Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial.

BACKGROUND: In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines. METHODS: In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ⩾median), and tumour burden (baseline sum of the longest diameter < vs ⩾median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated. RESULTS: Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy. CONCLUSIONS: AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC.

Intermittent dosing of axitinib combined with chemotherapy is supported by (18)FLT-PET in gastrointestinal tumours.

BACKGROUND: We evaluated week-on/week-off axitinib dosing plus chemotherapy in patients with gastrointestinal tumours, including tumour thymidine uptake by fluorine-18 3'-deoxy-3'-fluorothymidine positron emission tomography ((18)FLT-PET). METHODS: During a lead-in period, patients received twice daily (b.i.d.) axitinib 7 mg (n=3) or 10 mg (n=18) for 7 days followed by a 7-day dosing interruption; serial (18)FLT-PET scans were performed before day 1 and on days 7, 10, and 14. Axitinib plus FOLFIRI or FOLFOX was then administered in 2-week cycles; axitinib was interrupted on day 10 of each cycle for 7 days. RESULTS: The maximum tolerated dose of axitinib was 10 mg b.i.d., in a week-on/week-off schedule, combined with FOLFIRI or FOLFOX. Common all-causality grade 3 adverse events were neutropenia (38%), hypertension (33%), and fatigue (29%). Of 21 patients, 2 (10%) had a partial response and 12 (57%) had stable disease. Following 7 days of continuous axitinib dosing, tumour (18)FLT uptake decreased -49% from baseline and recovered to -28% and -17% from baseline, respectively, after 3 and 7 days of axitinib interruption. CONCLUSION: Axitinib administered in a week-on/week-off schedule combined with FOLFIRI or FOLFOX is supported by (18)FLT-PET data and was well tolerated in patients with gastrointestinal tumours.

Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial.

BACKGROUND: Axitinib demonstrated greater progression-free survival vs sorafenib in a phase III study of previously treated patients with metastatic renal cell carcinoma. Here, we report patient-reported kidney-specific symptoms and health status, measured by the Functional Assessment of Cancer Therapy (FACT) Kidney Cancer Symptom Index (FKSI) and the European Quality of Life self-report questionnaire (EQ-5D). METHODS: In all, 723 patients received axitinib (starting dose 5 mg twice daily (b.i.d.)) or sorafenib (400 mg b.i.d.). The FKSI-15, including the disease-related symptoms (FKSI-DRS) subscale, was administered on day 1 before dosing, every 4 weeks and at end of treatment (EOT)/withdrawal. Statistical methods included a mixed-effects repeated-measures model. RESULTS: At baseline, patients in both arms had relatively high mean FSKI-15 and FKSI-DRS scores, comparable to the general US population. Subsequent on-treatment overall mean scores were similar between axitinib and sorafenib, and there was no substantial decline during treatment. Scores substantially worsened at EOT, mainly due to disease progression. CONCLUSION: Patient-reported outcomes were comparable for second-line axitinib and sorafenib and were maintained at relatively high levels while on treatment, but worsened at EOT. As duration of treatment was longer with axitinib than sorafenib, time to worsening of symptoms can be delayed longer with axitinib.

Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours.

BACKGROUND: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy. METHODS: A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m(-2) weekly), docetaxel (100 mg m(-2) every 3 weeks) or capecitabine (1000 or 1250 mg m(-2) b.i.d., days 1-14). RESULTS: Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand-foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents. CONCLUSIONS: Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours.

BACKGROUND: This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours. METHODS: In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin. RESULTS: Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade ≥3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination. CONCLUSION: Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug-drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.

A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors.

BACKGROUND: Axitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway. METHODS: Patients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1-3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed. RESULTS: Thirty patients were enrolled (n = 16, 8, and 6 for cohorts 1-3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%). CONCLUSION: Axitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.

