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

A Phase II, Multicenter Trial Aiming to Evaluate the Clinical Interest of a Monotherapy With BKM120 , a Phosphoinositide 3-kinase (PI3K) Inhibitor in Patient With Metastatic Head and Neck Cancer Recurrent or Progressive Under Platin and Cetuximab-based Chemotherapy

The aim of this study is to determine the activity, to assess the safety and tolerance of BKM120 in adult patients with recurrent or metastatic head and neck cancer progressive under platin and cetuximab-based chemotherapy.

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)