Phase Ib Study of BKM120 With Cisplatin and XRT in High Risk Locally Advanced Squamous Cell Cancer of Head and Neck

- This phase Ib study is combining standard chemoradiotherapy with weekly cisplatin and
BKM120 to assess tolerability of this combination in high risk patients with locally
advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN). The investigators will
also obtain preliminary information about the efficacy of this treatment.

- The participant will receive the study drug buparlisib once daily, by mouth, for 45
days. The participant will be given a study drug-dosing diary for each cycle. It will
include special instructions for taking the study drug at home.

- The investigators are looking for the highest dose of the study drug that can be
administered safely without severe or unmanageable side effects, not everyone who
participates in this research study will receive the same dose of the study drug. The
dose given will depend on the number of participants who have been enrolled in the study
before and how well they have tolerated their doses.

- All participants will receive weekly cisplatin injection. Cisplatin will be given
intra-venously (IV) on days: (1, 8, 15, 22, 29, 36 and 43) at DFCI.

- All participants will receive daily radiotherapy with intensity-modulated radiotherapy
(IMRT) for 7 weeks, delivered at DFCI. IMRT is a type of 3-dimensional radiation therapy
that uses computer-generated images to show the size and shape of the tumor. Thin beams
of radiation of different intensities are aimed at the tumor from many angles. This type
of radiation therapy reduces the damage to healthy tissue near the tumor.

- The investigators would like to keep track of the participant's medical condition.
Follow-up will continue every 4 to 12 weeks after the end of treatment for the first
year and at the investigator's discretion thereafter.

Inclusion Criteria:

- Stage III/IV, locally advanced, biopsy proven squamous cell cancer of the head and
neck that undergo chemoradiation as their primary treatment with curative intent.

- Oropharynx (HPV positive and HPV negative), hypopharynx, larynx primaries, nasopharynx
as well as those with documented SCC of the cervical lymph nodes, with unknown
primaries.

- >10 pack years of tobacco use

- Age ≥ 18 years

- ECOG performance status ≤ 2

- At least one site of measurable disease

- Adequate bone marrow function as shown by: ANC > 1.5 x 109/L, Platelets >100 x 109/L,
Hb >9 g/dL

- Total calcium (corrected for serum albumin) within normal limits

- Magnesium ≥ the lower limit of normal

- Potassium within normal limits for the institution.

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal
range

- Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present;
or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients
with well documented Gilbert Syndrome)

- Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min

- Serum amylase ≤ ULN

- Serum lipase ≤ ULN

- Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)

- Signed informed consent

- INR ≤ 2

Exclusion Criteria:

- Distant metastatic disease

- Less than or equal to 10 pack years of tobacco history

- Received prior chemotherapy

- Received prior radiation to the head and neck or adjacent anatomical site

- Received prior treatment with a P13K inhibitor.

- Known hypersensitivity to BKM120 or to its excipients

- Acute or chronic liver, renal disease or pancreatitis

- Mood disorders ≥ CTCAE grade 3

- Diarrhea ≥ CTCAE grade 2

- Active cardiac disease

- History of cardiac dysfunction including any of the following:

- Patient has poorly

- Impairment of gastrointestinal (GI) function

- Currently receiving treatment with medication with a known risk to prolong the QT
interval or inducing Torsades de Pointes and the treatment cannot either be
discontinued or switched to a different medication prior to starting study drug.

- Chronic treatment with steroids or another immunosuppressive agent.

- Herbal medications and certain fruits within 7 days prior to starting study drug.

- Currently treated with drugs known to be moderate and strong inhibitors or inducers of
isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different
medication prior to starting study drug. Please refer to Appendix B for a list of
prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with weak
inhibitors of CYP3A is allowed).

- Undergone major surgery ≤ 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy.

- Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative
anticoagulant.

- Women who are pregnant or breast feeding or adults of reproductive potential not
employing an effective method of birth control.

- Known diagnosis of human immunodeficiency virus (HIV) infection

- History of another malignancy within 3 years, except cured basal cell carcinoma of the
skin or excised carcinoma in situ of the cervix