Enhanced efficacy of gemcitabine in combination with anti-CD20 monoclonal antibody against CD20+ non-Hodgkin's lymphoma cell lines in vitro and in scid mice

BACKGROUND: Despite exciting new targeted therapeutics against non-Hodgkin's lymphoma (NHL), chemotherapy remains a cornerstone of therapy. While purine nucleoside analogs have significant activity in low grade NHL, the pyrimidine nucleoside analog gemcitabine has been less extensively studied, but has important activity. Use of the anti-CD20 monoclonal antibody rituximab in combination with chemotherapy for B-NHL is becoming prevalent in clinical practice, but has not been extensively studied in pre-clinical models. METHODS: We have tested the activity of gemcitabine ± rituximab in vitro and in scid/human NHL xenograft models. We used two t(14;18)+, CD20+ follicular B cell NHL cell lines, DoHH2 a transformed NHL line and WSU-FSCCL isolated from pleural fluid of a patient with indolent NHL. RESULTS: Gemcitabine is cytotoxic to DoHH2 and WSU-FSCCL cells in vitro, and the IC(50 )is 2–3 fold lower in the presence of rituximab. Apoptosis is also enhanced in the presence of rituximab. Clearance of NHL cells from ascites in scid mice is prolonged by the combination, as compared with either agent alone. Most importantly, survival of scid mice bearing human NHL cells is significantly prolonged by the combination of gemcitabine + rituximab. CONCLUSION: Based on our pre-clinical data showing prolonged survival of mice bearing human lymphoma cell line xenografts after treatment with gemcitabine + anti-CD20 antibody, this combination, expected to have non-overlapping toxicity profiles, should be explored in clinical trials

Phase 2 Study of Pemetrexed Plus Carboplatin, or Pemetrexed Plus Cisplatin with Concurrent Radiation Therapy Followed by Pemetrexed Consolidation in Patients with Favorable-Prognosis Inoperable Stage IIIA/B Non–Small-Cell Lung Cancer

IntroductionThere is no consensus chemotherapy regimen with concurrent radiotherapy (RT) for inoperable stage IIIA/B non–small-cell lung cancer. This trial evaluated pemetrexed with carboplatin (PCb) or cisplatin (PC) with concurrent RT followed by consolidation pemetrexed.MethodsIn this open-label, noncomparative phase II trial, patients with inoperable stage IIIA/B non–small-cell lung cancer (initially all histologies, later restricted to nonsquamous) were randomized (1:1) to PCb or PC with concurrent RT (64–68 Gy over days 1–45). Consolidation pemetrexed monotherapy was administered every 21 days for three cycles. Primary endpoint was 2-year overall survival (OS) rate.ResultsFrom June 2007 to November 2009, 98 patients were enrolled (PCb: 46; PC: 52). The 2-year OS rate was PCb: 45.4% (95% confidence interval [CI], 29.5–60.0%); PC: 58.4% (95% CI, 42.6–71.3%), and in nonsquamous patients was PCb: 48.0% (95% CI, 29.0–64.8%); PC: 55.8% (95% CI, 38.0–70.3%). Median time to disease progression was PCb: 8.8 months (95% CI, 6.0–12.6 months); PC: 13.1 months (95% CI, 8.3–not evaluable [NE]). Median OS (months) was PCb: 18.7 (95% CI, 12.9–NE); PC: 27.0 (95% CI, 23.2–NE). The objective response rates (ORRs) were PCb: 52.2%; PC: 46.2%. Grade 4 treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. Most patients completed scheduled chemotherapy and RT during induction and consolidation phases. No drug-related deaths were reported during chemoradiotherapy.ConclusionsBecause of study design, efficacy comparisons cannot be made. However, both combinations with concurrent RT were active and well tolerated

Clinical Efficacy and Predictive Molecular Markers of Neoadjuvant Gemcitabine and Pemetrexed in Resectable Non-small Cell Lung Cancer

