Temsirolimus With or Without Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Cancer Who Did Not Respond to Previous Therapy

Study Overview
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Brief Summary
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This phase II trial studies how well giving temsirolimus together with cetuximab works compared to temsirolimus alone in treating patients with recurrent and/or metastatic head and neck cancer who did not respond to previous therapy. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving temsirolimus together with cetuximab is more effective than giving temsirolimus alone.

Detailed Description
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PRIMARY OBJECTIVES: I. Primary endpoint is progression free survival (PFS) of cetuximab/temsirolimus combination cohort (Arm A) compared to temsirolimus alone (Arm B). SECONDARY OBJECTIVES: I. Progression-free survival (PFS) of cetuximab/temsirolimus combination group (Arm A) and temsirolimus control group (Arm B) compared to a historic control cohort. II. Subgroup analysis of myofibroblast (+) cohort (PFS). III. Overall survival (OS). IV. Toxicities. V. Response (Response Evaluation Criteria in Solid Tumors [RECIST])/absolute tumor shrinkage (waterfall plot analysis). VI. Activity of combination therapy (temsirolimus/cetuximab) after failure (progressive disease [PD]) of temsirolimus monotherapy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive temsirolimus intravenously (IV) over 30-60 minutes and cetuximab IV over 1-2 hours once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive temsirolimus as in Arm A. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may cross over to Arm A. After completion of study therapy, patients are followed up for a minimum of 8 weeks and then once a year for 5 years.

Official Title
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A T1 Translational Multicenter Randomized Phase II Study of Temsirolimus Versus Cetuximab Plus Temsirolimus in Patients With Recurrent / Metastatic Head and Neck Cancer, Who Failed Prior EGFR Based Therapy

Conditions
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Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Laryngeal Verrucous Carcinoma, Recurrent Lip and Oral Cavity Squamous Cell Carcinoma, Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary, Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Recurrent Oral Cavity Verrucous Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Recurrent Salivary Gland Carcinoma, Salivary Gland Squamous Cell Carcinoma, Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary, Stage IV Hypopharyngeal Squamous Cell Carcinoma, Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVA Laryngeal Squamous Cell Carcinoma, Stage IVA Laryngeal Verrucous Carcinoma, Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVA Major Salivary Gland Carcinoma, Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVA Oral Cavity Verrucous Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Laryngeal Squamous Cell Carcinoma, Stage IVB Laryngeal Verrucous Carcinoma, Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVB Major Salivary Gland Carcinoma, Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVB Oral Cavity Verrucous Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Laryngeal Squamous Cell Carcinoma, Stage IVC Laryngeal Verrucous Carcinoma, Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVC Major Salivary Gland Carcinoma, Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVC Oral Cavity Verrucous Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma, Tongue Carcinoma

