Apatinib in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a single-arm, phase II prospective study

Background: Apatinib, a vascular endothelial growth factor receptor (VEGFR) blocker, has demonstrated encouraging antitumor activities and tolerable toxicities in various cancer types. Recurrent or metastatic adenoid cystic carcinoma of the head and neck (R/MACCHN) carries a poor prognosis, and treatment options are currently limited. This study was conducted to explore the antitumor activity and safety of apatinib in patients with R/MACCHN. Methods: In this phase II single-arm, prospective study, patients aged 15–75 years with incurable R/MACCHN received apatinib at a 500 mg dose once daily until intolerance or progression occurred. The primary endpoint was the 6-month progression-free survival (PFS) rate based on RECIST version 1.1. The secondary endpoints included response rate, overall survival (OS), and safety. Efficacy was assessed in all dosed patients with at least one post-baseline tumor assessment. Results: Among 68 patients treated with apatinib, 65 were evaluable for efficacy analysis, with a median follow-up time of 25.8 months. The 6-month, 12-month, and 24-month PFS rates were 92.3% [95% confidence interval (CI): 83–97.5%], 75.2% (95% CI: 61.5–84.0%) and 44.7% (95% CI: 32.3–57.5%), respectively. The objective response rate (ORR) and disease control rate (DCR), as assessed by investigators, were 46.2% (95% CI: 33.7–59.0%) and 98.5% (95% CI: 91.7–100.0%), respectively. The median duration of response was 17.7 months [interquartile range (IQR) 14.0–20.9]. The 12-month and 24-month OS rates were 92.3% (95% CI: 83.0–97.5%) and 82.3% (95% CI: 70–90.4%), respectively. The most common adverse events of grades 3–4 were hypertension (5.9%), proteinuria (9.2%), and hemorrhage (5.9%). One patient developed a fatal hemorrhage. Conclusion: An encouraging PFS, a high ORR, and a manageable safety profile were observed in this study. It seems that the administration of apatinib in R/MACCHN is likely to have a clinically meaningful therapeutic benefit and warrants further investigation. This study was prospectively registered in ClinicalTrials.gov (NCT02775370; date of registration: 17 May 2016; date of first patient enrollment: 25 May 2016)

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Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.18.01859 ◽

2019 ◽

Vol 37 (18) ◽

pp. 1529-1537 ◽

Cited By ~ 22

Author(s):

Vatche Tchekmedyian ◽

Eric J. Sherman ◽

Lara Dunn ◽

Crystal Tran ◽

Shrujal Baxi ◽

...

Keyword(s):

Adverse Events ◽

Adenoid Cystic Carcinoma ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Overall Response ◽

End Point ◽

Adenoid Cystic

PURPOSE Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC. PATIENTS AND METHODS This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how MYB expression and genomic alterations relate to outcomes was conducted. RESULTS Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician’s discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1). CONCLUSION This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.

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Weekly docetaxel and cisplatin with capecitabine and bevacizumab (AVDCX) in patients with advanced esophagogastric cancer: Results of a phase Ib/II study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15078 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15078-e15078

Author(s):

Ofer Purim ◽

Yulia Kundel ◽

Udi Sadeh Gonik ◽

Efraim Idelevich ◽

Gal Medalia ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Performance Status ◽

Treatment Options ◽

Objective Response ◽

Progression Free Survival ◽

Phase Ib ◽

Weekly Docetaxel ◽

Esophagogastric Cancer ◽

Dose Levels

e15078 Background: Many efforts are being made to improve treatment options for advanced esophagogastric cancer (AEGC). The aim of this phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods: Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). To assure regimen's safety a short phase Ib part, with three dose levels, was planned. The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX and to determine the tumor response rate. Results: The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%) and these were usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. Eventually, the recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). The objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. Eighteen patients (82%) derived a clinical benefit: improvement of pain, weight or performance status without a deterioration of any of these factors, from treatment. The median overall survival was 11.3 months (range, 1.5-39.2+ months) and median progression-free survival was 8.7 months (range, 1.3–26.6 months). The 2-year OS rate reached 22.7%. Conclusions: AVDCX was associated with bevacizumab-related fatal toxicities. It seems to reproduce the efficacy of bevacizumab regimen AVAGAST trial, without a clue for significant improvement over common docetaxel regimens in AEGC.

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Tumor Growth Rate as a Prognostic Factor for Metastatic or Recurrent Adenoid Cystic Carcinoma of the Head and Neck Patients Treated with Carboplatin Plus Paclitaxel

10.21203/rs.3.rs-26488/v1 ◽

2020 ◽

Author(s):

Naoki Fukuda ◽

Yu Fujiwara ◽

Xiaofei Wang ◽

Akihiro Ohmoto ◽

Tetsuya Urasaki ◽

...

