A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1-14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m(-2) twice a day and of docetaxel from 75 to 100 mg m(-2). The dose-limiting toxicity (DLT) was asthenia grade 2-3 at a dose of 1000 mg m(-2) bid of capecitabine combined with docetaxel 100 mg m(-2). Neutropenia grade 3-4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m(-2) twice a day plus docetaxel 100 mg m(-2) was tolerable, as was capecitabine 1250 mg m(-2) twice a day plus docetaxel 75 mg m(-2).     

A phase I study of docetaxel and 5-fluorouracil in patients with advanced solid malignancies

Purpose: This study was undertaken to evaluate the feasibility of administering docetaxel (Taxotere; Rhône- Poulenc-Rorer) as a one-hour intravenous (i.v.) infusion on day 1 combined with 5-fluorouracil (5-FU) as a bolus i.v. injection for five (days 1–5) or three (days 1–3) consecutive days every four weeks.Patients and methods: Thirty-seven patients with advanced solid malignancies were treated with 115 total courses involving seven dose levels of the two regimens of docetaxel and 5-FU (docetaxel/5-FU [mg/m2]/mg/m2/d]). In an effort to reduce fluid retention and hypersensitivity phenomena related to docetaxel, patients received premedication with dexamethasone 8 mg orally twice daily for three consecutive days beginning 24 hours before treatment.Results: Severe (grade 4) neutropenia lasting longer than seven days with or without fever and/or severe mucositis, precluded further dose escalation above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1–5 every four weeks. The rates of these toxic effects were also unacceptably high above docetaxel 60 mg/m2 on day 1 and 5- FU 300 mg/m2/day administered on days 1–3 every four weeks. Nine patients experienced various manifestations of fluid- retention that were potentially related to study drugs. However, neither treatment delay nor discontinuation of treatment was required. Nausea, vomiting, diarrhea, and fatigue, were mild to modest in severity and occurred infrequently (<10% of courses). Two patients with metastatic breast cancer experienced complete responses and a partial response occurred in a patient with metastatic non-small-cell lung cancer.Conclusion: Based on the results of this study, the regimen of docetaxel 60 mg/m2 on day 1 followed by 5-FU 300 mg/m2/d i.v. for three or five days every four weeks is well tolerated and these doses are recommended for further evaluations. The feasibility of administering docetaxel 60 mg/m2 followed by 5-FU 300 mg/m2 for three or five days every four weeks and the preliminary antitumor activity noted indicate that further disease-directed studies of docetaxel and 5-FU are warranted in patients with relevant solid malignancies.     

Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients

Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18–40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan–Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations, the difference was not statistically significant (P = 0.10). However, we did not detect any somatic mutations in CAFs. Furthermore, we have shown a high prevalence (8.2-fold) of a silent variant (SNP, rs17849079) in the Arab breast cancer population compared with disease-free individuals.     

Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer

Background:

Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study.

Methods:

DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM.

Results:

Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71–1.17)) or OS (HR 0.95 (0.71–1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37–0.85) for RAS MT and HR 0.69 (0.5–0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic.

Conclusion:

Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.     

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.     

A phase I dose-escalation study of docetaxel with granulocyte colony-stimulating factor support in patients with solid tumours.

BACKGROUND: Docetaxel is a widely active cytotoxic agent. The principal dose-limiting toxicities (DLTs) of the 3-weekly regimen are neutropenia and febrile neutropenia. Use of prophylactic granulocyte colony-stimulating factor (G-CSF) may allow higher doses of docetaxel to be administered with potentially greater anticancer efficacy. The objectives of this study were to determine the maximum tolerated dose (MTD) and toxicity profile of docetaxel given with G-CSF support. PATIENTS AND METHODS: Eligible patients had solid tumours and were aged 18-75 years with a WHO performance status of up to 2. Strict criteria for liver function were followed. Patients may have received one previous regimen of chemotherapy in addition to adjuvant chemotherapy. Cohorts of three to six patients received docetaxel over 60-90 min every 3 weeks, commencing at 110 mg/m(2) and escalating at 10 mg/m(2) increments. Patients also received G-CSF 5 micro g/kg/day until neutrophil recovery. A 3-day corticosteroid prophylaxis was given. RESULTS: Twenty-nine patients with median age 55 years (range 29-75) were included. Fourteen (48%) had previously received chemotherapy. At the 170 mg/m(2) dose level (the MTD), two of three patients had DLTs and 160 mg/m(2) was determined to be the recommended dose. The principal DLTs were skin and neurosensory toxicity. Asthenia was frequent, especially at dose levels >/=140 mg/m(2). Grade 4 neutropenia occurred in only 10 patients (35%) and was not dose related, with febrile neutropenia in three patients (10%). CONCLUSIONS: Docetaxel may be escalated considerably above standard doses when administered with G-CSF support. The recommended dose for phase II studies is 160 mg/m(2). With escalated-dose docetaxel, DLTs were non-haematological and qualitatively similar to the toxicity profile at standard doses.     

