MLN8237 in Head and Neck Cancer

This is a phase 1b study of MLN8237, cetuximab and definitive radiation therapy for patients
with previously untreated locoregionally advanced HNSCC who are candidates for definitive
radiation therapy with curative intent with cetuximab as the radiosensitizer. The treatment
regimen consists of MLN8237 po bid for 7 days followed by 2 weeks off for 4 cycles with the
first 3 cycles of MLN8237 concurrent with RT. Three dose levels of MLN8237 are planned: 30,
40 and 50 mg po bid. Cetuximab will be given at the FDA-approved loading and maintenance
doses starting ~ 1 week prior to the initiation of radiation therapy and continuing for a
grand total of 12 weeks. Radiotherapy will be administered in 2-Gy fractions, 5 days a week,
to total dose of ~70 Gy according to standard departmental protocols. Correlative biomarker
assays on pre- and on-therapy biopsy specimens (tissue micro arrays analyzed by AQUA
quantitative immunofluorescence) will seek to establish proof-of-mechanism by determining if
the novel drug combination has the predicted effects on biochemical signaling pathways linked
to Aurora A and EGFR. Tumor samples will also be analyzed for Aurora A and EGFR expression by
IHC and FISH.

Inclusion Criteria:

1. Male or females greater than 18 years of age.

2. ECOG performance status of 0-1

3. Patients must have histologically or cytologically confirmed HNSCC of the oral cavity,
oropharynx, hypopharynx, larynx, nasopharynx or paranasal sinuses that is considered
after a multidisciplinary evaluation (surgery, medical oncology & radiation oncology)
to be appropriate for definitive cetuximab-based radiation therapy

4. No distant metastatic disease. Minimum work-up includes:

- History/physical examination within 4 weeks prior to registration, including
assessment of weight and weight loss in past 6 months and an examination by a
Medical Oncologist

- PET/CT scan within 6 weeks prior to registration

- CT scan or MRI of the head and neck (of the primary tumor and neck nodes) within
4 weeks prior to registration

5. Adequate organ and marrow function

6. Negative pregnancy test within 2 weeks prior to registration for women of childbearing
potential. The effects of MLN8237 on the developing human fetus are unknown. For this
reason and because MLN8237 agents as well as other therapeutic agents used in this
trial are known to be teratogenic, 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. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.

7. Male subject agrees to use an acceptable method for contraception during the entire
study treatment period through 4 months after the last dose of MLN8237.

8. Ability to understand and willingness to sign a written informed consent document with
the understanding that consent may be withdrawn by the subject at any time without
prejudice to future medical care.

Exclusion Criteria:

1. Systemic anti-neoplastic treatment within 21 days preceding the first dose of MLN8237.
Patients treated with non-cytotoxic small molecule drugs (eg, tyrosine kinase
inhibitors, such as erlotinib and hormonal agents, such as letrozole) must not have
received treatment with these drugs for at least 2 weeks before the first dose of
MLN8237 is administered.

2. Patient has already had definitive surgical treatment, excluding diagnostic biopsy of
the primary site or nodal sampling of neck disease. Prior radical or modified neck
dissection is also not permitted.

3. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields.

4. Primary tumor site is skin or salivary gland.

5. Uncorrected CTCAE, v. 4.0 grade 3-4 electrolyte abnormalities

6. Patients may not be receiving any other investigational agents or treatment with any
investigational products within 21 days before the first dose of study drug.

7. Patients with known brain metastasis are excluded from this clinical trial because of
their poor prognosis and because they often develop rapid progressive neurologic
dysfunction that would confound the evaluation of neurological and other adverse
events.

8. History of known allergic reactions attributed to compounds of similar chemical or
biologic composition to MLN8237 or cetuximab.

9. Patients may not be taking proton pump inhibitors, H2 antagonists or pancreatic enzyme
replacement. Subjects who refuse to limit use of alcohol are also excluded.

10. Severe, active co-morbidity

11. Clinical evidence of intestinal malabsorption. Examples include resection of pancreas
or upper small bowel, requirement for pancreatic enzymes, or any other condition that
would modify small bowel absorption of oral medications.

12. Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use
of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution,
including prior allogeneic bone marrow transplantation.

13. Prior radiotherapy to greater or equal to 25% of bone marrow. Whole pelvic radiation
is considered to be over 25%.

14. Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

15. Major surgery within 14 days prior to the first dose of study drug treatment.

16. Inability to swallow oral medication or to maintain a fast as required 2 hours before
and 1 hour after MLN8237 administration.

17. Known history of HIV infection, or active hepatitis B, or hepatitis C infection.
Testing is NOT required in the absence of clinical findings or suspicion.

18. Known history of uncontrolled sleep apnea syndrome and other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease; requirement for supplemental oxygen.

19. Patient has Grade 2 or higher peripheral neuropathy within 14 days before enrollment.

20. Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum -human chorionic gonadotropin (-hCG)
pregnancy test result obtained during screening. Pregnancy testing is not required for
post-menopausal or surgically sterilized women.

21. Treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin,
rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and
during the study.