Axitinib In Patients Research Articles

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma.

426 Background: Resistance to VEGF-targeted therapy is a major challenge in contemporary treatment of metastatic renal cell carcinoma (mRCC), and endoglin (CD105) activation may be an important mechanism leading to resistance. Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and mRCC cancer stem cells that is upregulated following VEGF inhibition. TRC105 is an anti-endoglin monoclonal antibody that potentiates bevacizumab (Bev) and VEGF receptor tyrosine kinase inhibitors (VEGFR TKI) in preclinical models. Methods: Heavily-pretreated mRCC pts with ECOG PS 0-1, and acceptable organ function were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg PO BID and then escalated per patient tolerance to a maximum of 10 mg PO BID). Results: Eighteen mRCC pts (median age=61.5; M:F 16:2; median number of prior therapies=3, including >1 VEGFR TKI, clear cell=13, prior axitinib allowed) were treated. TRC105 dose escalation proceeded from 8 mg/kg (n=3) to 10 mg/kg (n=15) without dose limiting toxicity. Low grade AEs characteristic of each drug were not increased in frequency or severity at the recommended phase 2 doses of the two drugs. Three pts (18%) were PR by RECIST and 8 of 17 pts (47%) exhibited >10% tumor reduction. Median PFS is not mature and is at least 5.8 months in the overall population and at least 5.9 months in ccRCC pts. The single patient who progressed on axitinib immediately prior to study entry remains progression free at month 5 with minor tumor regression. Conclusions: TRC105 at 8 and 10 mg/kg was well tolerated with axitinib in mRCC pts with signs of activity. A multicenter randomized phase II trial of axitinib +/- TRC105 is accruing at this time. Clinical trial information: NCT01806064.

Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US

Objective:Everolimus and axitinib are approved in the US to treat patients with advanced renal cell carcinoma (RCC) after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Two indirect comparisons performed to evaluate progression-free survival in patients treated with everolimus vs axitinib suggested similar efficacy between the two treatments. Therefore, this analysis compares the lifetime costs of these two therapies among sunitinib-refractory advanced RCC patients from a US payer perspective.Research design and methods:A Markov model was developed to simulate a cohort of sunitinib-refractory advanced RCC patients and estimate the cost of treating patients with everolimus vs axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. The model included the following resources: active treatments, post-progression treatments, adverse events, physician and nurse visits, scans and tests, and palliative care. Resource utilization inputs were derived from a US claims database analysis. Additionally, a 3% annual discount rate was applied to costs, and the robustness of the model results was tested by conducting sensitivity analyses, including those on dosing scheme and post-progression treatment costs.Results:Base case results demonstrated that patients treated with everolimus cost an average of $12,985 (11%) less over their lifetimes than patients treated with axitinib. The primary difference in costs was related to active treatment, which was largely driven by axitinib’s higher dose intensity. Results remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity and discount rates.Conclusion:The results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory advanced RCC patients in the US.

P1-5-4 - Association of Abcg2 Polymorphism with Plasma Concentrations of Axitinib in Patients with Renal Cell Carcinoma

Background: Axitinib is a selective inhibitor for VEGF receptors 1, 2, and 3 on renal cell carcinoma (RCC). The plasma concentrations and area under the blood concentration-time curve (AUC) of axitinib are known to correlate with response rate and survival rate in RCC patients. Breast cancer resistance protein (BCRP, ABCG2 gene) is an efflux ABC transporter, which is expressed at the apical membrane in intestine, and is involved in the absorption and excretion of various drugs. Several studies have demonstrated that ABCG2 polymorphism affects blood concentrations of oral anticancer drugs, especially molecular targeted drugs. To explore the relationship between pharmacokinetics and pharmacogenetics, we analyzed plasma concentrations of axitinib and ABCG2 polymorphism in RCC patients.Method: Eight RCC patients treated with axitinib at Nagoya University Hospital were enrolled in this study. All patients were orally administered 5mg axitinib twice a day. The blood samples were collected before (0 hr) and 0.5, 1, 2, 4 and 6 hr after administration of axitinib (6 points) on day 1 and day 8, respectively. The plasma concentrations of axitinb were analyzed by UPLC-MS/MS. The genetic polymorphism of ABCG2 was determined by real-time PCR. This study was approved by the ethical committee of Nagoya University Hospital, and all patients gave written informed consent.Result: The standard concentration-curve of axitinib in human plasma was linear in the range of 1-100 ng/mL. Intra- and inter-day precision ranged from 1.5 to 7.9% and accuracy were all less than 15%. The maximum concentration and AUC of axitinb in one patient carrying ABCG2 421A/A genotype were markedly higher than those carrying ABCG2 421C/A or C/C genotype on day 8.Conclusion: The plasma concentration of axitinb was analyzed accurately and reproducibly by UPLC-MS/MS. Our findings suggest that ABCG2 polymorphism, especially 421A/A genotype, may influence the plasma concentration of axitinib.

