Efficacy Study of REOLYSIN® in Combination With Paclitaxel and Carboplatin in Platinum-Refractory Head and Neck Cancers

Randomized, Double-blind, Multicenter Two-Stage Adaptive Phase 3 Study of Intravenous Administration of REOLYSIN (Reovirus Type 3 Dearing) in Combination With Paclitaxel and Carboplatin Versus the Chemotherapy Alone in Patients With Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck Who Have Progressed on or After Prior Platinum-Based Chemotherapy

The purpose of this Phase 3 study is to evaluate overall survival and progression free survival following intravenous administration of REOLYSIN (Reovirus Serotype 3 Dearing) in combination with paclitaxel and carboplatin versus chemotherapy treatment alone, in patients with metastatic or recurrent Squamous Cell Carcinoma of the Head and Neck.

Squamous cell carcinoma of the head and neck is the sixth most common cancer in the world. More than 50% of patients diagnosed with advanced regional disease will relapse locally or at distant sites. Initial therapeutic options include irradiation, surgery and chemotherapy. The most commonly used agents are cisplatin and carboplatin, generally in combination with 5-FU or a taxane. Erbitux has been approved for use in first-line with radiation and in second-line as monotherapy. Only about a third of the patients will respond to first-line platinum-based therapy and the median overall survival is about 6-9 months.

Preliminary assessment of a Phase 1-2 study conducted in the UK investigating the combination of REOLYSIN, carboplatin and paclitaxel suggested that patients with head and neck carcinomas may represent a group of patients in whom this treatment combination is active. Studies have also shown that paclitaxel and carboplatin combination therapy may be effective in head and neck cancers, even in heavily pretreated patients and those resistant to previous treatment. These results strongly support the utility of the carboplatin/paclitaxel combination as a control arm for salvage therapy in platinum refractory patients, a patient group with few and poor treatment options and with no gold standard therapy.

This Phase 3 study is designed to compare response rates following intravenous administration of REOLYSIN (Reovirus Type 3 Dearing) in combination with paclitaxel and carboplatin versus chemotherapy treatment alone, in patients with metastatic or recurrent Squamous Cell Carcinoma of the Head and Neck.

Overall survival is a primary endpoint of this trial. Patients will be clinically evaluated after each course of treatment and radiologically every 6 weeks on and after treatment. The safety of the paclitaxel and carboplatin with intravenous blinded placebo or intravenous blinded REOLYSIN will also be assessed.

Inclusion Criteria: Each patient MUST:

• have recurrent or metastatic (R/M) histologically confirmed squamous cell carcinoma (SCC) of the head and neck (oropharynx, oral cavity, larynx, hypopharynx) or squamous cell nasopharynx cancer (NPC) with distal metastasis(es) and no secondary cancers (Patients with NPC without distal metastasis(es) or with undifferentiated NPC are not eligible).
• have at least one lesion that is measurable by computed tomography or magnetic resonance imaging (Lesions persisting in previously treated radiation fields are considered not evaluable for response except if representing a relapse in a mucosal or nodal lesion that previously demonstrated a complete response. Any new lesion within the previous radiation fields is acceptable for determination of response and/or progression).
• have completed first line chemotherapy for R/M SCCHN which progressed on or within 190 days following the completion of platinum or platinum-based chemotherapy.
• have no continuing acute toxic effects (except alopecia) of any prior radiotherapy, chemotherapy, or surgical procedures. Any surgery involving the SCC for which the patient is being treated (except biopsies) must have occurred at least 28 days prior to study enrollment.
• have received no chemotherapy, radiotherapy, immunotherapy or hormonal therapy within 28 days.
• have ECOG Performance Score of ≤ 2.
• have life expectancy of at least 3 months.
• absolute neutrophil count (ANC)≥ 1.5 x 10^9/L ; platelets ≥100 x 10^9/L]; hemoglobin ≥9.0 g/dL; serum creatinine ≤1.5 xULN; bilirubin ≤1.5 x ULN; AST/ALT ≤2.5 x ULN.
• negative pregnancy test for females with childbearing potential.
• Be wiling and able to comply with scheduled visits, the treatment plan, and laboratory tests.

Exclusion Criteria: No patient may:

• receive concurrent therapy with any other investigational anticancer agent while on study.
• have been treated with a taxane for SCCHN.
• have current -- or with a history of -- brain metastases because of their poor prognosis and because of the frequent development of progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• be on chronic immunosuppressive therapy or have known HIV infection or active hepatitis B or C.
• be a pregnant or breast-feeding woman. Female patients of childbearing potential must agree to use effective contraception, be surgically sterile, or be postmenopausal. Male patients must agree to use effective contraception or be surgically sterile. Barrier methods are a recommended form of contraception.
• have clinically significant cardiac disease (New York Heart Association, Class III or IV) including, but not limited to, pre-existing arrhythmia, uncontrolled angina pectoris, or myocardial infarction within 1 year prior to study entry.
• have dementia or any altered mental status that would prohibit informed consent.
• have any other acute, or 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 Principal Investigator, would make the patient inappropriate for this study.