Phase II Trial of HM781-36B in Patients With Metastatic/Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) After Failure of or Unfit for Platinum-containing Therapy

Study Overview
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Brief Summary
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Head and neck cancer is the sixth most common cancer and more than 650,000 new cases are diagnosed each year worldwide. About 60% of the HNSCC patients present with unresectable locally advanced disease at diagnosis and treated with multimodality approach. Despite such approach, majority (70%) of patients develop local or/and regional recurrences. Additional 10% of patients present with distant metastasis at diagnosis. Most patients with recurrent or metastatic disease are treated with single agent chemotherapy, combination chemotherapy or targeted therapies. Despite its public health magnitude, HNSCC in Asian countries has received a limited attention for the drug development and cancer-related research. In fact, HNSCC ranked 7th among men and 10th among women by incidence in China, the largest producer and consumer of tobacco and alcohol. Recently, Chen et al. documented a 1:1:2 subset distribution for cancers of oral cavity, pharynx, and larynx in China, similar to the distribution reported in Korea but quite different from the general distribution of 5:2:3 in whites. Ethnic disparities in HNSCC also include its prognosis and this is partly explained by HPV-active disease ratio and genetic factors. Therefore, there is a strong need for an additional research in patients with HNSCC in Asia. Epidermal growth factor receptor (EGFR) is often over-expressed, and have been related to poor prognosis in patients with HNSCC. The association between EGFR-activated signaling pathways and tumor cell survival are well documented in many studies. EGFR targeting strategies showed clinical anti-tumor efficacy in patients with HNSCC, especially with monoclonal antibody, cetuximab. In the Extreme study, it was shown that the addition of cetuximab to platinum-5-FU significantly prolonged the median overall survival from 7.4 months to 10.1 months compared to platinum-5FU alone in the first-line setting. HM781-36B is a irreversible pan-HER inhibitor. In preclinical studies, HM781-36B has much lower IC50 values than gefitinib in cell lines engineered to express EGFRvIII mutations and produces tumor growth inhibition in gefitinib-resistant xenografts. A phase I trial of HM781-36B in patients with advanced solid tumors showed clinically significant anti-tumor activity and a phase II trials of HM781-36B in patients with non-small cell lung cancer and advanced gastric cancer are currently ongoing. We suggest a phase II trial of HM781-36B in patients with recurrent or metastatic HNSCC who are resistant or ineligible/intolerant to platinum-based chemotherapy. The aim of current trial is to evaluate the antitumor efficacy and safety profile of HM781-36B and to identify biomarker to predict the tumor response to HM781-36B.

Conditions
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HNSCC

Intervention / Treatment
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* Drug: HM781-36B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed squamous cell carcinoma of head and neck Age ≥ 20 years ECOG PS 0-1 Documented progressive disease after platinum-based (either cisplatin or carboplatin) concurrent chemoradiation including induction chemotherapy for curative aim or Documented progressive disease after platinum-based (either cisplatin or carboplatin) chemotherapy for palliative aim or Ineligible to platinum-based (either cisplatin or carboplatin) chemotherapy or chemoradiation due to decline in renal function and patient's intolerance At least one bidimensionally measurable disease as defined by RECIST ver 1.1 Adequate organ function for treatment Absolute neutrophil count (ANC) ≥ 1000cells/mm3 Platelets ≥ 100000 cells/mm3 Estimated creatinine clearance ≥ 50mL/min, or serum creatinine < 1.5 x institution upper limit of normal Bilirubin ≤ 1.5 x upper limit of normal(ULN) AST(SGOT) ≤ 2.5 x ULN (5.0xULN if hepatic metastases) ALT(SGPT) ≤ 2.5 x ULN (5.0xULN if hepatic metastases) The patient has provided signed informed consent and is amenable to compliance with protocol schedules and testing Exclusion Criteria: Nasopharyngeal carcinoma Patients who are subjected to local treatment (surgery or radiation) Previous treatment with small molecule EGFR tyrosine kinase inhibitors (Cetuximab is permitted) Three or more previous systemic cytotoxic chemotherapy Any major operation or irradiation within 4 weeks of baseline disease assessment Patients who have received prior systemic chemotherapy, immunotherapy or study drug within 4 weeks Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug Patients with uncontrolled CNS metastatic involvement. However, patients with metastatic CNS tumors may participate in this study if the patient is clinically stable not receiving steroid therapy more than 1 week from prior therapy completion (including radiation and/or surgery) to stating the study drug. Patients with known interstitial lung disease (ILD) or presented ILD on screening chest X-ray Congenital long QT syndrome or screening corrected QT interval (QTc) > 470msec Patients with uncontrolled or significant cardiovascular disease (AMI within 12 months, Unstable angina within 6 months, NYHA Class III, IV Congestive heart failure or left ventricular ejection fraction below local institutional lower limit of normal or below 45%, Congenital long QT syndrome, Any significant ventricular arrhythmia, Any uncontrolled second or third degree heart block, Uncontrolled hypertension) Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to study entry. Pregnant or breast-feeding women Other severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this trial.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HM781-36B<br> | Drug: HM781-36B<br> <br> * Other names: 45 mg p.o. daily and continuously (28-day treatment as one treatment cycle);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Objective Tumor Response will be performed according to the Response Evaluation in Solid Tumor Criteria 1.1 (RECIST 1.1) | 28th day of 1st chemotherapy cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response |  | 1years | 
| Duration of response |  | 1years | 
| Progression-Free Survival |  | 1years | 
| Overall Survival |  | 1years | 
| Toxicity profile | Overall safety profile and toleration of HM781-36B will be characterized by type, frequency, severity (as graded by the NCI CTCAE v4.02), timing and relationship of study therapy of adverse events and laboratory abnormalities. Quantitative variables will be summarized in descriptive terms. | 1years | 
| Quality of Life (QoL) | Questionnaire | 1years | 
| Identification of predictive markers of treatment | To explore KRAS and HER family mutation status in tissue at the end of treatment; To explore the pre- and post-treatment levels of shed proteins/receptors related to HER signaling (possibly to include EGFR and HER-2 receptor extracellular domain (ECD) and E-cadherin); | 1years |