BackgroundA trial of neoadjuvant gemcitabine and pemetrexed (GP) chemotherapy in patients with resectable non-small cell lung cancer was conducted. The goal was to achieve a disease response rate of 50% and to determine if the expression levels of genes associated with GP metabolism are predictive of response.MethodsPatients had staging with a computed tomography scan, whole body F-18 fluorodeoxyglucose positron emission tomography, and mediastinoscopy. Four biweekly cycles of GP were given. Patients were restaged, and those with resectable stage IB-III disease had thoracotomy. Fresh frozen tumor specimens were collected before and after chemotherapy and the mRNA levels of 14 target genes determined by real-time reverse transcription polymerase chain reaction.ResultsFifty-two patients started therapy. The radiographic disease response rate was 35% (95% confidence interval 21.7-49.6%), and the progression rate was 6%. Forty-six patients had a thoracotomy. The complete tumor resection rate was 77% (40/52). There were no perioperative deaths or deaths related to chemotherapy. Tumor response to chemotherapy was inversely correlated with the level of expression of RRM1 (p < 0.001; regulatory subunit of ribonucleotide reductase) and TS (p = 0.006; thymidylate synthase); i.e., the reduction in tumor size was greater in those with low levels of expression.ConclusionsNeoadjuvant GP is well tolerated and produces an objective response rate of 35%. Tumoral RRM1 and TS mRNA levels are predictive of disease response and should be considered as parameters for treatment selection in future trials with this regimen

Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: A randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen

BACKGROUND: Cetuximab, in combination with platinum chemotherapy plus 5-fluoruracil (5-FU), is approved for the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab manufactured by ImClone (US commercial cetuximab) potentially results in higher systemic exposures than cetuximab manufactured by Boehringer Ingelheim (BI-manufactured cetuximab). This prospective, randomized, double-blind study compared the safety profiles of the two cetuximab formulations. METHODS: Patients with previously untreated locoregionally recurrent and/or metastatic SCCHN were randomly assigned to receive the same dose of US commercial cetuximab (Arm A) or BI-manufactured cetuximab (Arm B), each in combination with cisplatin or carboplatin plus 5-FU. The primary outcome was all-grade, all-cause treatment-emergent adverse events (TEAEs). RESULTS: The majority of patients experienced ≥1 TEAE, regardless of causality (Arm A: 75/77 patients, 97.4 %; Arm B: 68/71 patients, 95.8 %). TEAEs with the highest incidence included nausea, fatigue, and hypomagnesemia in both arms. The absolute risk difference between the two arms for patients experiencing at least one adverse event (AE) was 0.029 (p = 0.281, 95 % confidence interval [CI]: -0.024, 0.082) for AEs regardless of causality and 0.005 (p = 0.915, 95 % CI: -0.092, 0.103) for AEs possibly related to study drug. There were no significant differences between the two arms in the incidence of acneiform rash, cardiac events, infusion reactions, or hypomagnesemia. Overall survival, progression-free survival, and overall response rates were similar in the two arms. CONCLUSIONS: There were no clinically meaningful differences in safety between US commercial cetuximab and BI-manufactured cetuximab in combination with platinum-based therapy with 5-FU in patients with locoregionally recurrent and/or metastatic SCCHN. The use of US commercial cetuximab in this combination chemotherapy regimen did not result in any unexpected safety signals. The efficacy results of this study are consistent with the efficacy results of the cetuximab arm of the EXTREME study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01081041; date of registration: March 3, 2010)

Outcomes Associated with Brain Metastases in a Three-Arm Phase III Trial of Gemcitabine-Containing Regimens Versus Paclitaxel Plus Carboplatin for Advanced Non-small Cell Lung Cancer

