The BURAN Study of Buparlisib in Patients With Recurrent or Metastatic HNSCC

Inclusion Criteria:

1. Aged ≥18 years old.

2. Able to provide informed consent obtained before any trial related activities andaccording to local guidelines.

3. Patient has histologically and/or cytologically-confirmed HNSCC.

4. Patient has archival or new tumor tissue for the analysis of biomarkers andconfirmation of HPV status (if unknown). One tumor block (preferred) or arecommended minimum of 5 unstained slides for patients with known HPV status (fortumor DNA characterization) or a recommended minimum of 10 slides for patients whoseHPV status is unknown (5 slides for HPV testing plus 5 slides needed for biomarkertesting). Enrollment in the study is contingent on confirmation of the availabilityof an adequate amount of tumor tissue, except in rare special circumstances, whichmust be reviewed and approved by the sponsor.

5. Patient has either progressive or recurrent disease after treatment with PDL1/PD1based therapy for recurrent or metastatic disease:

6. PDLl/PD1 therapy alone for metastatic (monotherapy) disease

7. PDL1/PD1 in combination with chemotherapy for metastatic and recurrent disease

8. PDL1/PD1 used for metastatic disease, after or prior to receiving a platinumagent for locally advanced or metastatic disease.

10. Patient has received no more than two prior lines of systemic treatment forHNSCC (single agent chemotherapy used as a radiosensitizer is not counted as aprior line of therapy).

11. Patient has measurable disease as determined per RECIST version 1.1. If the onlysite of measurable disease is a previously irradiated lesion, documented progressionof disease and a four-week period since radiotherapy completion is required.

12. Patient has adequate bone marrow function and organ function as shown by thefollowing:

13. Absolute neutrophil count (ANC) ≥1.5 x 109/L.

14. Hemoglobin ≥9 g/dL (which may be reached by transfusion).

15. Platelets ≥100 x 109/L (which may be reached by transfusion).

16. International normalized ratio (INR) ≤1.5.

17. Calcium (corrected for serum albumin) within normal limits (WNL) or ≤ grade 1severity according to NCI-CTCAE version 5.0 if judged clinically notsignificant by the Investigator.Patients concomitantly taking bisphosphonates or denosumab for calciumcorrection are eligible.

18. Normal potassium and magnesium levels.

19. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5 xupper limit of normal (ULN) or < 3.0 x ULN if liver metastases are present.

20. Total serum bilirubin ≤ ULN or ≤ 1.5 x ULN if liver metastases are present; ortotal bilirubin ≤ 3.0 x ULN with direct bilirubin below or within normal rangein patients with well documented Gilbert's Syndrome. Gilbert's syndrome isdefined as presence of episodes of unconjugated hyperbilirubinemia with normalresults from cells blood count (including normal reticulocyte count and bloodsmear), normal liver function test results, and absence of other contributingdisease processes at the time of diagnosis.

21. Serum creatinine ≤ 1.5 x ULN or calculated and directly measured creatinineclearance (CrCL) > 30 mL/min.

22. Haemoglobin A1c (glycosylated hemoglobin; HbA1c) ≤8%.

23. Patient has Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

24. Patient is able to swallow and retain oral medication. Patients able to swallow oralmedication but mostly self-nourished through gastric or jejunal feeding tube areeligible.

25. Patients must apply highly effective contraception during and throughout the study,as well after the final dose of study treatment

Exclusion Criteria:

Patients meeting any of the following criteria will not be eligible for participation in the study:

1. Patient has received previous treatment with any protein kinase B (PKB/AKT),mammalian target of rapamycin (mTOR) inhibitors, or phosphatidylinositol 3 kinase (PI3K) pathway inhibitors.

2. Patient received treatment with a taxane as part of prior treatment for metastaticdisease.

3. Patient has symptomatic central nervous system (CNS) metastases. Patients withasymptomatic CNS metastases may participate in this study. Patient must havecompleted any prior local treatment for CNS metastases ≥ 28 days prior to the startof study treatment (including radiotherapy) and must be on a stable low dose ofcorticosteroid therapy. Radiosurgery must have been completed at least 14 days priorto start of study treatment.

4. Patient has received wide field radiotherapy ≤ 4 weeks or limited field radiationfor palliation ≤ 2 weeks prior to starting study treatment or who have adverseevents which have not recovered to grade 1 or better from previous chemotherapytreatment (except alopecia, autoimmune endocrine events must be stable andcontrolled).

