| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Head and Neck Squamous Cell Carcinoma (HNSCC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is as follows:
• To assess the overall survival (OS) of buparlisib in combination with paclitaxel compared to paclitaxel alone in patients with refractory, recurrent, or metastatic HNSCC.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
• To evaluate additional efficacy parameters: progression free survival (PFS), ORR, and DoR, by the Investigator and Independent Radiological Review Committee (IRRC).
• To evaluate efficacy parameters in subgroups of patients defined by the randomization strata.
• To assess the effect of buparlisib in combination with paclitaxel on patient’s symptoms and health-related quality of life (HRQoL).
• To assess the pharmacokinetics (PK) of buparlisib in combination with paclitaxel.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet the following criteria to be eligible for enrollment into the study:
1. Aged ≥18 years old.
2. Able to provide informed consent obtained before any study related activities and according 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 and confirmation of HPV status (if unknown). A recommended minimum of 5 slides for patients with known HPV status (for tumor DNA characterization) or a recommended minimum of 10 slides for patients whose HPV status is unknown (i.e. 5 slides for HPV testing and 5 slides for biomarker testing). Enrollment in the study is contingent on confirmation of the availability of an adequate amount of tumor tissue, except in rare special circumstances, which must be reviewed and approved by the sponsor. The quantity of slides to be provided is a recommendation; more slides may be requested to ensure testing can be complete.
5.Patient has either progressive or recurrent disease after treatment with PDL1/PD1 based therapy for recurrent or metastatic disease:
a.PDL1/PD1 therapy alone for metastatic or recurrent (monotherapy) disease
b.PDL1/PD1 in combination with chemotherapy for metastatic or recurrent disease
c.PDL1/PD1 used for metastatic disease, after or prior to receiving a platinum agent for locally advanced or metastatic disease.
d. For France patients only a specific inclusion criteria was added - please refer to PA5.01.
6.Patient has received no more than two prior lines of systemic treatment for recurrent or metastatic HNSCC (single agent chemotherapy used as a radiosensitizer is not counted as a prior line of therapy).
7. Patient has measurable disease as determined per RECIST version 1.1. If the only site of measurable disease is a previously irradiated lesion, documented progression of disease and a four-week period since radiotherapy completion is required.
8. Patient has adequate bone marrow function and organ function as shown by the following:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
b. Hemoglobin ≥ 9 g/dL (which may be reached by transfusion).
c. Platelets ≥ 100 x 109/L (which may be reached by transfusion).
d. International normalized ratio (INR) ≤ 1.5.
e. Calcium (corrected for serum albumin) within normal limits (WNL) or ≤ grade 1 severity according to NCI-CTCAE version 5.0 if judged clinically not significant by the Investigator. Patients concomitantly taking bisphosphonates or denosumab for calcium correction are eligible.
f. Normal potassium and magnesium levels or clinically acceptable levels as per investigator’s judgement and confirmation.
For France patients only a specific inclusion criteria was added - please refer to PA5.01.
g. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5 x upper limit of normal (ULN) or < 3.0 x ULN if liver metastases are present.
h. Total serum bilirubin ≤ ULN or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin below or within normal range in patients with well documented Gilbert’s Syndrome. Gilbert’s syndrome is defined as presence of episodes of unconjugated hyperbilirubinemia with normal results from cells blood count (including normal reticulocyte count and blood smear), normal liver function test results, and absence of other contributing disease processes at the time of diagnosis.
i. Serum creatinine ≤ 1.5 x ULN or calculated and directly measured creatinine clearance (CrCL) > 30 mL/min.
j. HbA1c≤8%.
