small molecular HIF-2α inhibitor, MK-6482, recently showed promising antitumor activity in a cohort of heavily pretreated ccRCC patients (pts) and in pts with von Hippel-Lindau–disease-associated RCC for which the FDA granted Breakthrough Therapy Designation to MK-6482. Methods: This randomized, open-label, multicenter phase II trial will evaluate the efficacy and safety of 2 doses of MK-6482 in pts with advanced RCC who have experienced progression after prior systemic therapy (NCT04489771). Eligible pts are male or female aged ≥18 years with histologically confirmed locally advanced or metastatic ccRCC (measurable disease per RECIST v1.1) who have experienced progression after 1-3 prior systemic therapies comprising an anti-PD-1/L1 agent combined with a VEGF-targeted tyrosine kinase inhibitor (TKI) or an anti-cytotoxic T lymphocyte-associated antigen-4 agent and have undergone no more than 3 prior systemic regimens; and a Karnofsky Performance Scale ≥70. Treatment progression on anti-PD-1/L1 combination therapy was defined as pts who received at least 2 doses of anti-PD-1/L1 therapy and demonstrated radiographic disease progression as assessed by the investigator. Pts who have received prior treatment with MK-6482 or another HIF-2α inhibitor, and those requiring intermittent or chronic supplemental oxygen, or with a baseline hemoglobin less than 10 g/dL, a history of human immunodeficiency virus, hepatitis B or hepatitis C infection, or active central nervous system metastases will be excluded. Approximately 150 pts will be randomly assigned 1:1 to oral MK-6482 120 mg once daily (QD) or 200 mg QD; treatment will continue until progression, unacceptable toxicity, or withdrawal. Pts will be stratified by International Metastatic RCC Database Consortium prognostic scores (0, 1-2, 3-6) and the number of prior TKI-containing therapies (0, 1, or 2-3). Imaging with computed tomography or magnetic resonance imaging will be undertaken on Week 9 from the date of randomization, every 8 weeks through Week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. Safety will be analyzed using a tiered approach. This study is recruiting. Clinical trial information: NCT04489771 .

Phase II study of sintilimab combined with FLOT regimen for neoadjuvant treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 216-216
Author(s):  
Ning Li ◽  
Zhi Li ◽  
Qiang Fu ◽  
Bin Zhang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Gastroesophageal Junction ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
R0 Resection ◽  
Resection Rate ◽  
First Choice

216 Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer, increasing 5-year overall survival from 23% with surgery alone to 45% with FLOT, Although FLOT has been recognized as the first choice for neoadjuvant chemotherapy in gastric or GEJ adenocarcinoma, its efficacy needs to be improved. Sintilimab, a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in various cancers. We aimed to assess the activity and safety profile of the combination of FLOT and sintilimab for neoadjuvant treatment of gastric or GEJ adenocarcinoma. Methods: In this ongoing, single-arm, phase II study, we recruited patients from Henan Cancer Hospital in China with histopathologically diagnosed resectable gastric or GEJ adenocarcinoma who had clinical T3/N+ or higher stage. Patients were given 4 cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 80 mg/m2, leucovorin 200 mg/m2, fluorouracil 2600 mg/m2, 24-h infusion on day 1, q2w) in combination with 3 cycles of sintilimab (200mg, iv, d1, q3w), followed by D2 surgery and 4 postoperative cycles of FLOT. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and R0 resection rate and adverse events . Results: A total of 20 patients were enrolled in the study between Aug 10 2019 and Sep 15 2020. One patient refused surgery, one person's disease progressed. Two patients have not yet completed neoadjuvant treatment . 16 pts who experienced D2 resection, 10 (62.5%) achieved major pathologic response (MPR), including 3 (18.8%) with a pathologic complete response (pCR) in primary tumor. The R0 resection rate was up to 93.8%, The grade 3 or 4 treatment-related adverse events (TRAE) included lymphopenia(25%), anaemia (20%),fatigue (20%),leucopenia (15%), neutropenia (5%), diarrhea(5%), Alanine aminotransferase increased(5%),There was no surgical delays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of sintilimab and FOLT is a safe and efficacious treatment option for patients with gastric or GEJ adenocarcinoma, 18.8% pCR rate and 62.5%MPR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: NCT04341857.

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