A phase 1b dose-escalation study of TRC105 (anti-endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC).

A phase 1b dose-escalation study of TRC105 (anti-endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC).

A-PREDICT: A phase II study of axitinib in patients with metastatic renal cell cancer unsuitable for nephrectomy (CRUKE/11/061).

TPS4597 Background: Patients presenting with metastatic renal cell carcinoma (mRCC) who cannot have palliative nephrectomy constitute a poor prognosis group. The vascular endothelial growth factor ...

Phase II study of axitinib in patients with progressive, recurrent/metastatic adenoid cystic carcinoma.

Phase II study of axitinib in patients with progressive, recurrent/metastatic adenoid cystic carcinoma.

Efficacy of axitinib in patients with metastatic renal cell carcinoma previously treated with both VEGFR-TKI and mTORI.

e15585 Background: Developments of molecular targeted therapy, including VEGFR-TKI and mTORI, have achieved improvements in PFS in the treatment of mRCC. However, resistance to drugs will occur in ...

Phase II trial evaluating axitinib for patients with unresectable, recurrent, or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

e17027 Background: Patients with R/M HNSCC experience poor survival outcomes with standard cytotoxic agents. Targeted therapies present an attractive alternative, particularly as various growth fac...

Editorial Comment to Activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor

Editorial Comment to Activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor

Activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor

Activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor

Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma

BackgroundPrevious studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective or heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery. ObjectiveTo prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC). Design, setting, and participantsThis was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible. InterventionPatients received axitinib 5mg for up to 12 wk. Axitinib was continued until 36h prior to surgery. Patients underwent partial or radical nephrectomy after axitinib therapy. Outcome measurements and statistical analysisThe primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST). Results and limitationsA total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers. ConclusionsAxitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC. Patient summaryIn this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use. Trial registrationThis clinical trial was registered with clinicaltrials.gov (NCT01263769).

Phase II trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.

441^ Background: Previous studies have shown minimal impact of tyrosine kinase inhibitors on primary renal tumors. In this phase II trial, we investigate the safety and role of the axitinib in downsizing tumors in patients with non-metastatic clear cell renal cell carcinoma (RCC) prior to surgical resection. Methods: Patients with clinical stage T2-T3b N0 M0 biopsy-proven RCC were eligible for this study. Patients received axitinib daily for 12 weeks prior to surgery. The primary outcome was objective response rate. Secondary outcomes included safety, tolerability, feasibility of administration of axitinib and quality of life (using FKSI-15). A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: Twenty-four patients were treated between 2011 and 2013. All patients had biopsy-proven clear cell RCC. Twenty-three patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. One patient stopped treatment before 12 weeks due to adverse events (AEs) and was taken to surgery early. Median reduction of primary renal tumor size was 28.3% (range 5.3-42.9%). Eleven patients (45.8%) experienced a partial response by RECIST, and 13 patients had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. No grade 4 AEs were observed. Intraoperatively, no complications or unusual bleeding were encountered. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted, while no grade 4 or 5 complications occurred. FKSI-15 did change over time (p < 0.0001), with quality of life worsening in comparison to the screening assessment by week 7 (p = 0.0004). However, by week 19, quality of life was not found to be statistically different from screening (p = 0.3344). Conclusions: Axitinib was clinically active and well tolerated in the neoadjuvant setting in patients with locally advanced non-metastatic ccRCC. Clinical trial information: NCT01263769.

Risk of proteinuria with the new angiogenesis inhibitor axitinib in patients with cancer.

e20602 Background: The use of axitinib, a potent inhibitor of vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of proteinuria with axitinib. Methods: Potentially relevant studies were identified by searching databases including Pubmed and abstracts presented at the American Society of Clinical Oncology annual meetings until June, 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidences of all-grade and high-grade (grade 3 or 4) proteinuria with axitinib were 22.7% (95% CI: 10.4-42.6%) and 3.8% (95% CI: 2.6-5.7%) respectively. The risk did not vary significantly with tumor types (P=0.13). There was no significant difference between RCC and non-RCC patients (P=0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 versus 17.5%, 95% CI: 7.4-36.3%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% versus 0.1%, 95% CI: 0-2.3%; P=0.031). When compared to another angiogenesis inhibitor sorafenib, axitinib did not have a significantly higher risk of all-grade (RR=1.48, 95% CI: 0.92-2.38, P=0.10) and high-grade proteinuria (RR=1.81, 95% CI: 0.68-4.85, P=0.24). Conclusions: There was a significant risk of proteinuria associated with the use of axitinib in cancer patients.

Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with axitinib in patients with previously treated metastatic renal cell cancer (RCC).

2533 Background: PF-04856884 is a recombinant humanized monoclonal antibody fused to two Ang-2 binding peptides. Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factors (VEGFs) that is approved for patients (pts) with advanced renal cell cancer who failed 1 prior therapy. Metastatic RCC (mRCC) is an angiogenic tumor sensitive to VEGF tyrosine kinase inhibitors. Resistance to VEGF targeted therapy may be mediated by Ang-2. Methods: In Part I (safety lead in) of the study, the primary endpoint was treatment related dose limiting toxicities (DLT) in pts with mRCC who had received 1-3 prior treatments. Pts received PF-04856884 (15 mg/kg/week) plus axitinib (5 mg BID) for 4 week cycles (the recommended Phase II dose of each) and were assessed for DLT, PK, and potential predictive biomarkers (Ang-2 and VEGF-A). For Part II (Phase II portion), pts with mRCC who had received 1 prior anti-VEGF agent were to be randomized to PF-04856884 + axitinib or axitinib alone to assess median progression free survival. Results: Part I enrolled 18 pts with median age of 62.5 years (39-82), and ECOG performance status of 0-1. One pt had a DLT of Grade 4 pulmonary embolism (PE). Most common related AEs: anorexia in 10 pts (56%), diarrhea 8 (44%), fatigue 8 (44%), nausea 7 (39%), hypertension 6 (33%) and vomiting 6 (33%). Treatment-related thromboembolic events (TEEs) were observed: PE in 2 pts (11%), and cerebrovascular accident (CVA), presumed bowel ischemia, and possible cardiac chest pain in 1 pt (6%) each. One pt had Grade 2 venous thrombosis unrelated to either treatment. Due to the reported TEE, PF-04856884 was reduced to 10 mg/kg in pts remaining on study and enrollment to Part II was not initiated. No significant PK interaction was observed. Two pts had partial response (PR) and 1 pt had unconfirmed PR. Twelve pts (66%) remained on study ≥91 days with a median duration of 120 days (8-279). Anti-PF-04856884 antibody results are not available. Conclusions: Due to the higher than expected TEEs, alternate doses of PF-04856884 and/or disease settings are being considered. Clinical trial information: NCT01441414.

The risk of proteinuria with the angiogenesis inhibitor axitinib in patients with cancer.

439 Background: The use of axitinib, a potent inhibitor of the vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of severe proteinuria when treated with axitinib. Methods: Potentially relevant studies were identified by searching databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings until June 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on all-grade and/or high-grade proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidence of all-grade proteinuria with axitinib was 22.7% (95% CI: 10.4-42.6%). There was no significant difference between RCC and non-RCC patients (p = 0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 vs. 17.5%, 95% CI: 7.4-36.3%). The overall incidence of high-grade (grade 3 or 4) proteinuria with axitinib was 3.8% (95% CI: 2.6-5.7%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% vs. 0.1%, 95% CI: 0-2.3%; p=0.031). When compared to sorafenib, another angiovsgenesis inhibitor, axitinib has elevated risk of proteinuria but without statistical significance (RR=1.48 for all-grade, 95% CI: 0.92-2.38, p = 0.10; RR=1.81 for high-grade, 95% CI: 0.68-4.85, p = 0.24). Conclusions: There was a significant risk of high-grade proteinuria associated with the use of axitinib in cancer patients. Adequate monitoring and appropriate use of axitinib is recommended to reduce renal complications.

Inhibition of tumor growth in a VEGFR TKI-resistant model of renal cell carcinoma using dalantercept combined with sunitinib.

