Ayako Mitsuma

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

Buparlisib (BKM120) is an oral pan‐phosphatidylinositol 3‐kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open‐label Phase I dose‐escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose‐limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first‐in‐man study of buparlisib in non‐Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment‐related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. 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. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non‐Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.

The Feasibility Study of Docetaxel in Patients with Anaplastic Thyroid Cancer

There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.

Genetic polymorphisms associated with oxaliplatin-induced peripheral neurotoxicity in Japanese patients with colorectal cancer.

OBJECTIVE Pharmacogenomic associations between severe oxaliplatininduced chronic peripheral neurotoxicity (OXCPN) (Grade 2 lasting for > 7 days or Grade 3) and 9 single nucleotide polymorphisms (SNPs) in 8 genes (TAC1, FOXC1, ITGA1, ACYP2, DLEU7, BTG4, CAMK2N1, and FARS2) were reported by the genomewide association study (GWAS) in Korean patients. The present study was designed to explore reliable predictors of OXCPN and thereby improve the management of metastatic colorectal cancer (CRC). METHODS We retrospectively investigated pharmacogenomic characteristics of OXCPN in 70 Japanese patients with CRC who received oxaliplatin-based chemotherapy and updated the results of our previous analysis of ERCC1 (C118T, rs11615 and C8092A, rs3212986) and GSTP1 (Ile105Val, rs1695) polymorphisms. RESULTS Univariate analysis suggested potential associations of severe OXCPN with rs843748 in ACYP2 and rs17140129 in FARS2, as well as with the absence of diabetes mellitus (DM) (p = 0.056, 0.072, and 0.029, respectively). There was no association between severe OXCPN and any of the 7 other SNPs. Multiple logistic regression analysis showed that an increased risk of severe OXCPN was related to rs17140129 and the absence of DM (p = 0.034 and 0.030, respectively). On updated analysis, polymorphisms of ERCC1 (C118T, rs11615) and rs10486003 in TAC1 were associated with time to the onset of Grade 1 OXCPN (p = 0.024 and 0.049, respectively). CONCLUSIONS Severe OXCPN is significantly related to rs17140129, found in the GWAS of Korean patients, in Japanese patients. Patients without DM are more likely to have OXCPN. The association between ERCC1 polymorphism and time to the onset of OXCPN was significant on updated analysis.

Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia.

BackgroundNilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML.Patients and methodsEight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28.ResultsAll 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3).ConclusionThese findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.

Prospective evaluation of corrected QT intervals and arrhythmias after exposure to epirubicin, cyclophosphamide, and 5-fluorouracil in women with breast cancer

BACKGROUND Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.BACKGROUND Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.

Pharmacokinetic study of S-1 in patients in whom inulin clearance was measured.

Objective: This pharmacokinetic study of S-1 was conducted in patients in whom glomerular filtration rate (GFR) was directly measured to explore the possibility of adjusting the S-1 dose on the basis of GFR in patients with normal or nearly normal renal function. Methods: S-1 was given to 12 patients twice daily for 28 consecutive days followed by 14 days of rest, repeated every 6 weeks. GFR was measured on the basis of inulin clearance (CLin) before the first day of treatment. Results: The area under the time-concentration curve (AUC) of 5-fluorouracil (5-FU) correlated with that of 5-chloro-2,4-dihydroxypyridine (CDHP, r = 0.750, p = 0.005). The AUC of CDHP correlated with the measured 24-hour creatinine clearance (CLcr) per subject (r = –0.620, p = 0.032), but not with the CLin (r = –0.356, p = 0.257). The AUC of 5-FU did not correlate with either the 24-hour CLcr per subject (r = –0.401, p = 0.187) or with the CLin (r = –0.300, p = 0.351). Conclusion: Dosage adjustment based on the GFR does not reduce individual variations in 5-FU concentrations among patients with normal or nearly normal renal function who receive S-1.

