Phase II study of irinotecan and cetuximab given every 2 weeks as second-line therapy for advanced colorectal cancer

BackgroundIrinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC.Patients and MethodsPatients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m² and irinotecan 180 mg/m² were administered intravenously (I.V.) on day 1 every 2 weeks.ResultsPatient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild-type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04).ConclusionsThe RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated.     

Mature results of a phase II trial of gemcitabine/paclitaxel given every 2 weeks in patients with advanced non-small-cell lung cancer

PURPOSE: This phase II study evaluated the efficacy and toxicity of gemcitabine/paclitaxel given every 2 weeks in patients with advanced-stage non-small-cell lung cancer. Treatment with 1 previous chemotherapy regimen was allowed. Patients received gemcitabine 3000 mg/m(2) intravenously over 30 minutes and paclitaxel 150 mg/m(2) over 3 hours every 2 weeks. PATIENTS AND METHODS: Forty-five patients were enrolled: 31 patients were chemotherapy naive and 14 patients were previously treated. The median age was 61 years, and the majority of patients had adenocarcinoma and stage IV disease. The minimum follow-up was 4.5 years. The response rate was 27% for all 45 patients and 32% for the 38 patients who were response evaluable. RESULTS: The response rate was 26% (31% response evaluable) for the patients who were chemotherapy-naive and 29% (33% response evaluable) for the patients who were previously treated. For the entire group, the median time to progression was 3.3 months; median overall survival was 9.4 months, and the 1-year and 2-year survival rates were 38% and 13%, respectively. The overall survival and time to progression durations were not significantly different between patients who were chemotherapy-naive and patients who were previously treated. The toxicities associated with treatment were minimal, with only 1 episode of grade 4 neutropenia and a low incidence of significant nonhematologic toxicity. CONCLUSION: Gemcitabine/paclitaxel is active in the treatment of non-small-cell lung cancer. The every-2-week schedule is likely to be responsible for the low level of toxicity seen with this regimen and could be used as the basis for the addition of other agents in future clinical trials.     

Phase II randomised trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Taxotere (docetaxel) at the dose of 75 mg/m(2) every 3 weeks is a standard therapy for pretreated non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety profile of two schedules of docetaxel administration (every 3 weeks versus weekly) in patients with pretreated NSCLC. PATIENTS AND METHODS: From February 2000 to February 2001, 125 patients with locally advanced or metastatic NSCLC were randomised after failure of a previous platinum-based regimen to receive either docetaxel 75 mg/m(2) administered every 3 weeks (Dq3w) or docetaxel 40 mg/m(2) given weekly for 6 weeks followed by 2 weeks of rest (Dqw). Safety evaluations focused on grade 3-4 neutropenia, febrile neutropenia, nausea-vomiting and asthenia. RESULTS: Patients' characteristics were well balanced between arms. The most common National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3-4 toxicity was neutropenia, which occurred in 48.4% of Dq3w patients versus 15.9% of Dqw patients (P=0.001). In addition, febrile neutropenia were observed in 6.5% of patients in Dq3w versus 0% in Dqw. Grade 3-4 asthenia was more frequent in Dqw. Other non-haematological toxicities were very rare. Regarding efficacy, there was a trend towards a better disease control rate in Dq3w: 32.2% versus 25.4% in Dqw. Median time to progression and survival were rather similar in both arms, respectively: 2.1 months (range 2-3.2) and 5.8 months (range 4.0-7.0) in Dq3w and 1.8 months (range 1.6-2.3) and 5.5 months (range 3.7-6.6) in Dqw. CONCLUSIONS: While both schedules had a favourable safety profile, a significant lower rate of severe neutropenia was observed in the weekly arm. Both regimens had similar efficacy. The weekly regimen could be considered as a good alternative for patients at risk of severe neutropenia.     

Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer.

PURPOSE: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). PATIENTS AND METHODS: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. RESULTS: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. CONCLUSION: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.     

Phase II randomized study of daily gefitinib treatment alone or with vinorelbine every 2 weeks in patients with adenocarcinoma of the lung who failed at least 2 regimens of chemotherapy

