A phase II trial of trastuzumab plus modified-FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer (BTC): Multi-institutional study of the Korean Cancer Study Group (KCSG-HB19-14).

TPS4161 Background: Biliary tract cancer (BTC), one of the most fatal cancers with limited treatment options, is generally rare in most high-income countries, but is relatively prevalent in South Korea. Recent genomic profilings have provided druggable molecular targets including HER2 amplification, which accounts for about 15% of total BTC patients. Trastuzumab is a humanized monoclonal antibody against HER2 with known efficacy in patients with HER2-positive breast and gastric cancer, and has not been tested prospectively in patients with HER2-positive BTC. The modified-FOLFOX regimen is currently being tested as a second-line therapy of BTC in phase III ABC-06 trial. This phase II study is investigating the combination of trastuzumab and modified-FOLFOX as second- or third-line treatment in HER2-postivie BTC. Methods: This study (KCSG-HB19-14; NCT04722133) is a phase II, multi-institutional, single arm trial to evaluate the efficacy and safety of trastuzumab plus modified-FOLFOX in gemcitabine/cisplatin refractory patients with HER2-positive BTC. The main inclusion criteria are HER2-positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/CEP17 ≥2.0, or ERBB2 gene copy number ≥ 6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (one or two previous cytotoxic chemotherapy lines permitted), ECOG 0 or 1, and adequate organ function. Patients receive trastuzumab-pkrb 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The study has a Simon's two-stage design, with objective response rate (ORR) per RECIST v1.1 as primary endpoint. Secondary endpoints included progression-free survival, disease control rate, overall survival, safety, quality of life and correlative biomarker exploration. Additional patients were to be recruited if pre-specified thresholds for ORR are met at the first stage. The study will enroll up to 34 patients and is currently recruiting at eight sites in South Korea. As of February 2021, 16 patients have been enrolled. The pre-specified activity goal for the first stage of accrual was met; second stage accrual began in February 2021. Clinical trial information: NCT04722133.

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A single arm, prospective multicenter phase II study FOLFIRINOX in patients with advanced and recurrent biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.tps514 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. TPS514-TPS514 ◽

Cited By ~ 3

Author(s):

Naminatsu Takahara ◽

Hiroyuki Isayama ◽

Yousuke Nakai ◽

Tatsuya Ioka ◽

Masashi Kanai ◽

...

Keyword(s):

Disease Progression ◽

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Intravenous Infusion ◽

Tumor Response ◽

Phase Ii Study ◽

Phase Iii ◽

Open Label ◽

Tract Cancer

TPS514 Background: The current standard of care for patients with advanced biliary tract cancer (BTC) is gemcitabine and cisplatin (GC) combination chemotherapy. Despite intensive researches, no trials have proved better overall survival (OS) over GC. Recently, FOLFIRINOX provided a remarkable survival benefit over gemcitabine in patients with metastatic pancreatic cancer. Given the promising results of FOLFIRI and FOLFOX in patients with advanced BTC, FOLFIRINOX can be an attractive option in patients with advanced BTC as well. Methods: This is a single-arm, open-label, multi-center phase II study to evaluate the safety and efficacy of FOLFIRINOX in patients with advanced BTC. The major inclusion criteria are as follows; unresectable or recurrent BTC, histologically or cytologically confirmed adenocarcinoma, no prior chemotherapy or radiation therapy, age of 20-75 years, an ECOG PS of 0 or 1, at least one measurable lesion, adequate hematological, liver and renal function. The major exclusion criteria are as follows; UGT genetic polymorphisms of homozygous UGT1A1*6 or *28 or heterozygous UGT1A1*6 and *28, massive pleural effusion or ascites. FOLFIRINOX consists of oxaliplatin of 85 mg/m2, irinotecan of 180 mg/m2, leucovorin of 400 mg/m2 administered by intravenous infusion and fluorouracil of 400 mg/m2 by intravenous bolus and of 2,400 mg/m2 by continuous intravenous infusion every 2 weeks. The primary outcome is progression-free survival (PFS), and the secondary outcomes are OS, tumor response and safety. PFS and OS will be calculated from the date of enrollment until the date of documentation of disease progression or death in patients without disease progression and the date of death. Tumor response will be evaluated according to the RECIST version 1.1 every 2 months. Safety will be evaluated with the CTCAE version 4.0. A total of 35 patients will be required to provide 75% power to detect an increase in median PFS from 6 months provided by standard care of GC to 10 months in patients receiving FOLFIRINOX, with a 24 months of recruitment and 18 months of follow-up. A phase III trial will be considered when this study shows the lower limit of the 80% confidence interval for PFS is longer than 6 months. Clinical trial information: UMIN000020801.

