| 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.1.3 | 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 biomarkers of response to buparlisib in combination with paclitaxel.
• 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 |
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). One tumor block (preferred) or a recommended minimum of 5 unstained 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 (5 slides for HPV testing plus 5 slides needed 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
5. Patient has either progressive or recurrent disease after treatment with PDL1/PD1 based therapy for recurrent or metastatic disease:
a. PDLl/PD1 therapy alone for metastatic (monotherapy) disease
b. PDL1/PD1 in combination with chemotherapy for metastatic and recurrent disease
c. PDL1/PD1 used for metastatic disease, after or prior to receiving a platinum agent for locally advanced or metastatic disease.
d. Patients enrolled in France must have received prior systemic therapy for recurrent or metastatic disease containing a combination of platinum chemotherapy and fluoropyrimidine (associated with cetuximab if PD-L1 expression is negative by CPS ; or with pembrolizumab if PD-L1 expression is positive by CPS) before study entry as per recommendations.
6. Patient has received no more than two prior lines of systemic treatment for 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
g. AST and 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. Haemoglobin A1c (glycosylated hemoglobin; HbA1c) ≤8%.
9. Patient has Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
10. Patient is able to swallow and retain oral medication. Patients able to swallow oral medication but mostly self-nourished through gastric or jejunal feeding tube are eligible.
For inclusion criteria 11 on contraception please refer to the protocol.
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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 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.
8. Patient is being treated at start of study treatment with any of the following drugs:
- Drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications, drugs with a known risk of inducing Torsades de Pointes.
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 study.
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 , History of documented congestive heart failure or documented cardiomyopathy and left ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition (MUGA) scan or ECHO, Myocardial infarction ≤six months prior to enrollment, Unstable angina pectoris, Serious uncontrolled cardiac arrhythmia, Symptomatic pericarditis, QT interval corrected according to the formula of Fridericia (QTcF) > 450 msec for males and > 470 msec for females, on the screening ECG, Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
14. Patient has impairment of GI function or GI disease that may significantly alter the absorption of study treatment.
15. Patient has a 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 or active severe personality disorders are not eligible.
16. Patient has other prior or concurrent malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, early gastric or GI cancer resected completely by endoscopy procedures or any other cancer from which the patient has been disease free for ≥ 3years.
17. Patient has a history of non-compliance to any medical regimen or inability to grant consent.
18. Patient is concurrently using or has used another approved or investigational cancer agent within 4 weeks of randomization.
For exclusion criteria 19 please refer to the protocol.
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 or boosters should not occur within 30 days of study start.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is OS for the entire (Intent-to-Treat [ITT]) population of patients. The interim endpoint of the study is ORR on a subset of patients with at least six months follow up at the time the last patient is enrolled |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary statistical analysis of the study will be based on OS data from all patients once 383 events (deaths) have occurred. This analysis is expected to occur when all patients have either discontinued from the study or been followed for a minimum of 12 months |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are as follows:
Efficacy:
• PFS
• Overall response rate (ORR)
• Duration of response (DoR)
• 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
• Biomarkers
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 |
All secondary analyses will be reported by treatment arm and analyses will be based on the ITT Population. PFS and DoR will be analyzed using the same methods as for the primary endpoint of OS. ORR will be analyzed using a Cochran-Mantel-Haenszel chi-square test with randomization factors as the strata.
Safety summaries and analyses will be performed on the Safety population. Descriptive statistics will be presented to summarize the safety data.
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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 | 14 |
| 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 |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| United Kingdom |
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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
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| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| 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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