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Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.

Ando Y, Inada-Inoue M, Mitsuma A, Yoshino T, Ohtsu A, Suenaga N, Sato M, Kakizume T, Robson M, Quadt C, Doi T - Cancer Sci. (2014)

Bottom Line: Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes.Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner.Best overall response was stable disease for six patients, including one unconfirmed partial response.

View Article: PubMed Central - PubMed

Affiliation: Nagoya University Hospital, Nagoya, Japan.

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Related in: MedlinePlus

Antitumor activity with buparlisib (100 mg/day) in a patient with head and neck squamous cell carcinoma and metastasis to the neck lymph node. A 58-year-old male patient experienced a 76% reduction in neck lesion size (from 59 mm at baseline to 14 mm in Cycle 4). As the second confirmation according to Response Evaluation Criteria In Solid Tumors was not obtained, this unconfirmed partial response was recorded as stable disease. The left internal carotid artery was compressed and narrowed by the tumor. During study treatment, fistulae developed in the skin of the neck region followed by arterial hemorrhage from the rapidly degraded tumor lesion. Although the patient recovered and restarted buparlisib at 50 mg/day in Cycle 5, they eventually died from hemorrhage 5 days after buparlisib discontinuation, which was considered unrelated to the study drug. Sequential images of computed tomography scans taken at baseline and on Cycle 4 Day 25 are shown. The arrow marks the region of interest.
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fig01: Antitumor activity with buparlisib (100 mg/day) in a patient with head and neck squamous cell carcinoma and metastasis to the neck lymph node. A 58-year-old male patient experienced a 76% reduction in neck lesion size (from 59 mm at baseline to 14 mm in Cycle 4). As the second confirmation according to Response Evaluation Criteria In Solid Tumors was not obtained, this unconfirmed partial response was recorded as stable disease. The left internal carotid artery was compressed and narrowed by the tumor. During study treatment, fistulae developed in the skin of the neck region followed by arterial hemorrhage from the rapidly degraded tumor lesion. Although the patient recovered and restarted buparlisib at 50 mg/day in Cycle 5, they eventually died from hemorrhage 5 days after buparlisib discontinuation, which was considered unrelated to the study drug. Sequential images of computed tomography scans taken at baseline and on Cycle 4 Day 25 are shown. The arrow marks the region of interest.

Mentions: Six patients treated at 100 mg/day experienced at least one SAE: abnormal hepatic function (Grade 3/4; including increased ALT/AST levels, n = 3), pneumonitis (Grade 3; n = 1), dyspnea (Grade 2; n = 1) and hyperglycemia (Grade 4; n = 1), infectious pneumonia (Grade 2; n = 1), delirium (Grade 2; n = 1) and hemorrhage (Grade 4; n = 1). With the exceptions of delirium and hemorrhage, these SAEs were all considered related to buparlisib. Two patients, both in the 100 mg/day cohort, died during the study period (i.e. including the time on treatment and the safety follow-up period) as a result of SAEs (hemorrhage and pneumonitis). The patient with hemorrhage died 5 days after discontinuation of buparlisib due to a fistula in one of the cancer lesions resulting from tumor necrosis (Fig.1): this was considered unrelated to buparlisib. A 71-year-old male patient died from aggravation of pneumonitis (Grade 5) 11 days after discontinuing buparlisib, for which a relationship to the study drug could not be ruled out. This patient was a non-smoker, with a diagnosis of adenocarcinoma of the rectum, multiple metastases, including the lung, pleura and lymph nodes, and a left pleural effusion, which was detected by a CT scan prior to study enrollment. A CT scan taken 32 days after the first dose of buparlisib administration showed pneumonitis and worsening disease with increased left pleural effusion. At the time of onset, infectious pneumonitis was suspected rather than interstitial pneumonia. Despite antibiotic treatment, the patient's condition remained unchanged. When a follow-up CT examination was performed 10 days after the last dose of buparlisib, ground glass opacities were found. The patient's respiratory function deteriorated abruptly, and the patient died the following day.


Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.