BACKGROUND: The objective of this study was to assess the efficacy of adding chronic, intermittent, low-dose vinorelbine to gefitinib treatment for patients who had adenocarcinoma of the lung who failed>or=2 regimens of chemotherapy. METHODS: Patients were randomized into 2 arms: Oral gefitinib 250 mg daily (the G arm) or vinorelbine 15 mg/m2 as an intravenous infusion on Day 1 and oral gefitinib 250 mg daily on Days 2 through 14 every 2 weeks (the GV arm). From August 2004 to October 2005, 48 patients were enrolled. Epidermal growth factor receptor (EGFR) exon 18 through 21 nucleotide sequence analysis and fluorescence in situ hybridization were performed in patients who had tumor tissue specimens available for analysis. RESULTS: After randomization, each arm had 24 patients. However, 3 patients refused vinorelbine treatment and were given gefitinib treatment only. Thus, 27 patients received G treatment, and 21 patients received GV treatment. Objective response rates were 55.6% in the G arm and 52.4% in the GV arm. All toxicities in both arms were mild. The 1-year progression-free survival rate was 57.1% in the GV arm and 21.2% in the G arm (P=.008). The median survival was 13.3 months in the G arm and 23.4 months in the GV arm (P=.1231). Three of 6 patients (50%) had an exon 19 in-frame deletion, and 2 of 10 patients had EGFR gene high polysomy or amplification (20%). CONCLUSIONS: Gefitinib was highly effective in ethnic Chinese patients with adenocarcinoma of the lung who failed previous platinum and taxane treatment. The addition of low-dose vinorelbine every 2 weeks produced a significantly better 1-year progression-free survival rate.     

A Multicenter Phase II Study of Docetaxel 60 mg/m2 as First-Line Chemotherapy in Patients with Advanced or Recurrent Breast Cancer

PURPOSE: Docetaxel is an active agent as first-line chemotherapy in patients with advanced breast cancer at a dosage of 100 mg/m2. However, the efficacy of this agent as a first-line drug when used at a lower dosage is unclear. This study was performed to evaluate the clinical efficacy and safety of 60 mg/m2 docetaxel for the treatment of breast cancer. PATIENTS AND METHODS: This study enrolled 23 patients with advanced and/or metastatic breast cancer, who had not been treated with an anthracycline or taxane previously. Treatment with docetaxel was continued in patients showing a response until there was evidence of disease progression or unacceptable toxicity. RESULTS: Among 20 fully evaluated patients, the overall response rate was 50.0% and the median time to progression was 31 weeks. The most commonly observed adverse events were neutropenia (78.2%) and fatigue (60.9%). Fluid retention occurred in only 8.7% of the patients. Adverse events did not cause discontinuation of the treatment. CONCLUSION: Docetaxel achieved good disease control with mild adverse events in first-line treatment at a dosage of 60 mg/m2.     

Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study.

BACKGROUND: Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive patients but optimal dose and schedule remain undetermined. This study aimed to select a dose-dense regimen for further assessment in phase III studies. PATIENTS AND METHODS: Ninety-nine patients with node-positive invasive breast adenocarcinoma were randomly assigned to docetaxel (Taxotere) (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 (TEC)x6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 x 4, then T 100 mg/m2 x 4 (EC-->T) or the reverse sequence (T-->EC), every 2 weeks, with pegfilgrastim support. The primary end point was the incidence of grade 4 toxicity. RESULTS: Dose intensity was almost doubled with dose-dense regimens, compared with TEC. Twenty-seven patients experienced grade 4 toxicity: 26%, 40% and 18% with TEC, EC-->T and T-->EC, respectively, mainly neutropenia, but febrile neutropenia occurred only in 11%, 10% and 3%. Grade 3-4 nail disorders, hand-foot syndrome and peripheral neuropathy occurred in 46%, 73% and 68% of patients with TEC, EC-->T and T-->EC, respectively. CONCLUSIONS: Dose-dense regimens yield more frequent and severe nonhematological toxic effects than standard dose TEC regimen. Though grade 4 toxicity rates appear acceptable with the T-->EC regimen, the incidence of grade 3-4 events makes it difficult to recommend either dose-dense regimen for further investigation.     

Phase II trial with alternating two drug schedules, CAP/MEC', for advanced (stage III Mo/M1) non-small-cell lung cancer

Sixty-eight evaluable patients with advanced squamous cell carcinoma (48), large cell carcinoma (2) and adenocarcinoma (18) of the lung were treated with a six-drug regimen delivering two monthly alternated combinations. The combinations were cisplatin, adriamycin and cyclophosphamide (CAP) and methotrexate, etoposide and CCNU (MEC'). Following a minimum of two courses, the overall response rate was 22% (confidence limits, 12% to 32%) (15/68, 2 complete responses and 13 partial responses); 47% (32/68) had stable disease and 31% (21/68) had progressive disease. The responses lasted a median of 3 months (range, 1-15 months). The actuarial median survival was 11 months in responsive patients, 10 months in stable disease patients, and 5 months in progressive patients. The overall median survival obtained was 9 months (range, 2-28+ months). Toxicity was minimal, and subjective tolerance of the treatment appeared good. However, this alternating program did not improve response rate or survival.     