A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer

BACKGROUND:

Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.

METHODS:

Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40‐75 mg/m² intravenously on day 1 of a 21‐day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21‐day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose‐limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.

RESULTS:

Fifteen patients were treated. Dose‐limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m². Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.

CONCLUSIONS:

Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs. Cancer 2012. © 2011 American Cancer Society.     

Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours

BackgroundPreclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab.MethodsTemsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150–250 mg/m², until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation.ResultsAmong 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m² and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration.ConclusionsCombination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development.     

Molecular alterations associated with liver metastases development in colorectal cancer patients

Background:

Understanding the molecular biology of colorectal cancer (CRC) provides opportunities for effective personalised patient management. We evaluated whether chromosomal aberrations, mutations in the PI(3)K signalling pathway and the CpG-island methylator phenotype (CIMP) in primary colorectal tumours can predict liver metastases.

Methods:

Formalin-fixed paraffin-embedded material from primary colorectal tumours of three different groups were investigated: patients with CRC without metastases (M0, n=39), patients who were treated with hyperthermal intraperitoneal chemotherapy for CRC metastases confined to the peritoneum (PM, n=46) and those who had isolated hepatic perfusion for CRC metastases confined to the liver (LM, n=48).

Results:

All samples were analysed for DNA copy number changes, PIK3CA, KRAS, BRAF mutations, CIMP and microsatellite instability. The primary CRCs of the LM group had significantly higher frequency of amplified chromosome 20q (P=0.003), significantly fewer mutations in the PI(3)K signalling pathway (P=0.003) and fewer CIMP high tumours (P=0.05). There was a strong inverse correlation between 20q and the PI(3)K pathway mutations.

Conclusion:

The development of CRC liver metastases is associated with amplification of chromosome 20q and not driven by mutations in the PI(3)K signalling pathway.     

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.     

A phase II study of capecitabine and docetaxel combination chemotherapy in patients with advanced gastric cancer

Capecitabine and docetaxel have considerable single-agent activity in gastric cancer with distinct mechanisms of action and no overlap of key toxicities. A synergistic interaction between these two drugs is mediated by taxane-induced upregulation of thymidine phosphorylase. We investigated the activity and the feasibility of capecitabine and docetaxel combination chemotherapy in patients with previously untreated advanced gastric cancer (AGC). From September 2001 to March 2003, 42 patients with AGC received 21-day cycles of oral capecitabine (1250 mg x m(-2) twice daily on days 1-14) and docetaxel (75 mg x m(-2) i.v. on day 1). The patients received a total of 164 cycles of chemotherapy. The median age was 53.5 years (range 33-73 years). The overall response rate in the 38 efficacy-evaluable patients was 60% (95% confidence interval, 45-74%). The median progression-free survival was 5.2 months (range, 1.0-15.5+ months) and the median overall survival was 10.5 months (range, 2.9-23.7+ months). The most common grade 3/4 adverse events were hand-foot syndrome (HFS: G3 50%), neutropenia (15%) and leucopenia (12%). Further studies of this combination are clearly warranted, albeit with lower doses of both agents (1000 mg x m(-2) twice daily and 60 mg x m(-2)) to reduce the rate of HFS and onycholysis.     

A phase I,dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours

Background:

Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.

