Activity and Safety Study of BKM120 in Monotherapy in Patient With Metastatic Head and Neck Cancer Recurrent or Progressive

BKM120 is a PI3K inhibitor. The PI3K/Protein kinase B (AKT) signalling pathway deregulation is frequently observed in Head and neck cancer. In addition to its role in tumor genesis, the PI3K/AKT pathway seems to be involved in resistance to cetuximab.

In this context, the study proposal is to evaluate the clinical interest of a monotherapy with a PI3K inhibitor (BKM120, Novartis) in patients with metastatic head and neck cancers refractory or relapsing under platin and cetuximab based- chemotherapy. Since resistance to cetuximab can result from phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, PIK3CA amplification or mutation upstream in the PI3K pathway, BKM120 activity will be evaluated in two parallel independent cohorts of patients: patients presenting a PI3KCA mutation and patients without a PI3KCA mutation.

Inclusion criteria

• 1. Adult men and women ≥ 18 years at the day of inform consent signature.
• 2. Patients with metastatic or relapsed squamous cell head and neck carcinoma .
• 3. Documented progression or relapse after platin and cetuximab or anti-epidermal growth factor receptor (EGFR) -based chemotherapy at time of study drug start
• 4. Documented mutational status of PIK3CA before study drug start
• 5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 .
• 6. At least one measurable lesion by CT-scan as per RECIST 1.1 .
• 7. Life expectancy > 12 weeks.
• 8. Patients must be able to swallow capsules.
• 9. Adequate bone marrow, renal and liver function as defined by the following tests :
• Absolute neutrophil count ≥ 1.0 x 109/L,
• Platelet count > 100 x 109/L,
• Haemoglobin value above 9 g/dL,
• international normalized ratio (INR) ≤ 1.5
• Serum Creatinine ≤ 1.5 upper limit of normal (ULN)
• Glomerular filtration rate calculated using Cockcroft-Gault formula > 60ml/min (or MDRD formula for patients older than 65 years)
• Potassium, calcium, magnesium within normal limits for the institution
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < ULN (or < 3.0 x ULN if liver metastases are present))
• Serum bilirubin within normal range (or ≤ 1.5 ULN if liver metastases are present; or total bilirubin ≤ 3.0 ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome)
• Fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L.
• 10. Women of childbearing potential (entering the study after a confirmed menstrual period and who have a negative pregnancy test within ≤ 72 hours before initiating study treatment) must agree to use two methods of medically acceptable forms of contraception during the whole treatment period and for 1 month (= 5 x t½ of BKM120) after the last treatment intake.
• 11. Fertile males must use a highly effective contraception during dosing of any study agent + [5 x t1/2] + 12 weeks = contraception through 16 weeks after final dose of study therapy and should not father a child in this period. Female partner of male study subject: highly effective contraception during dosing of study agent + 4 weeks after final dose of study therapy
• 12. Patient should be able and willing to comply with study visits and procedures as per protocol.
• 13. Patient should understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed.
• 14. Patients must be covered by a medical insurance.

Exclusion criteria

• 1. Patient having received previous treatment with PI3K and/or mammilian target of rapamycin (mTOR) inhibitors.
• 2. Patient with symptomatic central nervous system (CNS) metastases.
• 3. Patient with a concurrent malignancy or has a malignancy within 3 years of study enrollment, (with the exception of adequately treated basal or squamous cell carcinoma or non-melanomatous skin cancer).
• 4. Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist:
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others),
• Patients with active severe personality disorders (defined according to Diagnostic and Statistical Manual (DSM) - IV) are not eligible.

Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug.

• ≥ CTCAE grade 3 anxiety,
• or meets the cut-off score of ≥ 12 in the Patient Health Questionnaire (PHQ) -9 or a cut-off of ≥ 15 in the generalized anxiety disorder (GAD) -7 mood scale, respectively,
• or selects a positive response of '1, 2, or 3' to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9).
• 5. Patient concurrently using other approved or investigational anti-neoplasic agent.
• 6. Patient who has received anticancer therapy < 2 weeks or investigational treatment < 4 weeks prior the initiation of study drug.
• 7. Patient who has received radiotherapy ≤ 4 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia).
• 8. Patient having had major surgery within 14 days prior to starting study drug or has not recovered from major side effects of the surgery.
• 9. Patient with poorly controlled diabetes mellitus (i.e. HbA1c > 8 %)
• 10. Patient with active cardiac disease including any of the following:
• Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO),
• corrected QT interval (QTc) > 480 (female) or 470 msec (male) on screening ECG (using the corrected QT Fridericia (QTcF) formulae),
• Angina pectoris that requires the use of anti-anginal medication,
• Ventricular arrhythmias except for benign premature ventricular contractions,
• Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication,
• Conduction abnormality requiring a pacemaker,
• Valvular disease with documented compromise in cardiac function,
• Symptomatic pericarditis.
• 11. Patient with a history of cardiac dysfunction including any of the following:
• Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function,
• History of documented congestive heart failure (New York Heart Association functional classification III-IV),
• Documented cardiomyopathy,
• Other cardiac arrhythmia not controlled with medication.
• 12. Patient currently receiving treatment with QT prolonging medication known to have a risk to induce Torsades de Pointes, and if the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
• 13. Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120
• 14. Patient receiving chronic treatment (> 5 days) with steroids or another immunosuppressive agent. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment (e.g., dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment, are eligible.
• 15. Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate her participation in the clinical study
• 16. Patient has a history of non-compliance to medical regimen.
• 17. Patient is currently being treated with drugs known to be strong inhibitors or inducers of isoenzyme Cytochrome P450 family 3 subfamily A member 4 (CYP3A), and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
• 18. Patient has a known history of HIV infection.
• 19. Pregnant or nursing (lactating) woman.
• 20. Patient has a known hypersensitivity to any of the excipients of BKM120.
• 21. Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy.
• 22. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin, or fondaparinux is allowed.
• 23. Patient has acute viral hepatitis or a history of chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, typically defined by elevated AST/ALT (persistent or intermittent), high HBV DNA level, HBsAg positive, or high HCV RNA level (testing not mandatory)