Ando Y, Inada-Inoue M, Mitsuma A, Yoshino T, Ohtsu A, Suenaga N, Sato M, Kakizume T, Robson M, Quadt C, Doi T - Cancer Sci. (2014)

Antitumor activity with buparlisib (100 mg/day) in a patient with head and neck squamous cell carcinoma and metastasis to the neck lymph node. A 58-year-old male patient experienced a 76% reduction in neck lesion size (from 59 mm at baseline to 14 mm in Cycle 4). As the second confirmation according to Response Evaluation Criteria In Solid Tumors was not obtained, this unconfirmed partial response was recorded as stable disease. The left internal carotid artery was compressed and narrowed by the tumor. During study treatment, fistulae developed in the skin of the neck region followed by arterial hemorrhage from the rapidly degraded tumor lesion. Although the patient recovered and restarted buparlisib at 50 mg/day in Cycle 5, they eventually died from hemorrhage 5 days after buparlisib discontinuation, which was considered unrelated to the study drug. Sequential images of computed tomography scans taken at baseline and on Cycle 4 Day 25 are shown. The arrow marks the region of interest.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317947&req=5

fig01: Antitumor activity with buparlisib (100 mg/day) in a patient with head and neck squamous cell carcinoma and metastasis to the neck lymph node. A 58-year-old male patient experienced a 76% reduction in neck lesion size (from 59 mm at baseline to 14 mm in Cycle 4). As the second confirmation according to Response Evaluation Criteria In Solid Tumors was not obtained, this unconfirmed partial response was recorded as stable disease. The left internal carotid artery was compressed and narrowed by the tumor. During study treatment, fistulae developed in the skin of the neck region followed by arterial hemorrhage from the rapidly degraded tumor lesion. Although the patient recovered and restarted buparlisib at 50 mg/day in Cycle 5, they eventually died from hemorrhage 5 days after buparlisib discontinuation, which was considered unrelated to the study drug. Sequential images of computed tomography scans taken at baseline and on Cycle 4 Day 25 are shown. The arrow marks the region of interest.
Mentions: Six patients treated at 100 mg/day experienced at least one SAE: abnormal hepatic function (Grade 3/4; including increased ALT/AST levels, n = 3), pneumonitis (Grade 3; n = 1), dyspnea (Grade 2; n = 1) and hyperglycemia (Grade 4; n = 1), infectious pneumonia (Grade 2; n = 1), delirium (Grade 2; n = 1) and hemorrhage (Grade 4; n = 1). With the exceptions of delirium and hemorrhage, these SAEs were all considered related to buparlisib. Two patients, both in the 100 mg/day cohort, died during the study period (i.e. including the time on treatment and the safety follow-up period) as a result of SAEs (hemorrhage and pneumonitis). The patient with hemorrhage died 5 days after discontinuation of buparlisib due to a fistula in one of the cancer lesions resulting from tumor necrosis (Fig.1): this was considered unrelated to buparlisib. A 71-year-old male patient died from aggravation of pneumonitis (Grade 5) 11 days after discontinuing buparlisib, for which a relationship to the study drug could not be ruled out. This patient was a non-smoker, with a diagnosis of adenocarcinoma of the rectum, multiple metastases, including the lung, pleura and lymph nodes, and a left pleural effusion, which was detected by a CT scan prior to study enrollment. A CT scan taken 32 days after the first dose of buparlisib administration showed pneumonitis and worsening disease with increased left pleural effusion. At the time of onset, infectious pneumonitis was suspected rather than interstitial pneumonia. Despite antibiotic treatment, the patient's condition remained unchanged. When a follow-up CT examination was performed 10 days after the last dose of buparlisib, ground glass opacities were found. The patient's respiratory function deteriorated abruptly, and the patient died the following day.

Bottom Line: Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes.Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner.Best overall response was stable disease for six patients, including one unconfirmed partial response.

View Article: PubMed Central - PubMed

Affiliation: Nagoya University Hospital, Nagoya, Japan.

Show MeSH
Related in: MedlinePlus