The BURAN Study of Buparlisib (AN2025) In Combination with Paclitaxel Compared to Paclitaxel Alone, in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

JRCT ID: jRCT2011210034

Registered date:13/09/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Head and neck squamous cell carcinoma
• Date of first enrollment: 01/07/2021
• Target sample size: 40
• Countries of recruitment: United States,Japan,Canada,Japan,Europe,Japan,Asia,Japan,Australia,Japan
• Study type: Interventional

Intervention(s)

arm A:Daily buparlisib (100 mg) in combination with weekly paclitaxel (80 mg/m2)
arm B:Weekly paclitaxel (80 mg/m2) alone

Outcome(s)

• Primary Outcome: To assess the OS of buparlisib in combination with paclitaxel compared to paclitaxel alone in patients with recurrent or metastatic HNSCC.

Secondary Outcome

1. To evaluate additional efficacy parameters: progression free survival (PFS), ORR, and DoR, by the Investigator and Independent Radiological Review Committee (IRRC).
2. To evaluate efficacy parameters in subgroups of patients defined by the randomization strata.
3. To assess the effect of buparlisib in combination with paclitaxel on patients symptoms and health-related quality of life (HRQoL).
4. To assess the pharmacokinetics (PK) of buparlisib in combination with paclitaxel.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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). 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. For sites in China, it is recommended a minimum of 7 unstained slides for patients with known HPV status (for tumor DNA characterization) or a minimum of 10 slides for patients whose HPV status is unknown (3 slides for HPV testing plus 7 slides, for biomarker testing.
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.
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 investigators judgement and confirmation.
For China only: Normal potassium and magnesium levels or <= grade 1 severity according to NCI-CTCAE version 5.0 if judged clinically not significant by the Investigator.
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 Gilberts Syndrome. Gilberts 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. Patients must apply highly effective contraception during and throughout the study, as well after the final dose of study treatment, as detailed below:
a. 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 partners last buparlisib dose, or until at least 6 months after their partners last paclitaxel dose, whichever is longer.
b. 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 and United Kingdom), whichever is longer.
c. Highly effective contraception is defined as either:
o Total abstinence: When this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
o Female sterilization: When the female study patient has had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
o Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female study patients, the vasectomized male partner should be the sole partner for that patient.
o Using a combination of the following (both apply):
*Placement of an intrauterine device (IUD) or intrauterine system (IUS), and
*Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
Note: Hormonal contraception methods (e.g., oral, injected, implanted) are not allowed as buparlisib decreases the effectiveness of hormonal contraceptives.
Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child-bearing potential.

Exclude 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 diseases), eye drops, or local injections (e.g., intra-articular), or < 10 mg prednisolone or equivalent.
8. Patients is being treated at start of study treatment with drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications.
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 Investigators 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 human immunodeficiency virus (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 treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
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. Note: 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 treatment.
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 (or 5 half-lives of agent used, whichever is shorter) of randomization.
19. 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.
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 patients 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 patients C1D1 or during cycle 1.

Related Information

• Primary Sponsor: Kanmuri Kazuhiro
• Secondary ID(s): NCT04338399