Keyword(s):

Growth Rate ◽

Prognostic Factors ◽

Tumor Growth ◽

Adenoid Cystic Carcinoma ◽

Head And Neck ◽

Objective Response ◽

Progression Free Survival ◽

Tumor Growth Rate ◽

Adenoid Cystic ◽

Exploratory Investigation

Abstract Background: Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC.Methods: We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors including tumor growth rate (TGR) was conducted.Results: A total of 26 ACC patients were enrolled. ORR and DCR were 11.5% and 76.9%; the median PFS and OS were 8.1 and 22.3 months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) TGR was associated with worse PFS (hazard ratio [HR] 7.00, 95%CI 1.34–36.53, p = 0.02) and OS (HR 29.33, 95%CI 3.38–254.80, p < 0.01). The median PFS (10.6 vs. 6.6 months, log-rank p < 0.05) and OS (48.5 vs. 16.9 months, log-rank p < 0.01) were significantly shorter in patients with higher TGR.Conclusions: Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

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A randomized phase II study of pembrolizumab with or without radiation in patients with recurrent or metastatic adenoid cystic carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.6082 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 6082-6082 ◽

Cited By ~ 3

Author(s):

Jonathan Daniel Schoenfeld ◽

Umair Mahmood ◽

Yu-Hui Chen ◽

Raymond H. Mak ◽

Jochen H. Lorch ◽

...

Keyword(s):

Adenoid Cystic Carcinoma ◽

Phase Ii ◽

Randomized Study ◽

Objective Response ◽

Progression Free Survival ◽

Distant Recurrence ◽

High Rate ◽

Tumor Growth Rate ◽

Adenoid Cystic ◽

Immune Biomarkers

6082 Background: Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by a high rate of distant recurrence. Systemic therapy has generally failed to produce durable benefit. Radiation (RT) is used for localized disease and as directed treatment for metastases. Here, we report the safety and efficacy of pembrolizumab (pembro) administered with or without hypofractionated RT in a phase II randomized study. Methods: Eligible patients (pts) had recurrent or metastatic ACC with evidence of progressive disease (PD) within the last 12 mos and >=1 measurable non-CNS lesion, along with 1-5 additional lesions deemed appropriate for RT to 30 Gy in 5 fractions. Pts were randomized to pembro alone (200 mg IV q3 weeks) or in combination with RT given within 7 days of cycle 1, day 1. The primary endpoint was objective response rate (ORR) outside the RT field by RECIST 1.1. Using a parallel two-stage design, if >=1 response out of 10 was observed in either arm, 10 more pts would be enrolled to that arm. If >=3 responded, the null hypothesis (ORR=5%) would be rejected in favor of a 25% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses of tumor growth rate (TGR) excluding RT lesions and immune biomarkers were exploratory. Results: Ten pts per arm were randomized into the trial’s first stage with median age 65 (45-79). No objective responses were seen. Stable disease (SD) was observed in 13 pts; 6 had PD as best response, 1 was unevaluable. Median PFS was 7 mos 95% CI (3 - 13 mos), with 9 pts without progression at 6 mos. 3 pts remain on study treatment (range 8-11 mos). In pts with SD, TGR decreased by >25% in 7 of 12 pts and by >75% in 4 pts. There was no difference in likelihood of SD or PFS between arms. Treatment related AEs (TRAEs) occurred in 18 pts but there were no G3-5 TRAEs. Among 8 biopsies analyzed, PD-L1+ tumor/immune cells ranged from 12-52%. Conclusions: Pembro alone or with hypofractionated RT was well tolerated. We observed no objective responses, but 65% of pts with PD prior to study entry achieved SD, the majority with decreased TGR, and 15% had prolonged SD. Additional strategies are needed to further delay progression and effect response. Clinical trial information: NCT03087019.

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Randomized phase II study of axitinib versus observation in patients with recurred or metastatic adenoid cystic carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6503 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6503-6503 ◽

Cited By ~ 1

Author(s):

Bhumsuk Keam ◽

Eun Joo Kang ◽

Myung-Ju Ahn ◽

Chan-Young Ock ◽

Keun Wook Lee ◽

...

Keyword(s):

