Associations between plasma concentrations of lenvatinib and angiopoietin and clinical responses to lenvatinib therapy in Japanese patients with thyroid cancer

Abstract The purpose of this study was to investigate the relationships among plasma concentrations (C0) of lenvatinib, angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in thyroid cancer patients. The median change rates of Ang-1 and Ang-2 at 1 month after treatment from baseline in all patients were − 15.3% and − 48.4%, respectively. However, the change of Ang-1 and Ang-2 at 1 month from baseline did not correlate with lenvatinib C0. In patients with partial response (PR) and stable disease to lenvatinib, Ang-2 at 1 month were significantly lower than Ang-2 at baseline (P < 0.001 and P < 0.05, respectively), but were not significantly lower in patients with progressive disease. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of the change rate of Ang-2 of -49.83%. In patients who continued treatment with lenvatinib for 1 year, Ang-2 at 1 month and 1 year were significantly lower than those at baseline (each P < 0.001). The change of Ang-2 at 1 month after treatment from baseline rather than simply the Ang-2 level at baseline may be important as a biomarker of the inhibitory effect of angiogenesis by lenvatinib.

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Associations Between Plasma Concentrations of Lenvatinib and Angiopoietin and Clinical Responses to Lenvatinib Therapy in Japanese Patients With Thyroid Cancer

10.21203/rs.3.rs-828572/v1 ◽

2021 ◽

Author(s):

Maho Kumagai ◽

Mitsuji Nagahama ◽

Yumiko Akamine ◽

Tomoko Ozeki ◽

Akifumi Suzuki ◽

...

Keyword(s):

Overall Survival ◽

Thyroid Cancer ◽

Progressive Disease ◽

Plasma Concentrations ◽

Japanese Patients ◽

Inhibitory Effect ◽

Change Rate ◽

Clinical Responses ◽

One Year ◽

Median Change

Abstract Purpose: The purpose of this study was to investigate the relationships among plasma concentrations of lenvatinib, angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in Japanese patients with thyroid cancer. Methods: Plasma concentrations of lenvatinib (C0) and Ang-1 and -2 were measured by HPLC and ELISA, respectively.Results: The median change rates of Ang-1 and Ang-2 at 1 month after treatment from baseline in 36 patients were -15.3% and -48.4%, respectively. However, the change of Ang-1 and Ang-2 at 1 month from baseline did not correlate with lenvatinib C0. In patients with partial response (PR) and stable disease to lenvatinib, Ang-2 at 1 month were significantly lower than Ang-2 at baseline (P < 0.001 and P < 0.05, respectively), but were not significantly lower in patients with progressive disease. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of the change rate of Ang-2 of -49.83%. A one year overall survival for patients having the change rate of Ang-2 of at least -49.83% and less than -49.83% were 62.5% and 40%, respectively. In patients who continued treatment with lenvatinib for 1 year, Ang-2 at 1 month and 1 year after treatment were significantly lower than those at baseline (each P < 0.001).Conclusion: The change of Ang-2 at 1 month after treatment from baseline rather than simply the Ang-2 level at baseline may be important as a biomarker of the inhibitory effect of angiogenesis by lenvatinib.

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The Use of Autologous LMP2-Specific Cytotoxic T Lymphocytes (CTL) for the Treatment of Relapsed EBV-Positive Hodgkin Disease and Non-Hodgkin Lymphoma.

Blood ◽

10.1182/blood.v106.11.773.773 ◽

2005 ◽

Vol 106 (11) ◽

pp. 773-773

Author(s):

Catherine M. Bollard ◽

Elizabeth Buza ◽

Helen Huls ◽

Teresita Lopez ◽

Stephen Gottschalk ◽

...