9. Patient has Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
10. Men should use an effective method of contraception and not father a child during the study and for the six-month period after treatment. Men are recommended to seek advice on conservation of sperm prior to treatment with paclitaxel as per product label. Female partners of male participants are to use highly effective contraception while the male participants are receiving treatment and for at least 90 days after their partner’s last buparlisib dose, or until at least 6 months after their partner’s last paclitaxel dose, whichever is longer. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use a highly effective contraceptive during the study and for at least 90 days after the final dose of buparlisib or as specified in the local prescription guidelines for paclitaxel (e.g., for six months after final dose of paclitaxel according to the product insert/Summary of Product Characteristics [SmPC] from France & UK, whichever is longer. |
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| E.4 | Principal exclusion criteria |
| 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 recurrent or metastatic disease.3.Patient has symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases may participate in this study. Patient must have completed any prior local treatment for CNS metastases ≥ 28 days prior to the start of study treatment (including radiotherapy) and must be on a stable low dose of corticosteroid therapy. Radiosurgery must have been completed at least 14 days prior to start of study treatment.4.Patient has received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study treatment or who have adverse events which have not recovered to grade 1 or better from previous chemotherapy treatment (except alopecia, autoimmune endocrine events must be stable and controlled).5.Patient has grade ≥ 2 neuropathy, colitis, pneumonitis, and uncontrolled endocrinopathies (e.g., hypothyroidism, diabetes with hemoglobin A1c > 8%) from previous treatment.6.Patient has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.7.Patient is currently receiving increasing or chronic treatment (>5 days) with corticosteroids or another immunosuppressive agent. The following uses of corticosteroids are permitted: single doses; standard premedication for paclitaxel, topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops, or local injections (e.g., intra-articular), or < 10 mg prednisolone or equivalent.9.Patient is currently receiving warfarin or other coumarin-derived anti-coagulant, for treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), fondaparinux or new oral anticoagulants (NOACs) is allowed.10.Patient has a known hypersensitivity and/or contraindication to paclitaxel, standard premedication for paclitaxel, or other products containing Cremophor®.11.Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the Investigator’s judgment, contraindicate patient participation in the clinical study (e.g., active or uncontrolled severe infection, chronic active hepatitis, immunocompromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease, etc).12.Patient has a known history of HIV infection (testing not mandatory).13.Patient has any of the following cardiac abnormalities: a.Symptomatic congestive heart failure within 12 months of the screening period. b.History of documented congestive heart failure (New York Heart Association functional classification III-IV) or documented cardiomyopathy and left ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO). c.Myocardial infarction ≤six months prior to enrollment. d.Unstable angina pectoris. e.Serious uncontrolled cardiac arrhythmia.f.Symptomatic pericarditis. g.QT interval corrected according to the formula of Fridericia (QTcF) > 450 msec for males and > 470 msec for females, on the screening electrocardiogram (ECG).14.Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug. 15.Patient has a medically documented history of mental disorders with poor control, including active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g., risk of doing harm to self or others), or active severe personality disorders (defined according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition [DSM-V]) are not eligible. For patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous six weeks prior to start of study drug. 20. Patient has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. Non-live COVID vaccinations/boosters may be administered during a patient’s participation of the trial, however it is recommended this not occur within 30 days of study start (C1D1) or during Cycle 1 for those patients randomized to the buparlisib arm. Patients are not to be excluded if administration of the non-live COVID vaccinations or boosters occurs within 30 days of a patient’s C1D1 or during cycle1. For exclusion criteria 8, 16 to 19 please refer to the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is OS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary statistical efficacy endpoint of the study is OS, defined as the time from randomization to death due to any cause. Patients who are not reported as having died at the time of analysis will be censored at the date when they were last known to be alive. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are as follows:
Efficacy:
• PFS as assessed by IRRC and by investigator
• Overall response rate (ORR) as assessed by IRRC and by investigator
• Duration of response (DoR) as assessed by IRRC and by investigator
• OS, PFS, ORR and DoR in subgroups of patients defined by the randomization strata (HPV status)
• Change from baseline in the global health status/Quality of life (QOL) and pain scale scores of the EORTC QLQ-C30, respectively.
• Time to definitive 10% deterioration in the global health status/QOL and pain scale scores of the EORTC QLQ-C30, respectively.
• EQ-5D-5L
Safety:
• AEs
• Clinical laboratory tests
• PHQ-9
• GAD-7
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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