Phase I/II Study of Postoperative Adjuvant Chemoradiation for Advanced-Stage Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN)

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies the side effects and best dose of linsitinib when given together with erlotinib hydrochloride and radiation therapy after surgery in treating patients with advanced or recurrent head and neck cancer. Erlotinib hydrochloride and linsitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy together with erlotinib hydrochloride and linsitinib may kill more tumor cells. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the MTD (maximally tolerated dose) of OSI-906 (linsitinib) when used in combination with erlotinib (erlotinib hydrochloride) and radiation therapy after surgery for advanced-stage cutaneous squamous cell carcinoma of the head and neck (cSCCHN). (Phase I) II. To estimate the 2-year overall survival (OS) compared to historical controls. (Phase II) SECONDARY OBJECTIVES: I. To determine the safety and tolerability of OSI-906 in combination with erlotinib and radiation therapy after surgery for advanced-stage cSCCHN. II. To estimate the 2-year disease specific and disease free survival. III. To determine the time to recurrence and patterns of failure. IV. To evaluate the effects of short-term preoperative treatment with erlotinib and OSI-906 on the expression epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R) and parallel or downstream molecular targets in cSCCHN in one third of the patients. OUTLINE: Optional non-therapeutic (biomarker) portion: Patients are randomized to 1 of 3 treatment arms. Arm A: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) and linsitinib PO twice daily (BID) on days 1-7 or 1-14. Arm B: Patients receive erlotinib hydrochloride PO QD and placebo PO QD or BID on days 1-7 or 1-14. Arm C: Patients receive linsitinib PO BID and placebo PO QD or BID on days 1-7 or 1-14. Treatment continues until 1 day before planned surgical resection (for up to 28 days if surgery is delayed). Therapeutic portion: This is a phase I dose-escalation study of linsitinib followed by a phase II study. Patients undergo standard QD conventional radiotherapy at the discretion of the treating physician. Patients receive concurrent linsitinib PO BID and erlotinib hydrochloride PO QD during the entire course of radiation in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6 and 12 weeks, every 12-16 weeks for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
-----------------
Phase I/II Study of Postoperative Adjuvant Chemoradiation for cSCCHN

Conditions
-----------------
Recurrent Skin Cancer, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Squamous Cell Carcinoma of the Skin, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity

Intervention / Treatment
-----------------
* Drug: erlotinib hydrochloride
* Drug: linsitinib
* Drug: placebo
* Radiation: radiation therapy
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have primary or recurrent advanced-stage (III/IV) squamous cell carcinoma of the skin of the face, ear, scalp or neck or of the lip A biopsy or preserved representative tumor block is required to confirm the diagnosis Patients must be surgical candidates with resectable disease; macroscopic complete resection of all tumor must be planned with curative intent Patients must be willing to receive postoperative radiation therapy and treatment with study drugs Both men and women and members of all races and ethnic groups will be included Life expectancy of greater than 12 months Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Absolute neutrophil count >= 1,500/microliter(uL) Hemoglobin >= 9 g/dL Platelets >= 100,000/uL International normalized ratio (INR) < institutional upper limit of normal (ULN) Total bilirubin =< 1.5 x institutional ULN Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 2.5 X institutional ULN Creatinine =< 1.5 X institutional ULN Fasting blood glucose < 125 mg/dL at baseline Patients-both males and females-with reproductive potential (i.e., menopausal for less than 1 year and not surgically sterilized) must practice effective contraceptive measures throughout the study; women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with known distant metastasis Patients who have had prior radiation treatment of the index cancer or area of disease Patients who have received any other investigational medication within 6 weeks of enrollment, or who are scheduled to receive an investigational drug during the course of the study Prior treatment with EGFR inhibitor for index cancer Prior treatment with an IGF-1R antagonist (small molecule inhibitor or antibody) Breast-feeding, pregnancy or of childbearing potential (including less than two years postmenopausal) and unable to confirm adequate contraception due to possible risk to fetus or infant Insulin-dependent and non-insulin dependent diabetes mellitus including any metformin or insulin use on an ongoing basis prior to enrollment Known severe hypersensitivity to erlotinib, other small molecule inhibitors of EGFR, or its excipients Hepatitis B or C infection (acute or chronic), known human immunodeficiency virus (HIV), or active uncontrolled infection, because of possible risk of lethal infection when treated with marrow suppressive therapy History of uncontrolled cardiac disease such as unstable angina pectoris, myocardial infarction within prior 6 months, untreated coronary artery disease, uncontrolled congestive heart failure, or cardiomyopathy with decreased ejection fraction Uncontrolled peptic or gastric ulcer disease or gastrointestinal bleeding within prior 6 months Corrected QT interval (QTc) > 450 msec; congenital long QT syndrome or previous history of QTc prolongation as a result from other medication Presence of left bundle branch block (LBBB); QTc with Bazett's correction that is unmeasurable, or >= 450 msec on screening electrocardiogram (EKG) Any concomitant medication that may cause QTc prolongation or concomitant medication that is associated with Torsades de Pointes Psychiatric illness/social situations that would limit compliance with study requirements Active smokers unwilling to quit smoking during treatment Use of the potent cytochrome P450 3A4 (CYP3A4) and cytochrome P450 1A2 (CYP1A2) inhibitors is not allowed; other less potent CYP3A4 and CYP1A2 inhibitors/inducers are not excluded Participation in another investigational trial while on this study is not allowed History of poorly controlled gastrointestinal disorders including acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, Crohn's disease, ulcerative colitis or other diseases which have the potential for bowel perforation Other malignancies except for resected cervical cancer in situ