Keyword(s):

T Cells ◽

Partial Response ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Progressive Disease ◽

Residual Tumor ◽

Cell Transplant ◽

Dose Escalation Study ◽

Non Hodgkin Lymphoma ◽

Clinical Responses

Abstract EBV-associated Hodgkin’s Disease (HD) and some non-Hodgkins lymphoma (NHL) show type II latency expressing the subdominant EBV antigens EBNA1, LMP1 and LMP2, which may serve as targets for immunotherapy approaches. In previous studies, we used polyclonal EBV-specific CTL in patients with relapsed EBV +ve HD and saw 2 complete and 1 partial response in 11 patients. Analyses of EBV-CTL lines showed that small populations of T cells reactive against the tumor-associated antigen LMP2 were present in the majority of the infused lines, with some expansion in the peripheral blood following infusion. We therefore hypothesized that CTL specifically targeting LMP2 might have greater efficacy in these patients. LMP2-CTL were generated from 14 patients using Dendritic Cells for initial stimulations then Lymphoblastoid Cell Lines (LCL) both of which had been genetically modified to overexpress LMP2 by transduction with an Ad5f35LMP2 vector. Polyclonal LMP2-CTL lines recognized 1–7 (median 2) LMP2 epitopes, as determined using pentamers and overlapping LMP2 peptide pools in ELISPOT assays. A mean of 22.8% (5–42.1%) of CD8+ T cells bound HLA-restricted LMP2 pentamers, compared to a mean of 0.11% (0.01–0.24%) of LMP2-pentamer positive CD8+ T cells found in CTL generated with genetically unmodified LCL from the same patients. So far, 11 patients have been treated on this dose escalation study - 6 patients have been treated on dose level (DL)1 (2 doses of CTL at 2x107/m2/dose given 2 wks apart in the outpatient clinic), 4 patients on DL2 (2x107/m2 and 1x108/m2) and 1 patient on DL3 (1x108/m2 and 2x108/m2). No immediate toxicity was observed. After CTL infusion, an increase in the frequency of EBV +/- LMP2-specific T cells could be detected in the blood in 8/10 evaluated patients (range 2–17.6 fold). Five of 6 patients who received LMP2-CTL as adjuvant therapy post stem cell transplant or chemotherapy remain in remission up to 22mths post LMP2-CTL. 1 patient presented with progressive disease 8 wks post CTL therapy. Five patients had detectable disease at the time of CTL therapy of whom 1 had progressive disease 8 wks post CTL and 4 had clinical responses (1 very good partial response and 3 clinical or radiologic complete responses). One of these 3 patients was evaluated 7 wks after receiving CTLs, which were predominantly CD4+ve (91.6%). Biopsies showed minimal residual NHL cells with increased CD4+ve T cells compared to pre-CTL biopsy specimens. Imaging studies performed 1 wk later were negative for NHL. This patient received 2 extra doses of CTL (given 8 wks apart) and re-evaluations showed CR on PET and CT scans. Two other patients had stable disease 8 wks post LMP2-CTL. Both patients received 2 further doses of LMP2-CTL. One patient is without evidence of disease 12 months post CTL. The other patient had a complete radiological response. This patient had a supraclavicular lymph node resection, which showed selective accumulation of LMP2-tetramer +ve T cells (0.3% compared to 0.01% in the peripheral blood) with few residual tumor cells. Immunotherapy with autologous LMP2-CTL is therefore well tolerated in patients with relapsed EBV+ve HD/NHL and infused LMP2-CTL cells can accumulate at tumor sites and induce clinical responses.

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Association of lenvatinib trough plasma concentrations with lenvatinib-induced toxicities in Japanese patients with thyroid cancer

Medical Oncology ◽

10.1007/s12032-019-1263-3 ◽

2019 ◽

Vol 36 (5) ◽

Cited By ~ 6

Author(s):

Mitsuji Nagahama ◽

Tomoko Ozeki ◽

Akifumi Suzuki ◽

Kiminori Sugino ◽

Takenori Niioka ◽

...

Keyword(s):

Thyroid Cancer ◽

Plasma Concentrations ◽

Japanese Patients ◽

Trough Plasma

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Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-Line Treatment of Advanced Esophageal Cancer Patients

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.4900 ◽

2006 ◽

Vol 24 (10) ◽

pp. 1612-1619 ◽

Cited By ~ 148

Author(s):

Maarten L. Janmaat ◽

Mariëlle I. Gallegos-Ruiz ◽

José A. Rodriguez ◽

Gerrit A. Meijer ◽

Walter L. Vervenne ◽

...

