Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL.

ABSTRACT: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas.

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL.

BACKGROUND: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen). CONCLUSIONS: Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).

Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer.

PURPOSE: Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. PATIENTS AND METHODS: Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied. RESULTS: No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. CONCLUSION: The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS: In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study 10 002.

To improve long-term outcomes for Burkitt leukaemia/lymphoma (BL) or aggressive lymphomas in adults, we assessed the benefit of adding rituximab and filgrastim support to a dose-dense modified chemotherapy regimen from the Cancer and Leukemia Group B (CALGB) 9251 trial. One hundred and five patients (aged 19-79 years) were enrolled; 27% were >60 years old; 47% had high or high-intermediate risk by International Prognostic Index (IPI) criteria. Common severe toxicities included stomatitis/upper gastrointestinal toxicity (69%), renal insufficiency (10%), neurological events (25%) and pulmonary events (18%). Seven died from treatment-related causes (one central nervous system bleed, four infections, two respiratory failure); five were >60 years old. Results in this adult population are encouraging as complete response (CR) was observed in 83% and 4-year event-free (EFS) and overall survivals (OS) were 74% and 78%, respectively. Results compare favourably to our prior chemotherapy alone study (CALGB 9251) but despite this, high-risk patients still had worse outcomes. In conclusion, short duration, intensive chemo-immunotherapy is feasible and should be considered in adults with BL as it results in high remission rates and durable remissions.

A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck.

PURPOSE: This study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). EXPERIMENTAL DESIGN: This phase II multiinstitutional study enrolled patients with recurrent/metastatic SCCHN into two cohorts: those without (arm A) and those with (arm B) before exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1,500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (PFS; arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy. RESULTS: Forty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, and 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed, and stable disease was the best response observed in 41% of arm A (median duration, 50 days, range, 34-159) and 17% of arm B subjects (median, 163 days, range, 135-195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62-374) and 155 (95% CI, 75-242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue. CONCLUSION: Lapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects.

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium.

BACKGROUND: Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-ß, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. PATIENTS AND METHODS: We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of a 28 day cycle. RESULTS: Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. CONCLUSION: Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.

Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75.

PURPOSE: Novel approaches are needed for patients with metastatic urothelial cancer (UC). This trial assessed the efficacy and toxicity of bevacizumab in combination with cisplatin and gemcitabine (CGB) as first-line treatment for patients with metastatic UC. PATIENTS AND METHODS: Chemotherapy-naive patients with metastatic or unresectable UC received cisplatin 70 mg/m(2) on day 1, gemcitabine 1,000 to 1,250 mg/m(2) on days 1 and 8, and bevacizumab 15 mg/kg on day 1, every 21 days. RESULTS: Forty-three patients with performance status of 0 (n = 26) or 1 (n = 17) and median age of 66 years were evaluable for toxicity and response. Grade 3 to 4 hematologic toxicity included neutropenia (35%), thrombocytopenia (12%), anemia (12%), and neutropenic fever (2%). Grade 3 to 5 nonhematologic toxicity included deep vein thrombosis/pulmonary embolism (21%), hemorrhage (7%), cardiac (7%), hypertension (5%), and proteinuria (2%). Three treatment-related deaths (CNS hemorrhage, sudden cardiac death, and aortic dissection) were observed. Best response by Response Evaluation Criteria in Solid Tumors was complete response in eight patients (19%) and partial response in 23 patients (53%), for an overall response rate of 72%. Stable disease lasting ≥ 12 weeks occurred in four patients (9%), and progressive disease occurred in six patients (14%). With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months). The study-defined goal of 50% improvement in PFS was not met. CONCLUSION: CGB demonstrates promising OS and antiangiogenic treatment-related toxicities in the phase II setting of metastatic UC. The full risk/benefit profile of CGB in patients with metastatic UC will be determined by an ongoing phase III intergroup trial.

Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemonaïve patients with stage IIIB/IV non-small cell lung cancer: Hoosier Oncology Group LUN06-116.

