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criskorea@korea.kr
  • Status : Approved
    • First Submitted Date : 2018/09/03
    • Registered Date : 2019/02/22
    • Last Updated Date : 2019/02/12
Background Information
1.Background  
CRIS Registration Number KCT0003545 
Unique Protocol ID 2017-11-082 
Public/Brief Title Combination chomotherapy of nanoxel and herzuma in patients with relapsed or metastatic salivary gland carcinoma : open label single arm multicenter phase II study 
Scientific Title Combination chomotherapy of nanoxel and herzuma in patients with relapsed or metastatic salivary gland carcinoma : open label single arm multicenter phase II study  
Acronym  
MFDS Regulated Study Yes
IND/IDE Protocol Yes
Registered at Other Registry Yes
Name of Registry/
Registration Number
ClinicalTrials.gov-NCT03614364 
Healthcare Benefit
Approval Status
Submitted pending
Institutional Review Board Information
2. Institutional Review Board/Ethics Committee  
Board Approval Status Submitted approval 
Board Approval Number SMC 2017-11-082-002 
Approval Date 2018-04-10 
Institutional Review Board  
- Name Samsung Medical Center Institutional Review Board  
- Address 81, Irwon-ro, Gangnam-gu, Seoul 
- Telephone 02-3410-2973 
Data Monitoring Committee No  
Contact Details
3.Contact Details  
Contact Person for Principal Investigator / Scientific Queries
- Name Myung-Ju Ahn 
- Title Professor 
- Telephone +82-2-3410-3438 
- Affiliation Samsung Medical Center 
- Address 81, Irwon-ro, Gangnam-gu, Seoul 
Contact Person for Public Queries
- Name Myung-Ju Ahn 
- Title Professor 
- Telephone +82-2-3410-3438 
- Affiliation Samsung Medical Center 
- Address 81, Irwon-ro, Gangnam-gu, Seoul 
Contact Person for Updating Information
- Name Myung-Ju Ahn 
- Title Professor 
- Telephone +82-2-3410-3438 
- Affiliation Samsung Medical Center 
- Address 81, Irwon-ro, Gangnam-gu, Seoul 
Status
4. Status Status  
Study Site Multi-center (Number of center : 2)
Overall Recruitment Status Recruiting  
Date of First Enrollment 2018-09-19 , Actual
Target Number of Participant 41
Primary Completion Date
Study Completion Date
Recruitment Status by Participating Study Site 1 
- Name of Study Site Samsung Medical Center 
- Recruitment Status Recruiting  
- Date of First Enrollment 2018-09-19 , Actual
Recruitment Status by Participating Study Site 2 
- Name of Study Site Pusan National University Yangsan Hospital 
- Recruitment Status Not yet recruiting  
- Date of First Enrollment 2019-02-28 , Anticipated
Source of Monetary / Material Support 정보
5. Source of Monetary/Material Support  
Source of Monetary/Material Support1 
- Organization Name Samyang Biopharmaceuticals 
- Organization Type Pharmaceutical Company  
- Project ID  
Sponsor Organization
6. Sponsor Organization  
Sponsor Organization 1 
- Organization Name Samsung Medical Center 
- Organization Type Medical Institute  
Study Summary
7. Study Summary  
Lay Summary Salivary gland cancers are rare, accounting for less than 5% of all cancers of the head and neck, and are among the most heterogeneous primary tumors that arise in the body, with very different natural histories according to the specific histologic subtypes. Salivary duct carcinomas (SDC) account for approximately 6% of all salivary gland cancers and area among the most aggressive salivary malignancies . Despite aggressive clinical management (complete surgical resection and chemoradiation) about 65% of patients with SDC die from progressive disease by 48 months. Due to the rarity of this disease and its protracted course, it is difficult to prospectively observe patients with such tumors, and there are few clinical trials investigating the efficacy of systemic therapy. Preclinically, paclitaxel and docetaxel have demonstrated activity against salivary gland cancers. Phase II trial of single-agent paclitaxel, conducted by Eastern Cooperative Oncology Group in 45 patients with advanced SGC. Eight partial responses were observed among the 31 patients with mucoepidermoid carcinoma (MEC) or adenocarcinoma, but no responses were identified in the 14 patients with ACC. Based on its impressive anti-tumor activity in patients with head and neck cancer, especially in MEC and adenocarcinoma. Ragusa et al.evaluated the activity of docetaxel in 4 patients with high grade MEC of the major salivary glands. The treatment was well tolerated, and there was complete response in two and partial response in the other two patients. In addition to the histologic resemblance between SDC and breast ductal carcinoma, another feature common to both tumor types is the strong overexpression of HER2, which is detected in a subset of cases and highly correlates with amplification of the HER2 locus. Overall frequency of HER2 gene amplification reported in the literature was in 14 of 32 (43.8%), 8 of 27 (30%), or 47 of 173 (27%) SDC cases. For patients with HER2-positive breast cancer, treatment with anti-HER2 agents, such as trastuzumab, can significantly improve disease-free and overall survival. These findings provide a rationale for exploring the effects of trastuzumab in the treatment of HER2-positive SDC. So far, only few patients with SDC have been enrolled in treatment regimens that included HER2 antagonists, and some case reports have shown encouraging results with an occasional complete response, Further study of paclitaxel in sensitive histologic subtypes may be in combination with targeted therapies. Recently, the combination of trastuzumab (Herceptin) and docetaxel seems to be highly active in patients with unresectable advanced HER2-positive salivary gland carcinoma of the ductal subtype, according to interim data from an open-label, single-arm phase II trial. With a median duration of follow-up of 17.8 months, the overall response rate (the trial’s primary endpoint) was 69%, and the clinical benefit rate (which additionally included stable disease for at least 6 months) was 87%. Median progression-free survival was 11.3 months, and median overall survival was 38.0 months.
