Ganetespib Window of Opportunity Study in Head and Neck Cancers

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.

• Ganetespib (Drug), also known as Hsp90 Inhibitor STA-9090, STA-9090: Given IV
• Therapeutic Conventional Surgery (Procedure): Undergo surgery
• Laboratory Biomarker Analysis (Other): Correlative studies

Primary outcomes

• Change in expression of biomarkers in tissue samples, assessed by immunohistochemistry (IHC) [Baseline to up to 24 months]: 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.
• Change in biomarker expression in blood samples [Baseline to up to 24 months]: 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.

Sex: All, ages: 19 Years to 79 Years

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

• Nabil F. Saba, MD, Principal investigator, Emory University/Winship Cancer Institute