Keyword(s):

Esophageal Cancer ◽

Partial Response ◽

Cancer Patients ◽

Progressive Disease ◽

Phase Ii Study ◽

Line Treatment ◽

Second Line ◽

Advanced Esophageal Cancer ◽

Egfr Gene ◽

Egfr Expression

Purpose The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity. Patients and Methods Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d. Response was evaluated every 8 weeks. Tumor material obtained before gefitinib treatment was investigated for gene mutations in EGFR, k-ras, and PIK3CA; protein expression levels of EGFR, p-Akt, and p-Erk; and EGFR gene amplification. Results Of the 36 enrolled patients, one (2.8%) achieved a partial response, 10 (27.8%) had stable disease, 17 (47.2%) experienced progression on treatment, and eight (22.2%) were not assessable for response. The progression-free survival time was 59 days, and the median overall survival time was 164 days. Although EGFR or PIK3CA mutations were absent, k-ras mutations were found in two patients with progressive disease. High EGFR gene copy number was identified in two patients experiencing partial response or progressive disease. A higher disease control rate (response plus stable disease) was observed in females (P = .038) and in patients with squamous cell carcinoma (SCC; P = .013) or high EGFR expression (P = .002). Conclusion Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. However, the patient outcome was significantly better in female patients and in patients demonstrating high EGFR expression or SCC histology. The selection of esophageal cancer patients for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors or SCC histology should be considered.

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Serum CYFRA 21.1 Level Predicts Disease Course in Thyroid Cancer with Distant Metastasis

Cancers ◽

10.3390/cancers13040811 ◽

2021 ◽

Vol 13 (4) ◽

pp. 811

Author(s):

Chaiho Jeong ◽

Jeongmin Lee ◽

Hyukjin Yoon ◽

Jeonghoon Ha ◽

Min-Hee Kim ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Patients ◽

Distant Metastasis ◽

Progressive Disease ◽

Kinase Inhibitor ◽

Braf V600e ◽

Disease Course ◽

Thyroglobulin Antibody ◽

Comparison Results

Background: Serum Cyfra 21.1, the soluble fragment of CK19, has been used as a prognostic tumor marker in various cancers, indicating poor tumor differentiation and increased metastasis. Methods: We analyzed the serum Cyfra 21.1 level in 51 consecutive patients with thyroid cancer manifesting distant metastasis treated with prior total thyroidectomy. Serum Cyfra 21.1 levels of 26 thyroid cancer patients without metastasis and 50 healthy individuals were used for comparison. Results: Higher serum Cyfra 21.1 levels were detected in thyroid cancer patients with distant metastasis compared with healthy subjects and thyroid cancer patients without metastasis (p = 0.012). Serum Cyfra 21.1 levels were significantly increased in patients with positive BRAF V600E mutation (p = 0.019), undergoing Tyrosine Kinase Inhibitor (TKI) therapy (p = 0.008), with radioiodine-refractory status (p = 0.047), and in disease progression compared with those manifesting stable disease (p = 0.007). In progressive disease with undetectable or unmonitored thyroglobulin because of thyroglobulin antibody, serum Cyfra 21.1 was useful as a biomarker for follow-up of disease course. Conclusion: Serum Cyfra 21.1 in thyroid cancer patients might represent an alternative biomarker predicting tumor progression, especially in cases not associated with serum Tg levels.

