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

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.

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/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