INTRODUCTION: : Bevacizumab is approved in combination with chemotherapy as first-line treatment for non-small cell lung cancer (NSCLC). Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis. METHODS: : ELIGIBILITY CRITERIA: ≥18 years of age, chemonaïve, stage IIIB/IV nonsquamous NSCLC, and Eastern Cooperative Oncology Group performance status 0 to 1. Patients were randomized to placebo or enzastaurin 500 mg orally daily (after a loading dose), plus pemetrexed 500 mg/m, carboplatin area under the curve 6, and bevacizumab 15 mg/kg, intravenously, every 21 days for four cycles. Patients without progression received maintenance therapy with bevacizumab and placebo or enzastaurin. The primary objective was progression-free survival (PFS). Planned sample size was 90 patients, one-sided alpha of 0.20, with two interim analyses: one for safety and the second for futility, with a PFS hazard ratio of 0.8857. RESULTS: : Forty patients were randomized. No unique safety concerns were noted at the first interim analysis. The early stopping rule for futility was met at the second interim analysis. Median PFS was 3.5 months and 4.3 months (hazard ratio: 1.04, 95% confidence interval: 0.49-2.21), and response rates were 20% and 30% (p = 0.462) for enzastaurin and placebo, respectively. Grade 3 or 4 toxicity was similar between the two arms. Two patients died on study because of respiratory arrest and pulmonary embolism. An additional patient died of sepsis secondary to a gastrointestinal perforation >30 days after study treatment discontinuation. CONCLUSIONS: : Enzastaurin does not improve efficacy when combined with pemetrexed, carboplatin, and bevacizumab. This combination does not warrant further study in NSCLC.

Fludarabine followed by alemtuzumab consolidation for previously untreated chronic lymphocytic leukemia: final report of Cancer and Leukemia Group B study 19901.

The humanized anti-CD52 monoclonal antibody alemtuzumab is an effective therapy for chronic lymphocytic leukemia (CLL). We examined the impact of alemtuzumab treatment after initial fludarabine treatment for feasibility and safety. Patients (N = 85) with previously untreated symptomatic CLL received fludarabine (25 mg/m(2)/day) for 5 days every 4 weeks for four cycles followed by 2 months of observation. Patients with stable disease or better response then received alemtuzumab 30 mg three times weekly for 6 weeks either intravenously (IV; cohort 1; N = 39) or subcutaneously (SC; cohort 2; N = 20). Of the 85 evaluable patients enrolled on our study, four (5%) attained a complete response (CR) and 43 (51%) attained a partial response after fludarabine induction for an overall response rate (ORR) of 55%. Thirty-nine patients received IV alemtuzumab for consolidation with improvement in CR to 27% and ORR to 73%. Twenty patients received SC alemtuzumab consolidation with improvement in CR to 17% and ORR to 69%. Toxicity from IV alemtuzumab included infusion-related reactions and infection. Mild local inflammation was common from SC alemtuzumab but there were virtually no systemic side effects. Nine of 59 (15%) patients had cytomegalovirus (CMV) infections; one patient died. The administration of alemtuzumab as consolidation therapy following an abbreviated fludarabine induction is feasible but requires close monitoring for CMV infection and other infectious events.

Pemetrexed plus cetuximab in patients with recurrent non-small cell lung cancer (NSCLC): a phase I/II study from the Hoosier Oncology Group.