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Lenvatinib Plus PD-1 Inhibitors as First-Line Treatment in Patients With Unresectable Biliary Tract Cancer: A Single-Arm, Open-Label, Phase II Study

Frontiers in Oncology ◽

10.3389/fonc.2021.751391 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qiyi Zhang ◽

Xingyu Liu ◽

Shumei Wei ◽

Lufei Zhang ◽

Yang Tian ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Phase Ii Study ◽

Objective Response ◽

Pathologic Response ◽

Line Treatment ◽

First Line ◽

Tract Cancer ◽

First Line Treatment

ObjectiveWe investigated lenvatinib plus programmed cell death-1 (PD-1) inhibitors as a first-line treatment for initially unresectable biliary tract cancer (BTC).MethodsIn this Phase II study, adults with initially unresectable BTC received lenvatinib (body weight ≥60 kg, 12 mg; <60 kg, 8 mg) daily and PD-1 inhibitors (pembrolizumab/tislelizumab/sintilimab/camrelizumab 200 mg or toripalimab 240 mg) every 3 weeks. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included surgical conversion rate, disease control rate (DCR), event-free survival (EFS), overall survival (OS) and tumor biomarkers.ResultsAmong 38 enrolled patients, the ORR was 42.1% and the DCR was 76.3%. Thirteen (34.2%) patients achieved downstaging and underwent surgery, six of whom (46.2%) achieved a major pathologic response (n=2) or partial pathologic response (n=4) in the primary tumor. In total, 84.2% of patients experienced ≥1 treatment-related adverse event (TRAE), 34.2% experienced a Grade ≥3 TRAE and no treatment-related deaths occurred. After a median follow-up of 13.7 months the median EFS was 8.0 months (95% CI: 4.6–11.4) and the median OS was 17.7 months (95% CI: not estimable).ConclusionsLenvatinib plus PD-1 inhibitors showed promising anti-tumor efficacy in patients with initially unresectable BTC and was generally well tolerated.Clinical Trial Registrationwww.chictr.org.cn, ChiCTR2100044476.

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A phase II trial of modified gemcitabine plus S-1 combination as the first-line treatment in patients with advanced biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.417 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 417-417

Author(s):

Nai-Jung Chiang ◽

Jen-Shi Chen ◽

Ming-Huang Chen ◽

Shih-Hung Yang ◽

Chiun Hsu ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Null Hypothesis ◽

Dose Intensity ◽

Progression Free Survival ◽

Phase Iii ◽

Standard Regimen ◽

Tract Cancer ◽

To Receive

417 Background: Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC) nowadays. Recent randomized phase II study (JCOG0805) showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a randomized phase III, UMIN 000001685, is currently ongoing to compare the efficacy of gemcitabine plus either S-1 (GS) or cisplatin (GC) in ABTC. Herein, we report the results of a single arm phase II of modified GS in Taiwanese ABTC patients, NCT02425137. Methods: Patients with chemonaïve ABTC were eligible to receive 800mg/m2 gemcitabine with 10 mg/m2/min infusion, on day 1 plus daily 80/100/120 mg of S-1 (based on BSA) days 1-10, in a 2-week cycle. With Optimal Simon’s two-stage design and (p0= 0.4, p1= 0.6) for 12-week disease control rate (proportion of patients with complete or partial response [CR/PR] or stable disease ≥ 12 weeks [SD≥ 12weeks]) and given error probabilities (alpha = 0.05, beta = 0.2), the null hypothesis (p0) would be rejected if 24 or more patients with CR/PR/SD≥ 12weeks were observed among 46 accruals. Tumor response was assessed by CT/MRI every 6 weeks according to RECIST v1.1. Results: Between May 2015 and April 2016, totally 46 evaluable patients were enrolled to receive a median of 9.5 cycles (range: 3-31) of modified GS. After a median of 8.7 months (95% CI, 6.7-9.1) follow-up, 10 (21.7%) patients achieved PR and additional 23 (50%) had SD>12weeks. The median progression-free survival and overall survival was 5.6 (95% CI, 4.4-7.2) and 10.8 (95% CI, 7.6-not reached) months, respectively. All grade 3 treatment-related AEs were < 5%. The dose intensity of S-1 and gemcitabine were both more than 95%. Conclusions: By the observation of 33 patients with PR/SD≥ 12weeks, the null hypothesis was rejected. Modified GS is an active regimen with excellent safety profiles and deserves further investigation for the management of Asian ABTC patients. Clinical trial information: NCT 02425137.