370 Background: Antagonists of VEGF/VEGFR pathway have demonstrated clinical utility in patients with metastatic renal cell carcinoma (RCC); however, the therapeutic responses tend to be short-lived. Thus, there is a need for new treatments to overcome the acquired resistance to the current standards of care. Methods: We have used a murine xenograft model of RCC to study the relationship of the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) superfamily pathways and the VEGF pathways. Additionally, we have studied the effects of BMP9/10 inhibition on RCC tumor growth and performed MRI based tumor blood flow analyses to study antiangiogenic activity of the treatments. To explore the role of BMP9/10/ALK1 signaling in resistance to VEGFR inhibition, we used dalantercept (human ALK1-Fc fusion protein) as a ligand trap for BMP9 and 10. Results: We have found evidence of upregulation of BMP10 in A498 RCC xenograft tumors that have developed resistance to sunitinib. In tumors that had developed resistance to sunitinib, addition of ALK1-Fc to sunitinib led to prolonged tumor stabilization compared to either agent alone. Imaging of tumors revealed that addition of ALK1-Fc to sunitinib prevented the resumption in blood flow that is generally seen with continued sunitinib. Conclusions: These murine xenograft model data demonstrate that inhibition of ALK1 receptor pathway in combination with inhibition of VEGFR pathway may be a useful strategy for the treatment of RCC. A phase II randomized study of dalantercept in combination with axitinib in patients with metastatic RCC after progression on VEGFR/TKI therapy is ongoing.

Axitinib for the Management of Metastatic Renal Cell Carcinoma

In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2–6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advancedRCCpreviously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable noncumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95%CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95%CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6).In the three studies, themost common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients.An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.

Axitinib second-line therapy for metastatic renal cell carcinoma (mRCC): Five-year (yr) overall survival (OS) data from a phase II trial.

4547 Background: Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1–3. Axitinib in patients (pts) with cytokine-refractory mRCC (Rixe et a...

Baseline patient-reported kidney cancer-specific symptoms as an indicator for median survival in sorafenib-refractory metastatic renal cell carcinoma

The goal of the study was to determine the relationship of baseline Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI) scores with median progression-free survival (mPFS) and median overall survival (mOS) after treatment with axitinib in patients with sorafenib-refractory metastatic renal cell carcinoma. As part of a multicenter, open-label, phase II study, patients (N = 62) reported symptoms at baseline using the FKSI, with higher scores indicating less severe symptoms. A Weibull (fully parametric) model was fit to time-to-event data to establish the relationship of baseline FKSI score with mPFS and mOS. Kaplan-Meier curves were obtained as sensitivity analyses. Longer progression-free and overall survivals were associated with higher (more favorable) baseline FKSI-15 and FKSI disease-related symptoms (FKSI-DRS) subscale specific to kidney cancer scores. For example, for FKSI-15 scores of 0 (most symptoms), 30, and 60 (no symptoms), the mPFS were 0.72, 3.83, and 20.43 months, respectively, and the mOS were 1.05, 6.27, and 37.53 months. Similar patterns and interpretations were observed for the FKSI-DRS scores. The results from the Kaplan-Meier analyses supported the parametric model. Baseline patient-reported kidney cancer symptoms are linked to mPFS and mOS in a clear and interpretable way. These results support the evaluation of patient-reported symptoms at baseline in clinical trials and in clinical practice to measure symptom severity and potentially predict progression-free and overall survival outcomes. The results provide a heightened opportunity to use patient data not only to assist in medical treatment planning but also to prepare patients, who have advanced disease and an already reduced expected lifespan, with an opportunity to deal with the psychosocial aspects of the dying process.

Effect of axitinib (AG‐013736) on fatigue, thyroid‐stimulating hormone, and biomarkers: A phase I study in Japanese patients

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, antitumor activity, and recommended starting dose of axitinib in patients with advanced solid tumors. Twelve patients received single-dose axitinib 5 mg and were monitored for > or =48 h. Continuous 5 mg twice-daily dosing was then initiated. One patient had dose-limiting toxicity (grade 3 proteinuria and fatigue). Common treatment-related adverse events were anorexia, fatigue, and diarrhea. Grade 3 treatment-related adverse events were fatigue and hypertension. Maximum axitinib plasma concentration occurred 1-4 h after steady-state dosing. Eleven patients experienced thyroid-stimulating hormone elevation; time-course change and fatigue onset appeared to be related in some patients. Significant correlation was observed between thyroid-stimulating hormone change and area under the plasma concentration-time curve (AUC; r = 0.80, P = 0.005). Axitinib decreased plasma soluble vascular endothelial growth factor receptor 2 (s-VEGFR2), with significant correlation between change in s-VEGFR2 and AUC (r = -0.92, P < 0.0001). Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib. Tumor size decreased in nine patients. The time-course of thyroid-stimulating hormone change appeared correlated with fatigue. There were significant correlations between thyroid-stimulating hormone or s-VEGFR2 and axitinib exposure. Axitinib 5 mg twice-daily is the recommended starting dose for Japanese patients. This trial is registered with ClinicalTrials.gov, identifier NCT00447005.