5. Patient has grade ≥ 2 neuropathy, colitis, pneumonitis, , and uncontrolledendocrinopathies (e.g., hypothyroidism, diabetes with hemoglobin A1c > 8%) fromprevious treatment

6. Patient has had major surgery within 14 days prior to starting study treatment orhas not recovered from major side effects.

7. Patient is currently receiving increasing or chronic treatment (>5 days) withcorticosteroids or another immunosuppressive agent. The following uses ofcorticosteroids are permitted: single doses; standard premedication for paclitaxel,topical applications (e.g., rash), inhaled sprays (e.g., obstructive airwaysdiseases), eye drops, or local injections (e.g., intra-articular), or < 10 mgprednisolone or equivalent.

8. Patient is being treated at start of study treatment with any of the followingdrugs:

9. Drugs known to be strong or moderate inhibitors or inducers of isoenzymecytochrome P450 3A4 (CYP3A4) including herbal medications (see Table 16).

10. Drugs with a known risk of inducing Torsades de Pointes. Note: The patient musthave discontinued strong inducers for at least one week and must havediscontinued strong inhibitors before the treatment is initiated. Switching toa different medication prior to starting study treatment is allowed.

11. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant,for treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weightheparin (LMWH), fondaparinux or new oral anticoagulants (NOACs) is allowed.

12. Patient has a known hypersensitivity and/or contraindication to paclitaxel, standardpremedication for paclitaxel, or other products containing Cremophor®.

13. Patient has other concurrent severe and/or uncontrolled medical conditions thatwould, in the Investigator's judgment, contraindicate patient participation in theclinical study (e.g., active or uncontrolled severe infection, chronic activehepatitis, immunocompromised, acute or chronic pancreatitis, uncontrolled high bloodpressure, interstitial lung disease, etc).

14. Patient has a known history of human immunodeficiency virus (HIV) infection (testingnot mandatory).

15. Patient has any of the following cardiac abnormalities:

16. Symptomatic congestive heart failure within 12 months of the screening period.

17. History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV) or documented cardiomyopathy and leftventricular ejection fraction (LVEF) <50% as determined by multiple gatedacquisition (MUGA) scan or echocardiogram (ECHO).

18. Myocardial infarction ≤six months prior to enrollment.

19. Unstable angina pectoris.

20. Serious uncontrolled cardiac arrhythmia.

21. Symptomatic pericarditis.

22. QT interval corrected according to the formula of Fridericia (QTcF) > 450 msecfor males and > 470 msec for females, on the screening electrocardiogram (ECG).

23. Currently receiving treatment with medication that has a known risk to prolongthe QT interval or inducing Torsades de Pointes, and the treatment cannot bediscontinued or switched to a different medication prior to starting studytreatment.

24. Patient has impairment of gastrointestinal (GI) function or GI disease that maysignificantly alter the absorption of study treatment (e.g., ulcerative diseases,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowelresection).

25. Patient has a medically documented history of or active major depressive episode,bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a historyof suicidal attempt or ideation, or homicidal ideation (e.g., risk of doing harm toself or others), or active severe personality disorders (defined according to theDiagnostic and Statistical Manual of Mental Disorders Fifth Edition [DSM-V]) are noteligible. Note: For patients with psychotropic treatments ongoing at baseline, thedose and the schedule should not be modified within the previous six weeks prior tostart of study treatment.

26. Patient has other prior or concurrent malignancy except for the following:adequately treated basal cell or squamous cell skin cancer, or other adequatelytreated in situ cancer, early gastric or GI cancer resected completely by endoscopyprocedures or any other cancer from which the patient has been disease free for ≥ 3years.

27. Patient has a history of non-compliance to any medical regimen or inability to grantconsent.

28. Patient is concurrently using or has used another approved or investigational canceragent within 4 weeks of randomization.

29. Patient is pregnant or nursing (lactating). Patients with elevated human chorionicgonadotrophin (hCG) at baseline that is judged to be related to the tumor areeligible if hCG levels do not show the expected doubling when repeated five to sevendays later, or pregnancy has been ruled out by vaginal ultrasound.

30. Patient has received a live vaccine within 30 days of planned start of studytherapy. Note: Seasonal influenza vaccines for injection are generally inactivatedflu vaccines and are allowed; however intranasal influenza vaccines (eg, Flu-Mist®)are live attenuated vaccines, and are not allowed. Non-live COVID vaccinations orboosters should not occur within 30 days of study start.