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Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa153 ◽

2020 ◽

Vol 50 (12) ◽

pp. 1395-1402

Author(s):

Noriko Fukuhara ◽

Tomohiro Kinoshita ◽

Kazuhito Yamamoto ◽

Hirokazu Nagai ◽

Koji Izutsu ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Partial Response ◽

Adverse Events ◽

Follicular Lymphoma ◽

Plasma Concentrations ◽

Japanese Patients ◽

Lymphocytic Leukemia ◽

Phosphatidylinositol 3 Kinase ◽

Phase 1B ◽

Phosphatidylinositol 3

Abstract Objective Idelalisib is an orally administered, highly selective inhibitor of phosphatidylinositol 3-kinase-δ. In this phase 1b study, the safety, tolerability and pharmacokinetics of idelalisib, an oral inhibitor of phosphatidylinositol 3-kinase-δ, were evaluated in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma. Methods In total, six patients (follicular lymphoma: n = 3, chronic lymphocytic leukemia: n = 3) were enrolled to receive idelalisib 150 mg twice daily. Results No dose-limiting toxicities were reported. The most common adverse events were diarrhea (n = 5), gastritis (n = 3), insomnia (n = 3) and pyrexia (n = 3). The most common ≥grade 3 adverse events were diarrhea (n = 2), increased transaminase levels (n = 2) and decreased appetite (n = 2). The maximum idelalisib plasma concentrations (Cmax) were achieved at 2.50 h (range: 1.50–4.00 h). The mean idelalisib plasma concentrations decreased over time but remained detectable in most patients at 12 h. All enrolled patients underwent efficacy evaluation by investigators, and five patients (follicular lymphoma: n = 2, chronic lymphocytic leukemia: n = 3) achieved partial response. The median duration of partial response was 14.5 months (range: 3.7–31.3 months). Conclusion Idelalisib 150 mg twice daily was considered tolerable in Japanese patients with follicular lymphoma or chronic lymphocytic leukemia. (Clinical trial registration: NCT02242045)

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Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563217731432 ◽

2017 ◽

Vol 55 (3) ◽

pp. 385-393 ◽

Cited By ~ 1

Author(s):

Masaki Tashiro ◽

Takafumi Naito ◽

Yoshiyuki Kagawa ◽

Junichi Kawakami

Keyword(s):

Cancer Patients ◽

Dopamine D2 Receptor ◽

Plasma Concentrations ◽

D2 Receptor ◽

Parent Drug ◽

Prolactin Secretion ◽

Nausea And Vomiting ◽

Serum Prolactin ◽

Antiemetic Efficacy ◽

Clinical Responses

Background Oral prochlorperazine, a dopamine D2 receptor antagonist, is largely metabolized to sulphoxide, 7-hydroxylate and N-desmethylate by cytochrome P450s (CYPs). This study evaluated the influence of CYP genotype on the plasma dispositions of prochlorperazine and its metabolites and their relationships with antiemetic efficacy and prolactin elevation in cancer patients. Methods Forty-eight cancer patients treated with oral prochlorperazine were enrolled. Plasma prochlorperazine and its metabolites concentrations and serum prolactin concentration were determined at 12 h after the evening dosing. The genotypes of CYP2C19, CYP2D6 and CYP3A5 and the incidences of nausea and vomiting were investigated. Results The plasma concentrations of the prochlorperazine metabolites were weakly correlated with that of the parent drug. The CYP genotypes did not affect the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine and its metabolites were not associated with the incidences of nausea and vomiting. The incidence of vomiting was significantly higher in females than in males. The serum prolactin concentration was weakly correlated with the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine metabolites rather than the parent drug had a weaker relation to serum prolactin concentration. Conclusions The CYP genotypes did not affect the plasma dispositions of prochlorperazine and its metabolites. The prochlorperazine metabolites did not have a strong effect on antiemetic efficacy, while they were slightly associated with prolactin secretion in cancer patients.

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Response to sorafenib treatment in advanced metastatic thyroid cancer

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/0004-2730000002839 ◽

2014 ◽

Vol 58 (1) ◽

pp. 37-41 ◽

Cited By ~ 8

Author(s):

Fabian Pitoia

Keyword(s):

Heart Failure ◽

Adverse Event ◽

Thyroid Cancer ◽

Partial Response ◽

Progressive Disease ◽

Tumor Regression ◽

Sorafenib Treatment ◽

Off Label ◽

Unacceptable Toxicity ◽

Metastatic Thyroid Cancer

Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma.Subjects and methods: Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months).Results: Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%.Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death.Conclusion: These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled.

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