Intervention / Treatment
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* Biological: Cetuximab
* Other: Laboratory Biomarker Analysis
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically/cytologically confirmed diagnosis of squamous cell carcinoma of head and neck origin not amenable to curative intent therapy; information on prior exposure to cetuximab (duration, single agent/combined with chemotherapy/combined with radiation, best response, interval prior to study entry) will be collected Progressive disease by RECIST criteria (or unequivocal clinical progression) on a cetuximab based therapy in any line of therapy for recurrent/metastatic disease; prior use of cetuximab for recurrent/metastatic disease is defined as palliative intent use either alone or in combination with chemotherapy with a minimum of 2 weeks of uninterrupted treatment with cetuximab; treatment with cetuximab during radiotherapy or chemoradiotherapy is not sufficient Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 Presence of measurable lesions by RECIST: patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan Knowledge of the anatomic site of the original tumor (oropharynx versus non-oropharynx) or alternatively human papilloma virus (HPV) status; the trial will stratify patients by oropharynx versus non-oropharynx origin; HPV(+) tumors will be counted in the oropharynx cohort, HPV(-) tumors in the non-oropharynx cohort; at a later point all patients will undergo HPV testing as part of this trial; any widely used form of HPV testing is acceptable (including but not limited to HPV in situ hybridization [ISH], p16 testing [immunohistochemistry (IHC)], HPV16 testing, polymerase chain reaction [PCR], hybrid capture, etc) Availability of formalin-fixed, paraffin-embedded (FFPE) tissue and blood FFPE: >=14 slides containing tumor, 18 recommended 7-10 slides 5 um thick, AND 7-10 slides 10 um thick, and cut with a clean blade (use new blade if possible or clean vigorously to avoid RNA/DNA, RNase contamination) Blood: two 10 cc ethylenediaminetetraacetic acid (EDTA) purple top tubes (blood); two 2 ml cryovials (serum) Patients with human immunodeficiency virus (HIV), not requiring highly active antiretroviral treatment (HAART) therapy are eligible Life expectancy of greater than 8 weeks Leukocytes >= 2,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits (unless proven Gilbert's disease, which after principal investigator [PI] approval patient may be included) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Creatinine within 1.5 X normal institutional limits Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation Ability to understand and the willingness to sign a written informed consent document Fasting glucose of =< 120 mg/dl and glycosylated hemoglobin (HbA1c) =< 7.5% Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier Patients may not be receiving any other investigational agents Patients with known, active brain metastases should be excluded from this clinical trial; patients with treated brain metastases stable for >= 12 weeks are eligible History of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus or cetuximab Concurrent life-threatening diseases: patients with diseases which with reasonable certainty do not limit life expectancy to 12 months or less are eligible; assessment of such concurrent illnesses should be by the principal investigator Use of strong inhibitors/inducers of CYP3A4 is not permitted Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study Breastfeeding should be discontinued if the mother is treated with temsirolimus HIV-positive patients with normal immune function (CD4 count > 200) are eligible if there are no drug interactions with temsirolimus or cetuximab; patients with impaired immune function are ineligible due to the risk of additional immunosuppression from temsirolimus therapy Concurrent administration of temsirolimus with vaccinations is to be avoided and a 14-day window from administration of the vaccine is advised; in emergent situations this policy may be revisited by the PI if deemed important for the patient's health Poorly controlled hyperglycemia (HbA1C > 7.5%) or hyperlipidemia are exclusion criteria; hyperglycemia or hyperlipidemia need to be appropriately managed and controlled Concurrent use of warfarin is allowed, but requires close monitoring of prothrombin time (PT)/international normalized ratio (INR) Patients with clinically significant pneumonitis/pulmonary infiltrates unless there is a known and treatable cause for the condition

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (cetuximab and temsirolimus)<br>Patients receive temsirolimus IV over 30-60 minutes and cetuximab IV over 1-2 hours once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Biological: Cetuximab<br>* Given IV<br>* Other names: IMC-C225;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|
| Experimental: Arm B (temsirolimus)<br>Patients receive temsirolimus as in Arm A. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may cross over to Arm A. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression determined using RECIST criteria: >=20% increase in the sum of the longest diameters of target lesions from nadir, occurrence of new lesions, or progression of non-target lesions. | From start of treatment to time of progression or death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from randomization until death from any cause | Up to 5 years | 
| Overall Response Rates (OR) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Statistics reported are for Overall Response (OR) = CR + PR. | Up to 5 years | 
| PFS vs. Historical Control Cohort | PFS at 4 months in Arm A and Arm B will each be compared with a 4-month historical control rate of 21.4%. The historical data appears in two publications, an ASCO abstract: Abidoye, ASCO Annual Meeting 2006: 5568 and de Souza, Davis, et al, Clin Cancer Res 2012; 18(8):2336-2343. | From start of treatment to time of progression or death of any cause, assessed at 4 months | 
| Grade 3 or Higher Hematological Toxicity | Incidence of hematological toxicities at least possibly related to study drug, graded based on Common Terminology Criteria for Adverse Events version 4 | Up to 5 years | 
| Percentage of Responses After Crossover From Control Arm to the Combination Arm, Assessed According to RECIST | Percentage of responses (if any) after crossover from the control arm to the combination arm will be evaluated qualitatively. This is includes complete and partial responses, and is different from Outcome Measure 8 below, which includes complete and partial responses as well as stable disease. | Up to 5 years | 
| PFS of Myofibroblast (+) Cohort |  | From start of treatment to time of progression or death of any cause, assessed up to 5 years | 
| Percentage of Responses/Disease Stabilization for Patients Crossing Over to the Combination Therapy After Progressing on Arm B. | Assessed according to RECIST. This is includes complete and partial responses as well as stable disease, and is different from Outcome Measure 6 above, which includes only complete and partial responses. | Up to 5 years |