CT-P6 (herzuma), biosimilar trastuzumab, showed equivalent efficacy
to reference trastuzumab and adverse events were similar. Nanoxel, nanoparticle formulation of the taxane, has shown to have minimized toxicity, along with an increase in the antitumor activity, due to selective accumulation of the drug in tumor.
Based on this hypothesis, we will investigate the phase II study to evaluate the efficacy of combination of nanoxel and herzuma in relapsed or metastatic salivary gland carcinoma patients.  
Study Design 정보
8. Study Design  
Study Type Interventional Study 
Study Purpose Treatment
Phase Phase2 
Intervention Model Single Group  
Blinding/Masking Open 
Allocation Non-RCT 
Intervention Type Drug  
Intervention Description D1 Nanoxel 75 mg/m2 + D5W 100mL MIV over 1hr
D1 Herzuma 8mg/kg (loading dose) + N/S 250mL miv over 90mins
6mg/kg (maintenance) + N/S 250mL MIV over 30mins (since 2 cycle) repeated every 3 weeks
In the case of Cycle 1,
Herzuma is administered on Day 1 and Nanoxel is administered on Day 2.
If the first dose is well tolerated, it may be administered Nanoxel immediately after the administration of the Herzuma.
(In case of discontinuation of nanoxel without progression, single agent herzuma can be administered until progression
Treatment will be continued until disease progression or unacceptable toxic effects.  
Number of Arms
Arm 1 Arm Label nanoxel and herzuma 
Target Number of Participant 41 
Arm Type Experimental 
Arm Description D1 Nanoxel 75 mg/m2 + D5W 100mL MIV over 1hr D1 Herzuma 8mg/kg (loading dose) + N/S 250mL miv over 90mins 6mg/kg (maintenance) + N/S 250mL MIV over 30mins (since 2 cycle) repeated every 3 weeks In the case of Cycle 1, Herzuma is administered on Day 1 and Nanoxel is administered on Day 2. If the first dose is well tolerated, it may be administered Nanoxel immediately after the administration of the Herzuma. (In case of discontinuation of nanoxel without progression, single agent herzuma can be administered until progression Treatment will be continued until disease progression or unacceptable toxic effects. 
Subject Eligibility Information
9. Subject  
Condition(s)/Problem(s) * Neoplasms
metastatic salivary duct carcinoma  
Rare Disease No
Inclusion
Criteria
Gender Both 
Age 20 Year ~ No Limit
Description ①Histologically-confirmed HER2 positive (immunohistochemistry [IHC] 3+, and/or fluorescence in situ hybridization[FISH] positive with ≥ two-fold amplification) salivary duct carcinoma(SDC), and other salivary gland carcinomas which are similar to SDC in histopathological findings, including adenocarcinoma, not otherwise specified, acinic cell carcinoma, squamous cell carcinoma, anaplastic carcinoma, high grade mucoepidermoid carcinoma, and carcinoma ex pleomorphic adenoma (Except for Adenoid cystic carcinoma)
② locally advanced, unresectable, relapse or metastatic cancer
③ Allow treatment of all previous orders
④ age ≥ 20 years
⑤ ECOG performance status 0-1
⑥ At least one measurable tumor lesion according to RECIST 1.1
⑦ Expected survival for approximately 12 weeks or longerExpected survival for approximately 12 weeks or longer
⑧ At least 4 weeks later after surgery or at least 2 weeks after radiotherapy
⑨ Organ function as evidence by the following;,
ANC ≥ 1,500 cells/mm3,
Hemoglobin ≥ 10 g/dL (transfusion allowed),
Platelet count ≥ 100,000 /mm3;
Total bilirubin ≤ 1.5 × ULN, AST/ALT ≤ 2.5 × ULN, (if liver metastases(+): AST, ALT ≤5.0 x ULN);
Creatinine clearance ≥ 50 mL/min or serum creatinine ≤ 1.5 x UNL
⑩ Echocardiography showed normal LVEF ≥55%)
⑪ Written informed consent  
Exclusion Criteria ① Those who have received Her-2 treatment (ex: Herceptin etc.)