Quantitative assessment of chemotherapy‐induced peripheral neurotoxicity using a point‐of‐care nerve conduction device

Chemotherapy‐induced peripheral neurotoxicity (CIPN) seriously impairs patients’ quality of life cumulatively and dose‐dependently. Because assessment of CIPN usually depends on patients’ subjective evaluation of symptoms, objective and quantitative measures are needed. We evaluated a point‐of‐care nerve conduction device (POCD), previously validated for the assessment of diabetic peripheral neuropathy. Sensory nerve action potential (SNAP) amplitude and sensory nerve conduction velocity (SNCV) of the sural nerve were measured using a portable, automated POCD (DPNCheck; NeuroMetrix Inc., Waltham, MA, USA) in patients with a clinical diagnosis of CIPN of grade 1 or higher. We compared SNAP and SNCV among patients with different grades of CIPN according to the Common Terminology Criteria for Adverse Events. A total of 50 patients (22 men, 28 women; median age, 64 years; grade 1/2/3, 21/18/11) were evaluated. Anticancer drugs responsible for CIPN were cisplatin in five patients, oxaliplatin in 15, carboplatin in 5, paclitaxel in 16, docetaxel in 14, nab‐paclitaxel in 7, vincristine in 6, and bortezomib in 3. Unadjusted SNAP was 8.45 ± 3.67 μV (mean ± SD) in patients with grade 1 CIPN, 5.42 ± 2.68 μV with grade 2, and 2.45 ± 1.52 μV with grade 3. Unadjusted SNCV was 49.71 ± 4.77 m/s in patients with grade 1 CIPN, 48.78 ± 6.33 m/s with grade 2, and 44.14 ± 7.31 m/s with grade 3. The adjusted SNAP after controlling for age significantly differed between each CTCAE grade (P < 0.001, ancova). The adjusted SNCV after controlling for age and height also differed significantly (P = 0.027). Differences in the severity of CIPN could be detected objectively and quantitatively using this POCD.

Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction.

A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m2 was given as an i.v. infusion once weekly for 3 weeks of a 4‐week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m2. No other patients had severe treatment‐related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.)

Abstract B188: A Phase l study of BYL719, an α-isoform selective PI3K inhibitor, in Japanese patients with advanced solid malignancies.

Background: BYL719 is an oral inhibitor that selectively targets the α-isoform of class l PI3K, which is encoded by PIK3CA, a frequently altered gene in human cancers. In a first-in-man Phase I study in mostly Western patients (including one Asian patient) with advanced solid malignancies harboring a PIK3CA alteration (mutation and/or amplification), the maximum tolerated dose (MTD) for once-daily (QD) BYL719 was declared as 400 mg, and preliminary antitumor activity was observed (Gonzalez-Angulo et al. ASCO 2013). Here, we report preliminary findings of an ongoing multicenter, open-label Phase l dose-escalation study in Japanese patients with advanced solid malignancies irrespective of PIK3CA alterations ([NCT01387321][1]). Methods: Patients were aged ≥18 years with histologically confirmed, advanced unresectable solid tumors, who had progressed despite standard therapy or for whom no standard therapy existed. Patients received continuous oral BYL719 QD in 28-day cycles until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. The primary objective was to determine the MTD and/or recommended phase 2 dose (RP2D) of BYL719 QD. MTD was defined as the highest drug dosage not causing medically unacceptable does limiting toxicities (DLTs) in >33% of treated patients during Cycle 1. Secondary objectives included assessments of preliminary antitumor activity (RECIST v1.1), safety (CTCAE v4), and PK profiles. Results: As of May 20, 2013, 24 patients (median age 56 years) were enrolled, receiving BYL719 QD at 90 mg (n=3), 180 mg (n=4), 270 mg (n=5), 350 mg (n=5), or 400 mg (n=7). DLTs occurred in 2 out of 4 evaluable patients at 400 mg QD (both had Grade [G] 3 maculopapular rash). Nineteen (79%) patients discontinued treatment [5 due to adverse event (AE); 11 disease progression; 2 patient/guardian decision; 1 death (due to disease progression)]. Median duration of exposure was 7.6 (range: 2.4-55.9) weeks. The most common suspected BYL719-related all-grade AEs (>25%) were maculopapular rash (50%), diarrhea (42%), hyperglycemia (38%), decreased appetite (29%), and pruritus (29%), and G3/4 AEs (≥10%) were maculopapular rash (29%) and hyperglycemia (13%). After May 20, 2013, one additional patient was enrolled at 350 mg QD, and no DLTs were observed out of 6 evaluable patients. Based on the Bayesian logistic regression model, 380 mg QD was the next recommended dose; however, considering the DLTs observed at 400 mg QD, 350 mg QD was declared as the RP2D. One patient with uterine clear cell carcinoma receiving 350 mg QD had an unconfirmed partial response. A dose-dependent increase of plasma exposure was observed and accumulation ratios were generally <1.5. Conclusions: In this Phase l, first-in-Japanese patients study of BYL719, 350 mg QD was declared as the RP2D and preliminary antitumor activity was observed. An expansion cohort is open at the RP2D in patients whose tumors harbor PIK3CA alterations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B188. Citation Format: Yoshihito Kogure, Yasuhide Yamada, Hideo Saka, Chiyoe Kitagawa, Satoru Iwasa, Noboru Yamamoto, Takuji Aoki, Tomoyuki Kakizume, Matthew Robson, Cornelia Quadt, Ayako Mitsuma, Takashi Shibata, Yuichi Ando. A Phase l study of BYL719, an α-isoform selective PI3K inhibitor, in Japanese patients with advanced solid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B188. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01387321&atom=%2Fmolcanther%2F12%2F11_Supplement%2FB188.atom