BACKGROUND: Brain metastases (BMs) are a common complication of non-small cell lung cancer (NSCLC). Because of historical data indicating a poor prognosis for patients with BM, few randomized phase III studies of advanced NSCLC have included patients with BM at presentation. Because the potential benefits of systemic therapy in patients with BM are uncertain, we analyzed data from a recent phase III study. METHODS: One thousand one hundred thirty-five chemonaïve patients with stage IIIB/IV NSCLC were randomized to receive gemcitabine/carboplatin, gemcitabine/paclitaxel, or paclitaxel/carboplatin. Stratification was based on presence or absence of BM, stage, and baseline weight loss. Patients with BM were required to be clinically stable after treatment with radiotherapy or surgery before entry. Results were retrospectively analyzed by presence or absence of BM at study entry. RESULTS: Rate of BM was 17.1% overall. The response rate was 28.9% for patients with BM (n = 194) versus 29.1% without BM (n = 941). Time to progression was 4.3 months with BM and 4.6 months without BM (p = 0.03). Median survival was 7.7 months (95% confidence interval: 6.7-9.3) among patients with BM (n = 194) and 8.6 months (95% confidence interval: 7.9-9.5) for patients without BM (n = 941), p = 0.09. Rates of hematologic adverse events were not different among patients with and without BM. CONCLUSIONS: There were no significant differences in response, survival, or hematologic toxicity for patients with or without BM; however, patients with BM had a small but significantly shorter time to progression. Nonprogressing patients with treated BM are appropriate candidates for systemic therapy and entry into clinical trials

Neoadjuvant Chemotherapy with Gemcitabine-Containing Regimens in Patients with Early-Stage Non-small Cell Lung Cancer

BACKGROUND: Surgical resection alone remains suboptimal for patients with early-stage (I or II) non-small cell lung cancer. Two similar randomized phase II trials were conducted to define an active preoperative regimen in this disease state. METHODS: In the first study, patients were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1 (GC) or gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1 (GCb). In the second trial, patients received the same regimen of GCb or gemcitabine 1000 mg/m2 on days 1 and 8 plus paclitaxel 200 mg/m2 on day 1 (GP). Cycles were repeated every 21 days for three cycles. The primary end point was pathologic complete response (pCR) rate. RESULTS: Eighty-seven eligible patients were randomized (GC n = 12, GP n = 35, and GCb n = 40), and 71 (82%) underwent surgery after chemotherapy. The confirmed pCR rate was 2.3% (2 of 87, 95% confidence interval 0.3-8.1). Clinical response rate was 28.7%, complete resection rate was 91.5% (65 of 71 patients), and perioperative mortality rate was 2.8%. As of October 2006, median survival for all patients was 45 months (65.5% censored), with 87.2% alive at 1 year and 69.8% alive at 2 years. DISCUSSION: Neoadjuvant chemotherapy with gemcitabine was feasible and well tolerated, and outcomes were similar to other reports of this treatment strategy. However, no regimen achieved the predefined pCR rate that would be sufficient to warrant further evaluation in the phase III setting. This trial design provides an efficient way of providing a rationale for choosing or rejecting regimens of potential value

Pemetrexed in Relapsed Small-Cell Lung Cancer and the Impact of Shortened Vitamin Supplementation Lead-In Time: Results of a Phase II Trial

INTRODUCTION: We undertook a phase II trial to assess the efficacy and safety of single-agent pemetrexed (P) in relapsed small-cell lung cancer (SCLC) patients. METHODS: Patients had limited- or extensive-stage SCLC, performance status 0 to 2, and one prior chemotherapy regimen. Initial P dose was 500 mg/m every 21 days. Planned sample sizes were 36 sensitive (S) patients in a two-stage sequential fashion with early stopping rule, and 25 refractory (R) patients in a single-stage design without stopping rule. Patients received folic acid and Vitamin B12 prior to P, and B12 could be given up until P treatment. Primary outcome measure was response rate. RESULTS: Enrollment occurred from July 2004 to March 2006. The stopping rule was invoked when <3 of 14 S patients responded. The protocol was amended to evaluate P 900 mg/m in cohorts of 40 S and 40 R patients. Overall, 121 patients were enrolled, with 116 patients treated. S (n = 53) and R (n = 63) patients were analyzed separately at both dose levels. Across the 4 treatment groups (S500, S900, R500, R900), 1 patient (2.63%) in the S900 group had a partial response. Overall, 18 patients (16%) had stable disease. Eighty-seven patients (75%) had progressive disease. Responses were not evaluable in 10 patients (8.6%). Overall response rate was 0.9%. Across treatment groups, disease control rates (partial response + stable disease) were 20%, 15.8%, 21.7%, and 12.5%, respectively. Median time to progression ranged from 1.2 to 1.5 months, median survival times ranged from 2.5 to 6.1 months, and 1-year survival rates ranged from 5.6 to 25.8%. Common grade 3/4 hematologic toxicities (at 500 and 900 mg/m) were neutropenia (16%; 9%) and leukopenia (11%; 8%), and nonhematologic toxicities were dyspnea (11%; 10%) and fatigue (16%; 9%). Retrospective analysis of cycle 1 events by timing of B12 administration showed no trend toward more frequent serious toxicities when B12 was given <7 days prior to P. CONCLUSIONS: Single-agent P 500 mg/m shows minimal activity in relapsed SCLC patients. P can be given at 900 mg/m without significant increase in serious toxicities, but does not seem to increase efficacy. B12 given <7 days before P does not seem to be associated with increased serious toxicities