PURPOSE: Pemetrexed is a standard treatment against recurrent non-small cell lung cancer (NSCLC), and cetuximab has single-agent activity against NSCLC. This study evaluates the safety and efficacy of the combination of these agents in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with recurrent NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1 were entered. Patients on the phase I portion of the study received cetuximab 400 mg/m2 intravenously (IV) on day -7 followed by weekly doses of cetuximab at 250 mg/m2 IV with escalating doses of pemetrexed every 3 weeks (dose levels: 500, 600, 750, 900 mg/m2) in a standard 3 + 3 design. Once the maximum tolerated dose (MTD) of the combination was determined, patients were enrolled on the phase II portion. The primary end point was to determine the median time to disease progression (TTP) (null hypothesis 12 weeks, alternative hypothesis 24 weeks). RESULTS: Thirty-six patients were enrolled (phase I: n = 13, phase II: n = 23). Patient characteristics included 60.6% men, median age 64 years (range, 37-80 years), 57.6% had performance status 0 and 54.6% had adenocarcinoma histology. The median number of previous regimens was 2 (range, 1-6). The maximum tolerated dose of pemetrexed in combination with cetuximab was determined to be 750 mg/m2. The median TTP was 14.6 weeks. The median survival time was 42 weeks and 1-year survival was 38.5%. CONCLUSION: The combination of pemetrexed at 750 mg/m2 every 21 days with weekly cetuximab at 250 mg/m2 was feasible; however, in this unselected patient population, the combination regimen does not seem to improve TTP compared with historical controls of either single agent.

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. METHODS: Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. FINDINGS: In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. INTERPRETATION: The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Treatment of myelodysplastic syndrome with 2 schedules and doses of oral topotecan: a randomized phase 2 trial by the Cancer and Leukemia Group B (CALGB 19803).

BACKGROUND: The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS). METHODS: Patients with previously untreated primary or therapy-related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if they were dependent on erythrocyte transfusion, had a platelet count<50,000/microL, or had an absolute neutrophil count<1000/microL with a recent infection that required antibiotics. Patients were randomized to receive oral topotecan either at a dose of 1.2 mg/m2 twice daily for 5 days (Arm A) or once daily for 10 days (Arm B) repeated every 21 days for at least 2 cycles. Responding patients continued until they developed disease progression or unacceptable toxicity or until they had received 2 cycles beyond a complete response. RESULTS: Ninety patients received treatment, including 46 patients on Arm A and 44 patients on Arm B. Partial responses with improvement in all 3 cell lines occurred in 6 patients (7%), and hematologic improvement (in 1 or 2 cell lines) was observed in 21 patients (23%), for an overall response rate of 30%. Response duration was longer on Arm A (23 months vs 14 months; P=.02). Seven of 14 patients with chronic myelomonocytic leukemia responded. There were 8 treatment-related deaths from infection (6 deaths) and bleeding (2 deaths). Diarrhea was the most frequent nonhematologic toxicity (grade 3, 11%; grade 4, 2%; grading determined according to the National Cancer Institute Comman Toxicity Criteria v.2.0). CONCLUSIONS: Oral topotecan in the dose and schedules evaluated in this trial demonstrated only a modest response rate with a troublesome toxicity profile in the treatment of MDS.

Arsenic trioxide in patients with adenocarcinoma of the pancreas refractory to gemcitabine: a phase II trial of the University of Chicago Phase II Consortium.

OBJECTIVES: There is no effective therapy for patients with metastatic pancreatic cancer who fail initial therapy with gemcitabine. Arsenic trioxide has potent antiproliferative and proapoptotic effects in pancreatic cancer cell lines. We conducted a multicenter phase II trial in patients with advanced pancreatic cancer who experienced disease progression on or after a gemcitabine-containing regimen. METHODS: Arsenic trioxide 0.3 mg/kg was administered intravenously over 1 hour daily for 5 consecutive days every 28 days. Restaging computed tomography scans were obtained every 2 cycles. RESULTS: Thirteen patients were enrolled between December 2002 and November 2003. Twenty-four cycles were administered (median 2; range 1-2). There were no grade 3/4 hematologic toxicities; grade 1/2 anemia and leukopenia occurred in 50% and 25% of patients, respectively. Grade 3 toxicities included fatigue and thrombosis in 17% of patients. Only 1 patient developed a prolongation of the QTc interval. There were no objective responses. Median progression-free survival was 1.6 months (95% confidence interval, 1.2-1.9). Median survival was 3.8 months (95% confidence interval, 1.6-6.8). CONCLUSIONS: Despite promising in vitro data, arsenic trioxide has no activity in pancreatic cancer patients who develop progressive disease after gemcitabine. Multicenter phase II trials are feasible in this patient population, and novel agents are clearly needed.

Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology.

PURPOSE: Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non-small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. PATIENTS AND METHODS: Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second >or= 1 L, and less than 5% weight loss. Patients received P 50 mg/m(2) intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m(2) IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m(2) IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). RESULTS: On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). CONCLUSION: Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

Treatment of elderly non-small cell lung cancer patients with three different schedules of weekly paclitaxel in combination with carboplatin: subanalysis of a randomized trial.

BACKGROUND: Administration of paclitaxel on a weekly schedule in combination with carboplatin is associated with a lower incidence of neuropathy and myelosuppression. The authors conducted subgroup analysis of their randomized phase II study of three different schedules of weekly paclitaxel with carboplatin to determine the efficacy of each regimen in elderly patients (aged > or = 70 years) with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC were randomized to one of three different weekly paclitaxel/carboplatin regimens. After four cycles of chemotherapy, those with objective response or stable disease were randomized to weekly paclitaxel or observation as maintenance therapy. Four hundred three patients were enrolled in the study, of whom 111 (28%) were aged 70 years or older. RESULTS: The treatment regimen of weekly paclitaxel (100 mg/m for 3 of 4 weeks) and carboplatin (area under the curve = 6 mg/ml/min once every 4 weeks) (arm 1) was associated with the best therapeutic index overall. The median survival and 1-year survival rates were 11.3 months and 50% for patients in the > or =70 years cohort versus 11.2 months and 46% for the <70 years cohort in arm 1. Efficacy results were comparable between the two groups in the other arms as well. Grade 4 neutropenia and febrile neutropenia occurred in 13.6% and 2.3% in the > or =70 years cohort compared with 4.5% and 1.1% in the <70 years cohort in arm 1. CONCLUSION: The weekly regimen of paclitaxel administered in combination with carboplatin is tolerated well by elderly NSCLC patients and has comparable efficacy with younger patients.

Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab. PATIENTS AND METHODS: Patients with previously untreated advanced pancreatic cancer received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Bevacizumab, 10 mg/kg, was administered after gemcitabine on days 1 and 15. Tumor measurements were assessed every two cycles. Plasma VEGF levels were obtained pretreatment. RESULTS: Fifty-two patients were enrolled at seven centers between November 2001 and March 2004. All patients had metastatic disease, and 83% had liver metastases. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19% of the patients, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%. CONCLUSION: The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.

Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation.

PURPOSE: To explore the efficacy and safety of three regimens of weekly paclitaxel plus carboplatin as initial therapy and the feasibility of subsequent maintenance therapy versus observation in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Four hundred one patients were randomly assigned to one of the following arms: arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (area under the curve [AUC] = 6) on day 1; arm 2, paclitaxel 100 mg/m2 and carboplatin (AUC = 2) weekly for 3 of 4 weeks; or arm 3, paclitaxel 150 mg/m2 cycle 1 and 100 mg/m2 cycle 2 and carboplatin (AUC = 2) weekly for 6 of 8 weeks. Patients who responded (n = 130) at week 16 were randomly assigned to either weekly paclitaxel therapy (70 mg/m2, 3 of 4 weeks; n = 65) or observation (n = 65). RESULTS: For the 390 assessable patients, the objective response rates observed with initial therapy were 32% for arm 1, 24% for arm 2, and 18% for arm 3. The median time to progression and median survival times were 30 and 49 weeks for arm 1, 21 and 31 weeks for arm 2, and 27 and 40 weeks for arm 3, respectively. The 1-year survival rates were 47% for arm 1, 31% for arm 2, and 41% for arm 3. CONCLUSION: Arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (AUC = 6) administered on day 1, demonstrates the most favorable therapeutic index in patients with advanced NSCLC.