Abstract B159: Phase I dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.

Background: Signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is critical to cancer cell growth, survival, and metabolism. BKM120 is a potent and highly specific oral pan-class I (α, β, γ, δ) PI3K inhibitor that has demonstrated clinical anti-tumor effects in a broad range of cancer types. Patients and methods: This was a phase I, open-label, dose-escalation study of single-agent BKM120 in Japanese patients with advanced solid tumors. Patients received 28-day cycles of continuous BKM120 once daily until disease progression, unacceptable toxicity, investigator9s decision or patient9s refusal. Eligible patients had histologically-confirmed, advanced unresectable solid tumors and had progressed on standard therapy, were unable to tolerate standard therapy, or had disease for which no standard therapy exists. Dose escalation, determined by agreement of investigators and the sponsor, was guided by an adaptive Bayesian logistic regression model with overdose control. Results: A total of 15 patients (median age 58 [range 22 to 71] yrs) received BKM120 once daily: 25 mg (n = 3), 50 mg (n = 3), and 100 mg (n = 9). The most common primary tumor sites were the salivary gland, rectum (n = 3 each), colon, and head & neck (n = 2 each). Patients were heavily pretreated (median 3 prior regimens [range 0–9]). One patient experienced a DLT (CTCAE grade 4 abnormal hepatic function at 100 mg BKM120 during cycle 1). Across all doses, the most common (≥ 4 patients) all-cause adverse events (AEs) were increased eosinophil count/eosinophilia, rash, increased blood insulin, constipation, decreased appetite, fatigue, increased alanine aminotransferase, anemia, increased insulin C-peptide, mood altered/psychiatric symptom, and pruritus. The most common (≥ 2 patients) non-dose limiting grade 3/4 AEs (all cause) were abnormal hepatic function (n = 5, including increased transaminase in 2 patients), and anemia (n = 2). Five patients experienced serious AEs (all cause): abnormal hepatic function (n = 3), pneumonitis, dyspnea, hyperglycemia, pneumonia, and delirium (n = 1 each). A patient with pneumonitis died 11 days after study drug discontinuation (100 mg cohort). There were 4 AE-associated discontinuations: 2 for increased transaminases (discontinuation on days 47 and 78 of treatment; 25 mg BKM120), 1 abnormal hepatic function (on day 30) and 1 increased lipase (on day 56; both 100 mg BKM120). Preliminary pharmacokinetic (PK) data showed rapid absorption, with Cmax occurring 1–3 hours post-dose. BKM120 accumulated ∼3-fold in achieving steady state. Doses ≥ 50 mg led to steady-state drug exposure (AUC0–24,ss) ≥ 10,000 ng*h/mL, a target preclinically estimated to be efficacious. Both Cmax and AUC increased dose proportionally between 25 and 100 mg. Five patients had stable disease (RECIST criteria) as the best response (8–24 weeks9 duration). Based on the overall safety profile of BKM120, dose escalation over 100 mg was not pursued, and the recommended dose was declared as 100 mg once daily. Conclusions: BKM120 administered orally once daily up to 100 mg was well tolerated. PK parameters were comparable with those of Western patients. Continuous BKM120 100 mg once daily was recommended in Japanese patients and will be taken forward in the clinical development program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B159.