Ganetespib Window of Opportunity Study in Head and Neck Cancers

Study Overview
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Brief Summary
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This pilot clinical trial studies how well ganetespib works before surgery in treating patients with stage I-IVA squamous cell carcinoma of the head and neck that can be removed by surgery. Ganetespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Studying samples of blood and tissue in the laboratory from patients receiving ganetespib may help doctors learn more about the effects of ganetespib on cells. It may also help doctors understand how well patients respond to treatment.

Detailed Description
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Ganetespib is a small molecule inhibitor of HSP90 that is currently being studied in several ongoing clinical trials. Investigators have demonstrated that ganetespib sensitizes colorectal cell lines to the effects of chemo radiotherapy in vitro. Ganetespib may have an anti-tumor effect in head and neck cancer. The investigators propose this pilot study as a first step to examine the activity of ganetespib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who have a planned surgical resection. Ganetespib has not been investigated in SCCHN. This protocol is a window of opportunity trial that will be looking at whether there is a rationale for pursuing this agent in future development of clinical trials that would then focus on therapeutic interventions with or without radiotherapy. There are therefore no clinical trials currently opened using ganetespib in SCCHN and listed on ClinicalTrials.gov. It is not clear if patients who receive this drug prior to surgery will benefit from this intervention. In this study, ganetespib will be administered twice weekly (doses approximately 72 hours apart) for 2 weeks, followed by surgery the day after the last dose of the study drug. There will be 3 dose levels, 80, 100 and 150mg/m² as highest dose. These doses were chosen based on the following considerations. In a Phase 1 study (protocol 9090-01) investigating a twice-weekly ganetespib treatment schedule, doses up to 173 mg/m² were well tolerated, with manageable diarrhea and fatigue being the most common adverse events. Extensive correlative studies and pharmacokinetic (PK)/pharmacodynamic (PD) modeling of preclinical data suggest that in humans the effective dose range for ganetespib is 70-150 mg/m². Therefore, 80 mg/m² is within the range of ganetespib effectiveness and 150 mg/m² twice weekly is a well-tolerated dose.

Official Title
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A Molecularly Driven Pilot Study of Preoperative Ganetespib in Resectable Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
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Stage I Hypopharyngeal Squamous Cell Carcinoma, Stage I Laryngeal Squamous Cell Carcinoma, Stage I Oral Cavity Squamous Cell Carcinoma, Stage I Oropharyngeal Squamous Cell Carcinoma, Stage II Hypopharyngeal Squamous Cell Carcinoma, Stage II Laryngeal Squamous Cell Carcinoma, Stage II Oral Cavity Squamous Cell Carcinoma, Stage II Oropharyngeal Squamous Cell Carcinoma, Stage III Hypopharyngeal Squamous Cell Carcinoma, Stage III Laryngeal Squamous Cell Carcinoma, Stage III Oral Cavity Squamous Cell Carcinoma, Stage III Oropharyngeal Squamous Cell Carcinoma, Stage IVA Hypopharyngeal Squamous Cell Carcinoma, Stage IVA Laryngeal Squamous Cell Carcinoma, Stage IVA Oral Cavity Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Ganetespib
* Procedure: Therapeutic Conventional Surgery
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have pathologically-confirmed, resectable, squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx Disease may be stage I, II, III or IVa (as long as it is deemed resectable by the surgical team) Tumor must be surgically resectable and curable with conventional surgery Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients must give documented informed consent to participate in this study Absolute-neutrophil count (ANC) ≥ 1500/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin ≤ within upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN Creatinine ≤ 1.5 x ULN Lipase levels < 1.5 x ULN Amylase levels < 1.5 x ULN Exclusion Criteria: Prior therapy with a known heat shock protein 90 (HSP90) inhibitor Poor venous access for study drug administration; in this case, patients would require a peripheral or central indwelling catheter for study drug administration; study drug administration via indwelling catheters is prohibited at this time unless silicone based catheters are used; anything other than catheters made from silicone are not allowed with ganetespib therapy History of severe allergic or hypersensitivity reactions to excipients (e.g., polyethylene glycol [PEG] 300 and polysorbate 80) Treatment with chronic immunosuppressant (e.g., cyclosporine following transplantation) Uncontrolled undercurrent illness including, but not limited to, human immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Other medications, or severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study Documented evidence of distant metastases or brain metastases Active malignancy besides head and neck squamous cell cancer (HNSCC) or primary skin basal cell carcinoma; (patients with a concomitant malignancy that has not progressed within 12 months of study entry are eligible) History of documented congestive heart failure (CHF), New York Heart Association class II/III/IV, with a history of dyspnea, orthopnea or edema that requires current treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics; NOTE: use of these medications for the treatment of hypertension is allowed Peripheral neuropathy that is grade 2 or higher Pregnancy or lactation; patients of child bearing age must agree to use adequate contraception Patients residing in prison CARDIAC EXCLUSION CRITERIA: Known serious cardiac illness or medical conditions, including but not limited to: Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide); use of other antiarrhythmic drugs is permitted Use of medications that have been linked to the occurrence of Torsades de pointes Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker Complete left bundle branch block (LBBB) History of long QT syndrome or a family member with this condition Corrected QT (QTc) > 470 ms (average of triplicate electrocardiogram [ECG] recordings); a consistent method of QTc calculation must be used for each patient's QTc measurements; QTcF (Fridericia's formula) is preferred Serum potassium, magnesium, or calcium levels in the following ranges: Potassium < 3.4 or > 5.1 mmol/L Magnesium < 1.4 or > 2.4 mg/dL Calcium < 8.9 or > 10.5 mg/dL

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 79 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: Treatment (ganetespib, surgery)<br>Patients receive ganetespib IV over 1 hour twice weekly for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery the day after the last dose of ganetespib. | Drug: Ganetespib<br>* Given IV<br>* Other names: STA-9090;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in expression of biomarkers in tissue samples, assessed by immunohistochemistry (IHC) | The biomarker expression of pre-, post-treatment, and their change will be described by summary statistics along with 95% confidence interval (CI) for the estimated mean. A paired sample Wilcoxon signed rank test will be considered to test whether the mean of post-treatment expression is different from the pre-treatment expression. This analysis will be done separately by each of the three dose levels, and by pooling all dose levels together. Kruskal-Wallis test will also be carried out. | Baseline to up to 24 months | 
| Change in biomarker expression in blood samples | The biomarker expression of pre-, post-treatment, as well as their change will be described by summary statistics along with 95% CI for the estimated mean. A paired sample Wilcoxon signed rank test will be considered to test whether the mean of post-treatment expression is different from that of the pre-treatment expression. This analysis will be done separately by each of the three dose levels, as well as by pooling all dose levels together. Kruskal-Wallis test will also be carried out. | Baseline to up to 24 months |