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Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline

Journal of Clinical Oncology ◽

10.1200/jco.18.02178 ◽

2019 ◽

Vol 37 (12) ◽

pp. 1015-1027 ◽

Cited By ~ 61

Author(s):

Rachna T. Shroff ◽

Erin B. Kennedy ◽

Melinda Bachini ◽

Tanios Bekaii-Saab ◽

Christopher Crane ◽

...

Keyword(s):

Decision Making ◽

Clinical Practice ◽

Adjuvant Therapy ◽

Biliary Tract ◽

Clinical Practice Guideline ◽

Biliary Tract Cancer ◽

Phase Iii ◽

Extrahepatic Cholangiocarcinoma ◽

Tract Cancer ◽

Randomized Controlled

PURPOSE To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population. RESULTS Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria. RECOMMENDATIONS Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

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A phase II study of gemcitabine as adjuvant treatment for biliary tract cancer after surgical resection.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.330 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 330-330 ◽

Cited By ~ 1

Author(s):

Sang Myung Woo ◽

Kyong-Ah Yoon ◽

Eun Kyung Hong ◽

Weon Seo Park ◽

Sung-Sik Han ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Vascular Invasion ◽

Phase Ii Study ◽

Cytidine Deaminase ◽

Hematologic Toxicity ◽

Open Label ◽

Extrahepatic Cholangiocarcinoma ◽

Tract Cancer

330 Background: The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. Methods: This clinical phase II study was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patents received gemcitabine 1000 mg/m2as an intravenous 30-min infusion on day 1, 8, and 15 for every 28 days. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry and eight SNPs in the CDA, hENT1, dCK, hCNT3 and RRM1 genes were evaluated. The relationship of each with patients’ clinical outcomes was assessed. Results: From January 2010 to July 2014, a total of 72 BTC patients (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma) were enrolled. At a median follow-up was 38.09 months (range: 4.14-68.29), 2-year recur- free survival (RFS) was 43% (95% CI, 33% to 57%). The most common grade 3 and 4 toxicity was neutropenia, which occurred in 8 patients (11%). There was one treatment-related death from pneumonitis. The Cox proportion hazard model was performed with the following nine variables; gross type, degree of tumor differentiation. pathologic T factor, N stage, vascular invasion, perineural invasion, lymphatic invasion, dosage, and each protein expression. In the multivariable model, DCK expression, vascular invasion, and lymph node metastasis, were significantly associated with RFS. None of the tested SNPs was significantly associated with RFS or with any hematologic or non-hematologic toxicity. Conclusions: Although the primary hypothesis of this study, defined as a 2-year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted. Clinical trial information: NCT01043172.

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A single-arm phase II trial of gemcitabine, oxaliplatin, and panitumumab in KRAS wild-type advanced biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.255 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 255-255

Author(s):

Marcus Smith Noel ◽

Jill N. Allen ◽

Thomas Adam Abrams ◽

Matthew Yurgelun ◽

Jason Edward Faris ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Performance Status ◽