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (adjuvant enzyme inhibitor and radiation therapy)<br>Optional non-therapeutic (biomarker) portion: Patients are randomized to 1 of 3 treatment arms. Arm A: Patients receive erlotinib hydrochloride PO QD and linsitinib PO BID on days 1-7 or 1-14. Treatment continues until 1 day before planned surgical resection (for up to 28 days if surgery is delayed). Therapeutic portion: This is a phase I dose-escalation study of linsitinib followed by a phase II study. Patients undergo standard QD conventional radiotherapy at the discretion of the treating physician. Patients receive concurrent linsitinib PO BID and erlotinib hydrochloride PO QD during the entire course of radiation in the absence of disease progression or unacceptable toxicity. | Drug: erlotinib hydrochloride<br>* Given PO<br>* Other names: OSI-774;Drug: linsitinib<br>* Given PO<br>* Other names: OSI-906;Radiation: radiation therapy<br>* Undergo radiation therapy<br>* Other names: therapy, radiation;Procedure: therapeutic conventional surgery<br>* Undergo planned surgery<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Erlotinib and Placebo (Sugar Pill)<br>Arm B: Patients receive erlotinib hydrochloride PO QD and placebo PO QD or BID on days 1-7 or 1-14. Treatment continues until 1 day before planned surgical resection (for up to 28 days if surgery is delayed). Therapeutic portion: This is a phase I dose-escalation study of linsitinib followed by a phase II study. Patients undergo standard QD conventional radiotherapy at the discretion of the treating physician. Patients receive concurrent linsitinib PO BID and erlotinib hydrochloride PO QD during the entire course of radiation in the absence of disease progression or unacceptable toxicity. | Drug: erlotinib hydrochloride<br>* Given PO<br>* Other names: OSI-774;Drug: placebo<br>* Given PO<br>* Other names: PLCB;|
| Experimental: OSI-906 and Placebo (Sugar Pill)<br>Arm C: Patients receive linsitinib PO BID and placebo PO QD or BID on days 1-7 or 1-14. Treatment continues until 1 day before planned surgical resection (for up to 28 days if surgery is delayed). Therapeutic portion: This is a phase I dose-escalation study of linsitinib followed by a phase II study. Patients undergo standard QD conventional radiotherapy at the discretion of the treating physician. Patients receive concurrent linsitinib PO BID and erlotinib hydrochloride PO QD during the entire course of radiation in the absence of disease progression or unacceptable toxicity. | Drug: linsitinib<br>* Given PO<br>* Other names: OSI-906;Drug: placebo<br>* Given PO<br>* Other names: PLCB;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with overall survival(OS) after two years of treatment (Phase II) | The 2-year OS and 95% confidence interval will be determined using Kaplan-Meier method. | Up to 2 years | 
| The maximum tolerated dose (MTD) of linsitinib when used in combination with erlotinib hydrochloride and radiation therapy (phase 1) | The MTD of linsitinib when used in combination with erlotinib hydrochloride and radiation therapy will be determined using a standard 3x3 dose-escalation scheme. The dose limiting toxicity (DLT) will be defined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.02). DLT is defined as any grade 3 non-hematologic toxicity attributed to treatment or grade 4 hematologic toxicity, neutropenic fever requiring hospitalization, or treatment delay due to hematologic toxicity. | up to 24 months | 
| The maximum tolerated dose (MTD) of linsitinib when used in combination with erlotinib hydrochloride and radiation therapy (phase 1) | The MTD of linsitinib when used in combination with erlotinib hydrochloride and radiation therapy will be determined using a standard 3x3 dose-escalation scheme. The dose limiting toxicity (DLT) will be defined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events CTCAE (v4.02). DLT is defined as any grade 3 non-hematologic toxicity attributed to treatment or grade 4 hematologic toxicity, neutropenic fever requiring hospitalization, or treatment delay due to hematologic toxicity. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with disease free survival |  | At 2 years | 
| Time to recurrence and patterns of failure |  | Up to 2 years | 
| Effects of short-term preoperative treatment with erlotinib hydrochloride and linsitinib on the expression EGFR, IGF-1R and parallel or downstream molecular targets in cSCCHN in one third of the patients |  | From baseline to time of surgery (after 7-14 days of study drug administration) | 
| Number of adverse events observed from linsitinib in combination with erlotinib hydrochloride and radiation therapy. |  | After completion of study therapy at 6 and 12 weeks | 
| Number of adverse events observed from linsitinib in combination with erlotinib hydrochloride and radiation therapy |  | Every 12-16 weeks for 2 years | 
| Number of adverse events observed from linsitinib in combination with erlotinib hydrochloride and radiation therapy |  | Every 6 months for 3 years and then annually thereafter |