② Severe or unstable cardiac disease, including (for example) coronary artery disease requiring increased doses of anti-anginal medication and/or coronary angioplasty (including stent placement) within the preceding 24 months(congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias)
③ Uncontrolled systemic illness such as DM, hypertension, hypothyroidism and infection, infectious fever
④ Patients with active hepatitis B, active hepatitis C, HIV
⑤ Pregnant and nursing women (Women of childbearing age should agree to use effective contraceptive methods from the first day of the study drug infusion to 7 months after the last dose of the study drug infusion, and agree to check for pregnancy test(result: negative)).
⑥ Male patients, those who did not consent to not donate sperm from the first day of the study drug infusion to 90 days after the last dose of study drug infusion
⑦ Within the past 5 years, a malignant tumor of the other site (except treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.)
⑧ Patients with meningiomas, active metastatic lesions under the brain or subdural (Exceptions are made when completing topical treatment (radiotherapy, stereotactic surgery) and using stable doses of anticonvulsants and steroids before starting clinical trial treatment).
⑨ Patients who were treated with anticancer treatments, radiotherapy, chemotherapy, clinical trial medication within 2 weeks before starting clinical trial
⑩ Toxicity above CTCAE grade 2, not resolved from previous chemotherapy (Except: hair loss, vitiligo)
⑪ Patient with history of rodent-derived protein, trastuzumab or hypersensitivity to the components of trastuzumab
⑫ Patient with severe respiratory distress due to progressive malignant tumors or who need oxygen supplementation
⑬ Patient with severe bone marrow suppression
⑭ Patient with Nanoxel and components of Nanoxel, severe hypersensitivity reactions to polysorbate 80
⑮ Patient with history of exposure to the following anthracycline cumulative doses
- Doxorubicin > 500mg/m2
- Liposomal doxorubicin > 500mg/m2
- Epirubicin > 720mg/m2
- Mitoxantrone > 120mg/m2
- Idarubicin > 90mg/m2
(If another anthracycline or two or more anthracyclines are used, the cumulative dose should not exceed 500mg/m2 doxorubicin equivalent capacity.)  
Healthy Volunteers  
Outcome Measure(s) Information
10. Outcome Measure(s)  
Type of Primary Outcome Efficacy 
Primary Outcome(s) 1 
- Outcome Objective Response rate 
- Timepoint The primary objective of this trial is an objective response rate.Objective response rates show CR or PR response at one or more visits and the response is defined as the number(%) of subjects that identified at least 4 weeks after. The maximum reaction is determined according to Recist 1.1. 
Secondary Outcome(s) 1 
- Outcome overall survival, progression-free survival, safety and toxicity, exploratory biomarker analysis 
- Timepoint The overall survival period refers to the period from the date of consent to the date of death or the last time the survival was confirmed. The time to treatment failure, progression-free survival (PFS), and overall survival are calculated using the Kaplan-Meier method and presented with median and 95% confidence intervals.It means the period from the acquisition date of the consent to the time of disease progression, the time of death, or the last time the disease has not progressed or confirmed its survival.Safety is assessed based on adverse events, standard clinical chemistry tests, and blood test results. The performance toxicity / symptoms of clinical trials are graded according to CTCAE 4.0. The response is reported as mild, moderate, severe or life threatening unless rated according to CACAE 4.03. Biomarker analysis is intended to show the correlation between the human epidermal growth factor receptor (HER2) gene and the therapeutic effect of the two drugs. 
Study Results and Publication Information
11. Study Results and Publication
Result Registerd No
Sharing of Study Data Information
12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)
Sharing Statement No