A randomized,phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small-cell lung cancer (NSCLC)

Background: This trial investigated the efficacy and safety of weekly cetuximab combined with two different schedules of paclitaxel/carboplatin for stage IIIB/IV non-small-cell lung cancer (NSCLC).Methods: A total of 168 patients with previously untreated stage IIIB/IV NSCLC were randomized to arm A, cetuximab (400 mg/m² day 1 followed by weekly 250 mg/m²) + paclitaxel (Taxol) (225 mg/m²)/carboplatin (AUC6) day 1 every 3 weeks or arm B, same cetuximab regimen plus paclitaxel (100 mg/m²) days 1, 8, and 15 every 3 weeks and carboplatin (AUC6) day 1 every 4 weeks. Treatment continued for a four-cycle maximum. Patients with a complete response, partial response, or stable disease after four cycles could receive cetuximab 250 mg/m²/week until disease progression or unacceptable toxicity. The primary end point was to evaluate progression-free survival (PFS).Results: Median PFS was 4.7 and 4.3 months for arms A and B, respectively (6-month PFS, 27.3% versus 30.9%). Median overall survival was 11.4 versus 9.8 months for arms A and B, respectively; estimated 1-year survival, 47.7% versus 39.3%; and objective response rate, 29.6% versus 25%. The regimen was well tolerated with rash and hematologic toxicity being most common.Conclusions: This study did not meet the prespecified benchmark of 35% 6-month PFS rate; both combination schedules of cetuximab plus paclitaxel/carboplatin were feasible and equivalent for treating advanced NSCLC.     

Randomised, multicentre phase II study assessing two doses of docetaxel (75 or 100 mg/m2) as second-line monotherapy for non-small-cell lung cancer.

BACKGROUND: The survival benefit associated with first-line chemotherapy in advanced lung cancer led to the need for second-line chemotherapy. Docetaxel (Taxotere) has proven efficacy in both settings. This study evaluated the safety and efficacy of two doses of docetaxel in patients with non-small-cell lung cancer who had failed first-line platinum-based chemotherapy. PATIENTS AND METHODS: In total, 182 patients from 24 French centres were randomised and treated with either docetaxel 75 mg/m(2) (arm A) or 100 mg/m(2) (arm B) every 3 weeks. Baseline characteristics were well balanced, except more patients in arm A had metastatic disease (91.4% versus 78.7%) and therefore the median number of sites involved for arm A was three compared with two for arm B. RESULTS: Median time to treatment failure was 1.34 months [95% confidence interval (CI) 1.28-1.64] for arm A and 1.64 months (95% CI 1.34-2.62) for arm B. Median overall survival was 4.7 months (95% CI 3.8-5.9) for arm A versus 6.7 months (95% CI 4.8-7.1) for arm B. According to a blinded expert panel, disease control was achieved in 35 (43.8%) patients in arm A and 39 (49.4%) patients in arm B. More patients in arm B experienced grade 3-4 neutropenia (B: 72.7% versus A: 44.0%), asthenia (B: 20.2% versus A: 10.8%) and infection (B: 6.7% versus A: 2.2%). Three treatment-related deaths were reported in each arm. CONCLUSIONS: The optimal docetaxel dosage in this second-line setting is 75 mg/m(2), as it has a more favourable safety profile and on balance a similar efficacy to the 100 mg/m(2) dose.     

A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129.

BACKGROUND: ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group. PATIENTS AND METHODS: Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m(2) every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m(2) on the basis of emergent data from studies ongoing at the time. RESULTS: Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m(2) and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m(2). Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m(2) and two patients (10%) at 120 mg/m(2). Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients. CONCLUSION: ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.     

Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3 weeks in solid tumours: an ECSG/EORTC study

CHS 828 is a new guanidino-containing drug. The aim of this study was to determine the maximum tolerated dose (MTD), the recommended dose and the toxicity of CHS 828. CHS 828 was given orally once every 3 weeks. The starting dose was 50 mg, which was escalated to 500 mg. A total of 107 courses was administered to 37 patients. At the 500-mg dose level, two of three patients experienced dose-limiting toxicities (DLT) (grade 3 mucositis and grade 4 thrombocytopenia), establishing this as the MTD. One of seven patients treated at 420 mg dose experienced DLT (grade 4 leucopenia, grade 4 mucositis and grade 4 diarrhoea), and this was considered the recommended dose for phase II studies. Vomiting, haematuria, leucopenia and thrombocytopenia were other significant toxicities. The pharmacokinetics of CHS 828 showed large variations both between and within patients. No objective responses were seen. A dose of 420 mg of CHS 828 administered every 3 weeks is the recommended dose, while 500 mg is the MTD.     

