Temsirolimus (Torisel®) and Erlotinib (Tarceva®) in Platinum-Refractory/Ineligible, Advanced, Squamous Cell Carcinoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of Temsirolimus (Torisel®) and Erlotinib (Tarceva®) in Platinum-Refractory or -Ineligible, Advanced, Squamous Cell Carcinoma of the Head and Neck

Conditions
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Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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 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 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 Easter Cooperative Oncology Group (ECOG) performance status 0-2 at time of informed consent 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 Able to provide written, voluntary consent Patients with reproductive potential must use an effective contraceptive method. Male or female, age ≥ 18 years Life expectancy ≥ 12 weeks Exclusion Criteria: Nasopharyngeal primary site, if WHO grade II or III Prior treatment blocking the epidermal growth factor receptor (EGFR), in the advanced disease setting Prior treatment blocking EGFR in the curative-intent setting, if delivered in the previous 6 months Prior treatment with a drug blocking the mammalian target of rapamycin (mTOR) Sensitivity to temsirolimus or erlotinib Uncontrolled metastatic disease of the central nervous system Radiotherapy within the 2 weeks before Cycle 1' Day 1 Surgery within the 2 weeks before Cycle 1' Day 1 Pregnant or lactating females Myocardial infarction or ischemia within the 6 months preceding study treatment Any co morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications No other concurrent, investigational anti-neoplastic agent will be permitted 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

Ages Eligible for Study
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Minimum Age: 18 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: Temsirolimus and Erlotinib<br>Erlotinib (Tarceva) at 150 mg by mouth daily + Temsirolimus (Torisel) at 15 mg intravenously weekly. Each cycle is comprised of 28 days | Drug: Erlotinib<br>* Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of informed consent.<br>* Other names: OSI-774;Drug: Temsirolimus<br>* In the absence of Grade 3 or higher toxicity, a single, intra-patient dose increase of temsirolims to 20 mg intravenously weekly is permitted after the first 28 day cycle. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of informed consent.<br>* Other names: CCI-779;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | The time from treatment initiation to disease progression or death by any cause. Progression is evaluated according to modified Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by computerized tomography (CT) or magnetic resonance imaging (MRI): Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or unequivocal progression of existing non-target lesion, the appearance of new lesions, death due to disease without prior objective documentation of progression, or global deterioration in health status attributable to disease requiring a change in therapy without objective evidence of progression. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Profile | Toxicities (i.e. Adverse Events) are evaluated prior to each treatment and during any clinical visit. Toxicity will be evaluated per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The number of patients affected by adverse events of grade 3 or higher will be reported. | 3 years | 
| Overall Response Rate (ORR) | Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by computerized tomography (CT) or magnetic resonance imaging (MRI:) Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Overall response rate (ORR) is the sum of the percentages of patients achieving complete and partial responses | 3 years | 
| Overall Survival (OS) | The time from treatment initiation to death by any cause | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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squamous cell carcinoma, head, neck, aerodigestive