Paul Bycott

Axitinib Is an Active Treatment for All Histologic Subtypes of Advanced Thyroid Cancer: Results From a Phase II Study

PURPOSE Patients with advanced, incurable thyroid cancer not amenable to surgery or radioactive iodine ((131)I) therapy have few satisfactory therapeutic options. This multi-institutional study assessed the activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer. PATIENTS AND METHODS Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I were enrolled onto a single-arm phase II trial to receive axitinib orally (starting dose, 5 mg twice daily). Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors was the primary end point. Secondary end points included duration of response, progression-free survival (PFS), overall survival, safety, and modulation of soluble (s) VEGFR. RESULTS Sixty patients were enrolled. Partial responses were observed in 18 patients, yielding an ORR of 30% (95% CI, 18.9 to 43.2). Stable disease lasting > or = 16 weeks was reported in another 23 patients (38%). OBJECTIVE responses were noted in all histologic subtypes. Median PFS was 18.1 months (95% CI, 12.1 to not estimable). Axitinib was generally well tolerated, with the most common grade > or = 3 treatment-related adverse event being hypertension (n = 7; 12%). Eight patients (13%) discontinued treatment because of adverse events. Axitinib selectively decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT, demonstrating its targeting of VEGFR. CONCLUSION Axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advanced thyroid cancer.

Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study

BACKGROUND Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment. METHODS Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011. FINDINGS In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44.2% (95% CI 30.5-58.7). Median response duration was 23.0 months (20.9-not estimable; range 4.2-29.8). However, 12 of 23 initial responders progressed with response duration ranging from 4.2 months to 26.5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15.7 months (8.4-23.4, range 0.03-31.5) and median overall survival was 29.9 months (20.3-not estimable; range 2.4-35.8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline. INTERPRETATION Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.

Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study

BACKGROUND Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING Pfizer.

Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study

BACKGROUND Axitinib (AG-013736) is a potent and selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, which have an important role in pancreatic cancer. The aim of this study was to assess the safety and efficacy of gemcitabine plus axitinib versus gemcitabine alone. METHODS Between January and August, 2006, 103 patients with unresectable, locally advanced, or metastatic pancreatic cancer were randomly assigned in a two to one ratio to receive gemcitabine (1000 mg/m(2)) plus axitinib 5 mg twice daily (n=69) or gemcitabine (1000 mg/m(2)) alone (n=34) by a centralised registration system. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00219557. FINDINGS All randomised patients were included in the efficacy analyses. Median overall survival was longer with gemcitabine plus axitinib than with gemcitabine alone (6.9 [95% CI 5.3-10.1] months vs 5.6 [3.9-8.8] months). The hazard ratio for survival with gemcitabine plus axitinib versus with gemcitabine alone, adjusted for stratification factors, was 0.71 (95% CI 0.44-1.13). The most common grade 3 or worse adverse events were fatigue (15 [22%] patients in the gemcitabine plus axitinib group vs one [3%] in the gemcitabine alone group), abdominal pain (eight [12%] vs five [16%]), and asthenia (eight [12%] vs one [3%]). INTERPRETATION Gemcitabine plus axitinib showed a similar safety profile to gemcitabine alone; the small, non-statistically significant gain in overall survival needs to be assessed in a randomised phase III trial.

Phase 1 Clinical and Pharmacokinetics Evaluation of Oral CI-1033 in Patients with Refractory Cancer

Purpose: To determine the tolerability and pharmacokinetics of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, administered over 14 consecutive days of a 21-day cycle. Design: Phase 1, multicenter trial involving patients with solid tumors that are refractory to standard therapy. CI-1033 was administered initially at 300 mg/day to a minimum cohort of three patients. Dose escalation proceeded at ≤40% increments. Patients were evaluated for toxicity, pharmacokinetic profile, and evidence of response. Results: Thirty-two patients entered the trial and were evaluable for safety assessment. Dose-limiting toxicity (diarrhea, rash, and/or anorexia) occurred at the 560 mg dose level; the maximum tolerated dose was 450 mg. No patients achieved objective responses and six patients achieved stable disease. Plasma CI-1033 concentrations increased with increasing dose. CI-1033 was not eliminated in urine to any appreciable extent. Conclusions: CI-1033 is suitable for phase 2 testing at the 450 mg/day dose level when administered for 14 days in a 21-day cycle. The pharmacokinetic profile is consistent with biologically relevant plasma concentrations over the dosing interval.

Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments.

In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient‐reported outcomes were assessed.

A Quantitative Approach for Making Go/No-Go Decisions in Drug Development

There are many decision points along the product development continuum. Formal clinical milestones, such as the end of phase 1, phase 2a (proof of mechanism or proof of concept), and phase 2b provide useful decision points to critically evaluate the accumulating data. At each milestone, sound decisions begin with asking the right questions and choosing the appropriate design as well as criteria to make go/no-go decisions. It is also important that knowledge about the new investigational product, gained either directly from completed trials or indirectly from similar products for the same disorder, be systematically incorporated into the evaluation process. In this article, we look at metrics that go beyond type I and type II error rates associated with the traditional hypothesis test approach. We draw on the analogy between diagnostic tests and hypothesis tests to highlight the need for confirmation and the value of formally updating our prior belief about a compounds effect with new data. Furthermore, we show how incorporating probability distributions that characterize current evidence about the true treatment effect could help us make decisions that specifically address the need at each clinical milestone. We illustrate the above with examples.

Five-year survival in patients with cytokine-refractory metastatic renal cell carcinoma treated with axitinib.

BACKGROUND In a phase II study of axitinib for cytokine-refractory metastatic renal cell carcinoma, median overall survival (OS) was 29.9 months (95% CI, 20.3 to not estimable months). PATIENTS AND METHODS Long-term survival data were collected retrospectively from 52 patients with cytokine-refractory metastatic renal cell carcinoma who received axitinib in a completed phase II study (protocol 1), 11 of whom enrolled in a continuing access protocol (protocol 2), for the current observational study (protocol 3). In a post hoc analysis, the patients were grouped into quartiles based on cycle 1 day 1, 1- to 2-hour post-dose axitinib plasma levels to explore the impact of drug exposure on efficacy. RESULTS The 5-year survival rate was 20.6% (95% CI, 10.9%-32.4%), with a median follow-up of 5.9 years. Frequent all-grade adverse events were fatigue (n = 38; 73.1%), diarrhea (n = 34; 65.4%), hypertension (n = 33; 63.5%), and nausea (n = 33; 63.5%). Quartile 3 patients (axitinib level, 45.2-56.4 ng/mL; n = 12) had the best clinical outcome: objective response rate 82%, median progression-free survival (PFS) 28.3 months, and median OS that was not reached after 5 years. CONCLUSIONS Axitinib was well tolerated and provided an estimated 5-year survival rate of 20.6% for cytokine-refractory metastatic renal cell carcinoma. Exploratory analyses showed numerically higher objective response rate and longer OS and PFS in patients who achieved post-first-dose axitinib plasma concentrations within a specific range.

Health-related quality of life during treatment for renal cell carcinoma: results from a phase II study of axitinib

Introduction. Patients with metastatic renal cell carcinoma (RCC) are often treated with cytokine therapy, although the effect is modest and second-line therapy is often warranted. Relatively little is known regarding the impact on health-related quality of life (HRQOL) in cytokine-refractory patients. This study examined the HRQOL of patients with metastatic RCC treated with axitinib, a new targeted therapy that affects the vessels supplying blood to the tumor. Material and methods. Patients with metastatic RCC and progression following first-line cytokine therapy were enrolled into a single-arm, open-label multicenter phase II trial. Axitinib was administered orally twice daily until disease progression or intolerance. The primary endpoint was objective response rate, with secondary endpoints being time to progression, overall survival, safety and HRQOL. The longitudinal analyses of the HRQOL data through 144 weeks of treatment, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, are presented here. Results. Fifty-two patients completed baseline HRQOL assessments. Statistically significant baseline–post-treatment changes were observed on the role, cognitive and social functioning scales as well as on the nausea and vomiting, pain and diarrhea symptoms. All of the changes were less than one-quarter of the category, with diarrhea being the exception at less than half a category, suggesting that the changes as reported by patients were not meaningful. Discussion. Treatment of metastatic RCC with axitinib demonstrated acceptable disruption in HRQOL functioning and symptoms when compared to baseline levels. From a patient-reported perspective, treatment with axitinib appears to be well tolerated.

Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial.

Objective Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study. Methods Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m2 once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival. Results Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months—not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4–10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525–2.274]). Median survival follow-up (range) was 5.1 months (0.02–12.3) with axitinib/gemcitabine vs. 5.4 months (1.8–10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival. Conclusions Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.