Reduced incidence of severe palmar-plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m2 every 4 weeks in previously treated patients with metastatic breast cancer

PURPOSE: The aim of this study was to assess whether the reduction in the total dose of pegylated liposomal doxorubicin (PLD) per cycle from 50 mg/m(2) every 4 weeks to 40 mg/m(2) every 4 weeks can effectively lower the incidence of treatment-related palmar-plantar erythrodysesthesia (PPE) and mucositis. METHODS: Patients received PLD 40 mg/m(2) every 4 weeks, and were evaluated for toxicity prior to each treatment and for response every 8 weeks. RESULTS: All patients were previously treated with at least one chemotherapy regimen for metastatic disease, and 72% of the patients had a prior exposure to an anthracycline. Forty-six evaluable patients received a median of four PLD cycles, with a median dose intensity of 10 mg/m(2)/week and a median cumulative dose of 160 mg/m(2). No National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 PPE was observed in these patients. NCI-CTC grade 3 or 4 mucositis occurred in 4.3% of patients, only. Response rates and survival results observed here were comparable to those observed with PLD 50 mg/m(2) every 4 weeks in a matched patient population. However, patients treated with PLD 40 mg/m(2) every 4 weeks experienced less PPE and mucositis and required clearly less dose reductions and treatment delays. CONCLUSION: The favorable safety profile observed in this study leads us to recommend the use of PLD 40 mg/m(2) every 4 weeks for patients with advanced breast cancer.     

Comparative study on vindesine plus cisplatin treatment of advanced non-small cell lung cancer--three divided doses (35 mg/m2, day 1, 8, 15) and single dose (80 mg/m2, day 1) of cisplatin. Chiba Lung Cancer Study Group]

Sixty-one patients with advanced non-small cell lung cancer were randomly allocated to receive vindesine (3 mg/m2, day 1, 8, 15) plus either three cisplatins (35 mg/m2, day 1, 8, 15) or one cisplatin (80 mg/m2, day 1). Among the 61 patients, the number of complete cases treated by the former administration schedule (group A) was 24 and by the latter schedule (group B) was 27. The response rate of group A was 25.0% and that of group B was 22.2%. There was no significant difference between survival curves of group A and B. The median survival times of group A and B were 8.5 months and 7.5, respectively. Regarding the incidence rate of various side effects, no difference was found between the two groups. However, according to the WHO grade of side effects, nausea/vomiting in group A was significantly milder than in group B. The grade of leukopenia in group A showed a tendency to be milder than in group B. In conclusion, in terms of tumor response, vindesine plus three doses of cisplatin was no better than conventional vindesine plus cisplatin chemotherapy, however side effects of the former were slightly less severe.     

ENGOT-ov-6/TRINOVA-2: Randomised,double-blind,phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer

AimsTrebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer.MethodsWomen with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m² once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated.ResultsTwo hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2–9.0) in the trebananib arm and 7.2 months (95% CI, 4.8–8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68–1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78–6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7–7.6]; placebo, 3.9 months [95% CI, 2.3–6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%).ConclusionsTrebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified.Trial registration: ClinicalTrials.gov, NCT01281254     

A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study

Ixabepilone is a tubulin-polymerizing agent with potential activityin squamous cell carcinoma of the head and neck (SCCHN). Patientswere eligible who had incurable, measurable SCCHN and less thantwo prior regimens for metastatic/recurrent disease. EasternCooperative Oncology Group performance status of less than orequal to one and adequate renal/hepatic/hematological functionwere required. Patients were randomly assigned to receive ixabepilone6 mg/m²/day x 5 days every 21 days (arm A) or 20 mg/m² on days1, 8, and 15 of a 28-day cycle (arm B). Each arm accrued taxane-naiveand -exposed strata in a two-stage design. The primary end pointwas response. Eighty-five eligible patients entered; there wasone response in a taxane-exposed patient among 32 patients onarm A. Five of 35 taxane-naive patients on arm B had partialresponses (14%). No taxane-exposed patient on arm B responded.Common grades 3 and 4 toxic effects were fatigue, neutropenia,and sensory/motor neuropathy. Median survival for arm A taxane-naiveand taxane-exposed patients is 5.6 and 6.5 months; for arm B,taxane-naive and taxane-exposed patients is 7.8 and 6.5 months.Weekly ixabepilone 20 mg/m² is active in taxane-naive patientswith SCCHN. A high incidence of motor and sensory grade 3 neuropathyresulted at this dose and schedule. Further development of ixabepilonein previously treated head and neck cancer is not warrantedon the basis of these data. Key words: antimicrotubule therapy, epothilone, squamous cell carcinoma of the head and neck Received for publication July 12, 2007. Revision received December 7, 2007. Accepted for publication December 10, 2007.     

Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer.

PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.