Objective Response ◽

Gallbladder Perforation ◽

Wild Type ◽

Gastrointestinal Malignancies ◽

Egfr Inhibition ◽

Tract Cancer

255 Background: Biliary Tract Cancer (BTC) encompasses a group of aggressive, genetically heterogeneous tumors with limited systemic treatment options. Currently platinum and gemcitabine-based therapy is the standard first-line treatment. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRASwild-type genetic subtypes of colon cancer. Methods: Patients with histologically confirmed, previously untreated unresectable or metastatic KRAS wild type biliary tract or gallbladder adenocarcinoma with ECOG performance status (PS) 0-2 were eligible. Patients were treated with Panitumumab 6mg/kg, Gemcitabine (GEM) 1000 mg/m2 (10 mg/m2/min), Oxaliplatin (OX) 85 mg/m2on days 1 and 15 of each 28 day cycle. The primary objective was to determine the objective response rate (ORR) by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression free survival (PFS), and overall survival. Results: Of the 38 patients screened, 31 patients were found to have KRAS wild type genotype and enrolled. The median age was 61 years old, 55% males, 100% of patients had an ECOG PS of <1. Twenty-five patients had intrahepatic cholangiocarcinoma, and 3 each had extrahepatic and gall bladder carcinoma. Twenty-eight patients completed at least 2 cycles of therapy and were evaluable for response. The ORR was 50% (95% CI 23.8-76.2). With a median follow-up of 11 months, median PFS was 10.5 months (95% CI, 3.8 - 23.9 months) and median OS was 24.8 months (95% CI, 9.0 months-no upper bound). The most common grade 3 toxicities were fatigue 23%, anemia 23%, neuropathy 16%, elevated AST/ALT 16%, hyponatremia 13%, nausea 13%, rash 10%, neutropenia 7%, and hypomagnesemia 7%. Grade 4 toxicities included leukopenia 10%, and 1 case (3%) each of gallbladder perforation, hematoma, anemia, hyperkalemia, hyponatremia and hypokalemia. Conclusions: Completed analysis of this phase II study of GEMOX-panitumumab for KRAS wild type advanced BTC reveals encouraging results with promising response rates and PFS. The toxicity profiles were expected and manageable. Further investigation of this regimen and anti-EGFR therapy is warranted. Clinical trial information: NCT01308840.

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Multicenter phase II study of trastuzumab deruxtecan (DS-8201) for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps4654 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS4654-TPS4654 ◽

Cited By ~ 2

Author(s):

Akihiro Ohba ◽

Chigusa Morizane ◽

Makoto Ueno ◽

Satoshi Kobayashi ◽

Yasuyuki Kawamoto ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Primary Endpoint ◽

Biliary Tract Cancer ◽

Topoisomerase I ◽

Phase Ii Study ◽

Pathological Examination ◽

Her2 Positive ◽

Durable Response ◽

Tract Cancer

TPS4654 Background: Biliary tract cancer (BTC) is one of the most lethal cancers with limited treatment options. Early clinical trials showed a hint of activity of HER2 blockade for HER2 positive BTC, the prevalence of which was reported to be from 5% to 20%. Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable terapeptide-based linker, and a topoisomerase I inhibitor, which showed durable response in HER2 positive breast cancer as well as in a wide spectrum of cancer subtypes in a phase I study. In addition, preclinical research demonstrated the effectiveness of trastuzumab deruxtecan for HER2 positive BTC patient derived xenograft model. This phase II study is being conducted to evaluate the efficacy and safety of trastuzumab deruxtecan for HER2 positive BTC. Methods: The main inclusion criteria are unresectable or recurrent BTC, histologically diagnosed as adenocarcinoma or adenosquamous carcinoma, confirmed HER2-expressing status by central pathological examination, refractory or intolerant to treatment including gemcitabine, and adequate organ function. Patients are registered and receive 5.4 mg/kg trastuzumab deruxtecan every 3 weeks until disease progression or unacceptable toxicities. Primary endpoint is the overall response rate (ORR) in HER2 positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/ CEP17 ≥2.0) patients by central imaging review. The ORR in all HER2-expressing patients (including HER2 low expressing defined as IHC/ISH status of 0/+, 1+/-, 1+/+, or 2+/-), progression-free survival, overall survival, and incidence of adverse events are assessed as secondary endpoints. Thirty-two patients will be enrolled, including 24 with HER2 positive BTC as primary cohort and 8 with HER2 low expressing BTC. The study has 80% power for primary endpoint in HER2 positive BTC patients, with one-sided alpha error of 5%; threshold ORR of 15% and expected ORR of 40%. Pharmacokinetics and circulating tumor DNA analyses serially are performed. The study was initiated in May 2019 with enrollment ongoing. A total of 15 patients were enrolled as of January 2020. Funding: Japan Agency for Medical Research and Development, and Daiichi Sankyo. Clinical trial information: JMA-IIA00423 .

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