High patient withdrawal rate

The primary hypothesis of this study is that the addition of mammalian target of rapamycin (mTOR) blockade to conventional epidermal growth factor receptor (EGFR) blockade will result in synergistic clinical activity in Squamous Cell Carcinoma of the Head and Neck (SCCHN), consistent with preclinical xenograft data. Patients will be treated with the combination of temsirolimus and erlotinib, at the previously established Maximal Tolerated Dose (MTD). The primary signal of efficacy will be progression free survival (PFS), anticipating that PFS will be prolonged compared to historical PFS in SCCHN patients treated with erlotinib or cetuximab monotherapy.

This is a phase II, multicenter, single arm, open-label study. Thirty-seven patients with advanced, platinum-refractory or platinum-ineligible squamous cell carcinoma of the head and neck will be sequentially enrolled to a single treatment arm. Patients will be treated with continuous, 28-day cycles of 150 mg of erlotinib by mouth daily and 15 mg of temsirolimus intervenously weekly. In the absence of grade 3 or higher toxicity in the first cycle, a single, intra-patient dose increase to 20 mg temsirolimus will be permitted.

Inclusion Criteria:

1. Histologically or cytologically confirmed squamous cell carcinoma of the head and neck, from any primary site. Nasopharyngeal carcinoma, World Health Organization (WHO) Grade I, will be included.

2. Advanced disease, fulfilling one of the criteria defined below:

   • Incurable disease as assessed by surgical or radiation oncology
   • Metastatic (M1) disease
   • Persistent or progressive disease following curative-intent radiation, and not a candidate for surgical salvage due to incurability or morbidity

3. Platinum-refractory or platinum-ineligible, fulfilling one of the criteria defined below:

   • disease progression during or after 4-6 cycles of platinum-containing therapy in the advanced setting
   • disease progression within 6 months of curative-intent treatment, which included platinum-based chemotherapy
   • ineligible for platinum-containing therapy, in the opinion of the medical oncologist, due to medical comorbidities or unacceptable risk for toxicity
   • patient refuses platinum-containing therapy

4. Measurable disease based on response evaluation criteria in solid tumors (RECIST)

   - disease in previously irradiated sites is considered measurable if there has been unequivocal progression of the lesion after radiotherapy, or the lesion contains residual carcinoma by biopsy more than 6 weeks after completion of radiotherapy

5. Easter Cooperative Oncology Group (ECOG) performance status 0-2 at time of informed consent

6. Adequate hematologic reserve and organ function

   • Absolute neutrophil count > 1200/µl
   • Platelet count > 100,000/µl
   • Renal function: Serum Creatinine ≤ 1.5x upper limit of normal (ULN)
   • Liver function: Total bilirubin ≤ 1.5x ULN, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x ULN

7. Able to provide written, voluntary consent

8. Patients with reproductive potential must use an effective contraceptive method.

9. Male or female, age ≥ 18 years

10. Life expectancy ≥ 12 weeks

Exclusion Criteria:

1. Nasopharyngeal primary site, if WHO grade II or III
2. Prior treatment blocking the epidermal growth factor receptor (EGFR), in the advanced disease setting
3. Prior treatment blocking EGFR in the curative-intent setting, if delivered in the previous 6 months
4. Prior treatment with a drug blocking the mammalian target of rapamycin (mTOR)
5. Sensitivity to temsirolimus or erlotinib
6. Uncontrolled metastatic disease of the central nervous system
7. Radiotherapy within the 2 weeks before Cycle 1' Day 1
8. Surgery within the 2 weeks before Cycle 1' Day 1
9. Pregnant or lactating females
10. Myocardial infarction or ischemia within the 6 months preceding study treatment
11. Any co morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications
12. No other concurrent, investigational anti-neoplastic agent will be permitted
13. History of prior malignancy within the prior five years, with the exception of non-melanoma carcinomas of the skin, and carcinoma in situ of the cervix

3 years