Methods:

Sunitinib was initially administered once daily at 37.5 mg per day on days 1–14 of a 21-day cycle, in which irinotecan 250 mg m⁻² was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.

Results:

In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug–drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1–14) with irinotecan 250 mg m⁻² (day 1), but no activity was observed at this dose.

Conclusion:

Although a higher sunitinib dose of 37.5 mg per day (days 1–14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.     

Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours

Background:

This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.

Methods:

Patients received intravenous aflibercept 4, 5, or 6 mg kg⁻¹ with docetaxel and cisplatin (75 mg m⁻² each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.

Results:

During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg⁻¹). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg⁻¹ and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.

Conclusion:

Aflibercept 6 mg kg⁻¹ with docetaxel and cisplatin 75 mg m⁻² every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.     

Front-line treatment of advanced breast cancer with docetaxel and epirubicin: A multicenter phase II study

Purpose:In a previous phase I trial we evaluated the toxicity anddetermined the maximum tolerated doses of the docetaxel (D)–epirubicin(Epi) combination. We conducted a multicenter phase II study to evaluate theefficacy and tolerability of this regimen as front-line treatment in womenwith advanced breast cancer (ABC). Patients and methods:Fifty-four women with ABC stage IIIB (4patients) or IV (50 patients) received front-line treatment with Epi 70mg/m² on day 1 and D 90 mg/m² on day 2. The median agewas 55 years, performance status (WHO) was 0–1 in 49 patients andvisceral disease was present in 45 (83%). Results:All patients were evaluable for toxicity and 50 forresponse. In an intent-to-treat analysis complete remission was observed in5(9%) patients, partial remission in 31 (57%) (overall responserate 66%, 95% confidence interval: 54%–79%),stable disease in 9 (17%) and disease progression in 9 (17%).After a median follow-up of 11.5 months, the median duration of responses was8 months, the median time to disease progression 11.5 months and the mediansurvival has not yet been reached. The probability of one-year survival was65%. Three hundred six cycles of treatment were administered (median6 cycles per patient). Grade 3 and 4 neutropenia was observed in 8(15%) and 31 (57%) patients, respectively, and febrileneutropenia in 19 (35%). Prophylactic rh-G-CSF was used in 45(83%) patients or 226 (74%) cycles. Other hematologic ornon-hematologic toxicities were usually mild. In five (9%) patients theleft ventricular ejection fraction (LVEF) was decreased by more than10% with the treatment. Two patients died during the treatment ofrespiratory failure without associated neutropenia. Conclusions:The combination of docetaxel–epirubicin is aneffective and well tolerated front-line treatment in patients with ABC.     

A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503)

Background:

The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor.

Methods:

Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping.

Results:

In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure.

Conclusion:

RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.     

Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours

To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1-16 mg kg(-1)), receiving ATN-161 administered as a 10-min infusion thrice weekly. Pharmacokinetic sampling of blood and urine over 7 h was performed on Day 1. Twenty-six patients received from 1 to 14 4-week cycles of treatment. The total number of cycles administered to all patients was 86, without dose-limiting toxicities. At dose levels above 0.5 mg kg(-1), mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg(-1), clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg(-1) when drug exposure (area under the curve) exceeded that associated with efficacy in animal models. There were no objective responses. Six patients received more than four cycles of treatment (>112 days). Three patients received 10 or more cycles (> or =280 days). ATN-161 was well tolerated at all dose levels. Approximately, 1/3 of the patients in the study manifested prolonged stable disease. These findings suggest that ATN-161 should be investigated further as an antiangiogenic and antimetastatic cancer agent alone or with chemotherapy.     

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-II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I-II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel-ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70-100 mg x m(-2) over 1 h on day 1 followed by ifosfamide 5-6 g x m(-2) divided over days 1 and 2 (2.5-3.0 g x m(-2) day(-1) over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32-72) years and performance status (WHO) of 1 (range, 0-2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3-68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3-24 months), median time to progression 6.5 month (0.1-26 month), and median overall survival 13 months (0.1-33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients-with 63% developing grade 4 neutropenia (相似文献