Adverse Events ◽

Randomized Trial ◽

Adenoid Cystic Carcinoma ◽

Phase Ii ◽

Objective Response ◽

Progression Free Survival ◽

Phase Ii Trials ◽

Adenoid Cystic ◽

Observation Methods ◽

Duration Of Response

6503 Background: Adenoid cystic carcinoma (ACC) does not respond to cytotoxic chemotherapy. Several anti-angiogenic agents were evaluated in single arm phase II trials. However, the role of chemotherapy is still controversial, because of natural stable disease course without chemotherapy and lack of randomized trial. We firstly conducted a randomized trial to evaluate the efficacy of axitinib compared to observation. Methods: In this multicenter, prospective phase II trial, we enrolled recurred, metastatic ACC patients who progressed within 9 months. Patients were randomly assigned either axitinib (5mg twice daily) or observation arm with 1:1 ratio. Crossover to the axitinib arm was permitted for patients in the observation arm who had disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), overall survival (OS), PFS, duration of response and adverse events. Results: A total of 60 patients randomly allocated to axitinib (N=30) and observation arm (N=30) and response evaluation was conducted in 57 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.2% (95% confidence interval [CI], 54.8 to 88.1%) in the axitinib arm and 23.2% (95% CI, 9.3 to 41.1%) in the observation arm (hazard ratio, 0.19; 95% CI, 0.08 to 0.45; P < 0.001). Median PFS was 10.8 months in axitinib arm and 2.8 months in observation arm ( P < 0.001). The ORR was 3.3% (95% CI, 0.1 to 17.2%) in the axitinib arm, and 0% (95% CI, 0 to 12.8%) in the observation arm. The disease control rate was 100% (95% CI, 88.4 to 100%) in the axitinib arm and 51.9% (95% CI, 32.0 to 71.3%) in the observation arm. After crossover, ORR of axitinib in the observation arm was 11.1% (95% CI, 2.4 to 29.2%). Median OS was not reached in axitinib arm, 28.5 months in observation arm ( P = 0.688). The most frequently reported adverse events of axitinib were grade 1 or 2 oral mucositis and fatigue. Detailed data of adverse events and mutational profile data will be presented. Conclusions: In this first randomized trial in patients with recurred or metastatic ACC, axitinib significantly increased 6-month PFS rate compared to observation. Clinical trial information: NCT02859012 .

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Apatinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck: A Single-Arm, Phase II Study

SSRN Electronic Journal ◽

10.2139/ssrn.3675449 ◽

2020 ◽

Author(s):

Guopei Zhu ◽

Lin Zhang ◽

Shengjin Dou ◽

Rongrong Li ◽

Jiang Li ◽

...

Keyword(s):

Adenoid Cystic Carcinoma ◽

Head And Neck ◽

Phase Ii ◽

Phase Ii Study ◽

Adenoid Cystic

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Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting

International Journal of Clinical Oncology ◽

10.1007/s10147-021-01900-4 ◽

2021 ◽

Author(s):

Shin Kariya ◽

Yasushi Shimizu ◽

Nobuhiro Hanai ◽

Ryuji Yasumatsu ◽

Tomoya Yokota ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Dissection ◽

Neck Cancer ◽

Median Overall Survival ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Japanese Patients ◽

Free Survival

Abstract Background To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. Methods Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. Results Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. Conclusions These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. Trial registration number UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436)

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High CXCR4 expression in adenoid cystic carcinoma of the head and neck is associated with increased risk of locoregional recurrence

Journal of Clinical Pathology ◽

10.1136/jclinpath-2019-206273 ◽

2020 ◽

Vol 73 (8) ◽

pp. 476-482 ◽

Cited By ~ 1

Author(s):

Thomas J W Klein Nulent ◽

Robert J J van Es ◽

Matthijs H Valstar ◽

Ludwig E Smeele ◽

Laura A Smit ◽

...

Keyword(s):

Adenoid Cystic Carcinoma ◽

Head And Neck ◽

Primary Tumour ◽

Treatment Options ◽

Cxcr4 Expression ◽

Proportional Hazard ◽

Free Survival ◽

Cox Proportional Hazard ◽

Adenoid Cystic ◽

Increased Risk

AimTreatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC.MethodsAfter histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990–2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model.ResultsSixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1–70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33–72 vs 12%, IQR 1–70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04).ConclusionCXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC.

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Phase II Trial of Weekly Intravenous Gemcitabine With Continuous Infusion Fluorouracil in Patients With Metastatic Renal Cell Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.12.2419 ◽

2000 ◽

Vol 18 (12) ◽

pp. 2419-2426 ◽

Cited By ~ 125

Author(s):

Brian I. Rini ◽

Nicholas J. Vogelzang ◽

Mary C. Dumas ◽

James L. Wade ◽

David A. Taber ◽

...

Keyword(s):

Continuous Infusion ◽

Phase Ii ◽

Renal Cell ◽

Response Rate ◽

Cell Cancer ◽

Objective Response ◽

Progression Free Survival ◽

Free Survival ◽

Phase Ii Studies ◽

Metastatic Rcc

PURPOSE: To determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Between June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m2 over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m2/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle. Patients had a Cancer and Leukemia Group B performance status of 0 or 1, with a median time since diagnosis of metastatic disease of 10 months (range, 0 to 129 months). Thirty-three patients (80%) had multiple metastatic sites, and 34 patients (83%) had prior chemotherapy or immunotherapy. RESULTS: Of the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. The duration of response for the seven partial responders was 2, 3, 7, 8, 10, 11, and 14 months. Median progression-free survival for the gemcitabine/5-FU group was 28.7 weeks versus 8 weeks for a similar cohort of patients treated on previous phase II studies at the University of Chicago (P = .008). The regimen was well tolerated, with fatigue, mucositis, nausea/vomiting, and grade 2 hematologic toxicities being most common. CONCLUSION: Weekly gemcitabine with continuous infusion 5-FU is an active combination in patients with metastatic RCC. Therapy was well tolerated and produced an improvement in progression-free survival over historical controls.

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