Isolated photon cross section in p&pmacr; collisions at radicals = 1. 8 TeV

We report a new measurement of the cross section for the production of isolated photons with transverse energies ( E(gamma)(T)) above 10 GeV and pseudorapidities |eta|<2.5 in p&pmacr; collisions at sqrt[s] = 1.8 TeV. The results are based on a data sample of 107.6 pb(-1) recorded during 1992-1995 with the D0 detector at the Fermilab Tevatron collider. The background, predominantly from jets which fragment to neutral mesons, was estimated using the longitudinal shower shape of photon candidates in the calorimeter. The measured cross section is in good agreement with the next-to-leading order QCD calculation for E(gamma)(T) greater, similar36 GeV.

Differential production cross section of Z bosons as a function of transverse momentum at sqrt

We present a measurement of the transverse momentum distribution of Z bosons produced in p&pmacr; collisions at sqrt[s] = 1.8 TeV from data collected by the DO experiment at the Fermilab Tevatron Collider. We find good agreement between our results and current resummation calculations, and also use our data to extract nonperturbative parameters for a particular version of the resummation formalism. The resulting values are significantly more precise than obtained in previous determinations.

Search for second-generation leptoquark pairs in &pmacr;p collisions at radicals = 1.8 TeV

We have searched for second-generation leptoquark (LQ) pairs in the &mgr;&mgr;+jets channel using 94+/-5 pb(-1) of &pmacr;p collider data collected by the D0 experiment at the Fermilab Tevatron during 1993-1996. No evidence for a signal is observed. These results are combined with those from the &mgr;nu+jets and nunu+jets channels to obtain 95% confidence level (C.L.) upper limits on the LQ pair production cross section as a function of mass and beta, the branching fraction of a LQ decay into a charged lepton and a quark. Lower limits of 200(180) GeV/c(2) for beta = 1(1 / 2) are set at the 95% C.L. on the mass of scalar LQ. Mass limits are also set on vector leptoquarks as a function of beta.

Measurement of the W boson mass using electrons at large rapidities

We report a measurement of the W boson mass based on an integrated luminosity of 82 pb(-1) from p&pmacr; collisions at sqrt[s] = 1.8 TeV recorded in 1994-1995 by the D0 detector at the Fermilab Tevatron. We identify W bosons by their decays to enu, where the electron is detected in the forward calorimeters. We extract the mass by fitting the transverse mass and the electron and neutrino transverse momentum spectra of 11 089 W boson candidates. We measure M(W) = 80.691+/-0.227 GeV. By combining this measurement with our previously published central calorimeter results from data taken in 1992-1993 and 1994-1995, we obtain M(W) = 80.482+/-0.091 GeV.

Small-angle muon and bottom-quark production in p&pmacr; collisions at radicals = 1.8 TeV

This Letter describes a measurement of the muon cross section originating from b-quark decay in the forward rapidity range 2.4<| y(&mgr;)|<3.2 in p&pmacr; collisions at sqrt[s] = 1.8 TeV. The data used in this analysis were collected by the D0 experiment at the Fermilab Tevatron. We find that next-to-leading-order QCD calculations underestimate b-quark production by a factor of 4 in the forward rapidity region.

Spin correlation in t&tmacr; production from p&pmacr; collisions at radicals = 1.8 TeV

The D0 collaboration has performed a study of spin correlation in t&tmacr; production for the process t&tmacr;-->bW(+)&bmacr;W-, where the W bosons decay to enu or &mgr;nu. A sample of six events was collected during an exposure of the D0 detector to an integrated luminosity of approximately 125 pb(-1) of sqrt[s] = 1.8 TeV p&pmacr; collisions. The standard model (SM) predicts that the short lifetime of the top quark ensures the transmission of any spin information at production to the t&tmacr; decay products. The degree of spin correlation is characterized by a correlation coefficient kappa. We find that kappa>-0.25 at the 68% confidence level, in agreement with the SM prediction of kappa = 0.88.