Evaluation of Buparlisib and Paclitaxel Versus Paclitaxel Monotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
- Trial ID
- 2024-517251-12-00
- Protocol
- AN2025H0301
- Sponsor
- Adlai Nortye USA Inc.
Trial statistics
Objectives
The primary objective of the BURAN study is to assess the **overall survival** (OS) of **buparlisib** in combination with **paclitaxel** compared to paclitaxel alone in patients with refractory, recurrent, or metastatic head and neck squamous cell carcinoma (HNSCC). This is clinically relevant as it aims to determine whether the addition of buparlisib can improve survival outcomes in this patient population, which is often associated with poor prognosis and limited treatment options.
Secondary objectives include:
- Evaluating additional efficacy parameters such as progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR).
- Assessing the effect of buparlisib in combination with paclitaxel on patients' symptoms.
Participants
The clinical trial involves a total of **285 participants** diagnosed with **recurrent or metastatic head and neck squamous cell carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants were selected based on their diagnosis of histologically and/or cytologically-confirmed head and neck squamous cell carcinoma (HNSCC) and must have either progressive or recurrent disease following treatment with PDL1/PD1 based therapy. The trial includes individuals who have received no more than two prior lines of systemic treatment for recurrent or metastatic HNSCC. Participants are required to have measurable disease as per RECIST version 1.1 and must demonstrate adequate bone marrow and organ function. The study population is characterized by a diverse range of ages and includes a vulnerable population. Lifestyle considerations such as the use of highly effective contraception during and after the study are mandated. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **buparlisib** in combination with **paclitaxel** compared to **paclitaxel** alone in patients with recurrent or metastatic head and neck squamous cell carcinoma. This is a randomized, double-blind, controlled trial with an estimated duration from November 2021 to April 2025. The primary endpoint is overall survival (OS), with secondary endpoints including progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), and safety assessments through adverse events (AEs) and clinical laboratory tests. Exploratory endpoints involve biomarker analysis.
Participants will undergo a sequence of study visits starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects. The expected length of participant involvement is up to 60 weeks, with conditions for early termination including significant adverse events or disease progression.
Key elements of the research methodology include the administration of **buparlisib** orally in capsule or tablet form, and **paclitaxel** intravenously. The trial will ensure adherence to ethical standards, requiring informed consent and the use of effective contraception by participants. The trial's design aims to provide robust data on the comparative effectiveness of the treatment regimens, contributing to the understanding of therapeutic options for this patient population.
Treatment
The clinical trial involves the administration of **Buparlisib**, a chemical compound, in various pharmaceutical forms. The experimental medication is provided as **Buparlisib 50 mg Capsules** and **Buparlisib 10 mg Capsules**, both in a hard capsule form. The active substance in these capsules is buparlisib, and they are manufactured by ADLAI NORTYE USA INC. The route of administration for these capsules is oral, with a maximum daily dose of 100 mg. The treatment period is set for a maximum of 60 days. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
Additionally, **Buparlisib** is also administered in tablet form, available as **Buparlisib 50mg Tablet** and **Buparlisib 40mg Tablet**. These tablets are also produced by ADLAI NORTYE USA INC. and contain the same active substance, buparlisib. The oral route is used for administration, with a maximum daily dose of 100 mg, and the treatment duration is limited to 60 days. Participant compliance is closely monitored to maintain the integrity of the trial data.
The trial includes a comparator treatment with **Paclitaxel**, a chemical compound provided as a 6 mg/ml concentrate for solution for infusion. This product is manufactured by FRESENIUS KABI LIMITED. The route of administration for paclitaxel is intravenous, with a maximum daily dose of 80 mg/m². The treatment period for paclitaxel is also set for a maximum of 60 days. The administration of paclitaxel is conducted under controlled conditions to ensure accurate dosing and participant safety.
Throughout the trial, participant compliance with the dosing schedules for both buparlisib and paclitaxel is monitored through regular assessments and documentation. This ensures that the trial's objectives, including the assessment of overall survival in patients with recurrent or metastatic head and neck squamous cell carcinoma, are accurately evaluated.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **overall survival (OS)**. This primary endpoint will compare the OS of patients receiving **buparlisib** in combination with **paclitaxel** to those receiving paclitaxel alone in individuals with refractory, recurrent, or metastatic head and neck squamous cell carcinoma (HNSCC). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR). These parameters will also be evaluated in specific subgroups to provide a comprehensive understanding of the treatment's efficacy.
Data collection for these endpoints will be conducted at predetermined intervals throughout the study, with specific timepoints not explicitly detailed. The analysis will involve comparing the treatment groups using statistical methods appropriate for survival data. Additionally, exploratory endpoints will include the analysis of biomarkers to further elucidate the treatment's impact. Safety assessments will be conducted in parallel, focusing on adverse events and clinical laboratory tests to ensure a comprehensive evaluation of the treatment's profile.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Aged ≥18 years old.
- Able to provide informed consent obtained before any study related activities and according to local guidelines.
- Patient has histologically and/or cytologically-confirmed HNSCC.
- Patient has archival or new tumor tissue for the analysis of biomarkers
- Patient has either progressive or recurrent disease after treatment with PDL1/PD1 based therapy for recurrent or metastatic disease.
- 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).
- 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.
- 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. 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%.
- Patient has Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
- Patients must apply highly effective contraception during and throughout the study, as well after the final dose of study treatment.
Exclusion Criteria
- 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.
- 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.
- 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.
- Patient has a known hypersensitivity and/or contraindication to paclitaxel, standard premedication for paclitaxel, or other products containing Cremophor®.
- Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
- 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.
- Patient has a history of non-compliance to any medical regimen or inability to grant consent.
- 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).
- Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
- 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).
- Patient received treatment with a taxane as part of prior treatment for recurrent or metastatic disease
- 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.
- 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).
- Patient has grade ≥ 2 neuropathy, colitis, pneumonitis, and uncontrolled endocrinopathies (e.g., hypothyroidism, diabetes with hemoglobin A1c > 8%) from previous treatment.
- Patient has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.
- Patient is pregnant or nursing (lactating). Patients with elevated human chorionic gonadotrophin (hCG) at baseline that is judged to be related to the tumor are eligible if hCG levels do not show the expected doubling when repeated five to seven days later, or pregnancy has been ruled out by vaginal ultrasound.
- 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 cycle 1.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 02 Nov 2021 | 5 |
 France | Not Recruiting | 02 Nov 2021 | 42 |
 Germany | Not Recruiting | 02 Nov 2021 | 29 |
 Hungary | Not Recruiting | 02 Nov 2021 | 10 |
 Italy | Not Recruiting | 02 Nov 2021 | 53 |
 Poland | Not Recruiting | 02 Nov 2021 | 12 |
 Spain | Not Recruiting | 02 Nov 2021 | 51 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Buparlisib 50mg Tablet | Test | TABLET | ORAL | 100 | 60 | PRD11550833 |
Buparlisib 40mg Tablet | Test | TABLET | ORAL | 100 | 60 | PRD11550832 |
Paclitaxel 6 mg/ml concentrate for solution for infusion | Comparator | CONCNETRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 80 | 60 | PRD409121 |
Buparlisib 50 mg Capsules | Test | CAPSULE, HARD | ORAL | 100 | 60 | PRD6966649 |
Buparlisib 10 mg Capsules | Test | CAPSULE, HARD | ORAL | 100 | 60 | PRD6966650 |