Phase 1/2 Dose Escalating Study of Twice-Monthly Pemetrexed and Gemcitabine in Patients with Advanced Cancer and Non-small Cell Lung Cancer

IntroductionPemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study.MethodsThe phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis.ResultsMaximum tolerated dose was gemcitabine 1500 mg/m2, followed by pemetrexed 500 mg/m2. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108–0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79–6.18), median survival was 10.1 month (95% CI: 5.95–14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%).ConclusionsTwice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients

A Comparison of White and African American Outcomes from a Three-Arm, Randomized, Phase III Multicenter Trial of Advanced or Metastatic Non-small Cell Lung Cancer

PURPOSE: To investigate the effect of race on the efficacy and safety of standard chemotherapy doublet regimens in African American patients, we conducted a subgroup analysis of a phase III randomized trial. PATIENTS AND METHODS: Chemonaïve patients with a performance status of 0 or 1 and stage IIIB or IV non-small cell lung cancer were randomized to arm A: gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1; arm B: the same schedule of gemcitabine plus paclitaxel 200 mg/m2 on day 1; or arm C: paclitaxel 225 mg/m2 on day 1 plus carboplatin area under the curve 6.0 on day 1. Cycles were repeated every 21 days up to 6. A site selection tool identified institutions with potential to recruit a minority population. Outcome and toxicity data of white and African American patients were compared. RESULTS: Of 1135 total patients, 972 were white (85.6%) and 138 were African American (12.2%). Median survival was 8.3 months for white patients (95% confidence interval [CI]: 7.7-9.3) and 9.1 months for African American patients (95% CI: 8.2-11.1). Response rates were 29.1 and 29.0%, respectively. Rates of grade 3 or 4 toxicities were comparable. Among African Americans, median survival was 7.2 months (95% CI: 5.1-10.1) for gemcitabine-carboplatin (n = 47), 10.5 months (95% CI: 7.1-15.4) for gemcitabine-paclitaxel (n = 42), and 10.2 months (95% CI: 8.5-13.2) for paclitaxel-carboplatin (n = 49). CONCLUSION: Whites and African Americans had similar outcomes, although there was some variability in survival among African Americans across the three treatment groups

US Cancer Centers of Excellence Strategies for Increased Inclusion of Racial and Ethnic Minorities in Clinical Trials

PURPOSE:: Participation of racial and ethnic minority groups (REMGs) in cancer trials is disproportionately low despite a high prevalence of certain cancers in REMG populations. We aimed to identify notable practices used by leading US cancer centers that facilitate REMG participation in cancer trials. METHODS:: The National Minority Quality Forum and Sustainable Healthy Communities Diverse Cancer Communities Working Group developed criteria by which to identify eligible US cancer centers-REMGs comprise 10% or more of the catchment area; a 10% to 50% yearly accrual rate of REMGs in cancer trials; and the presence of formal community outreach and diversity enrollment programs. Cancer center leaders were interviewed to ascertain notable practices that facilitate REMG accrual in clinical trials. RESULTS:: Eight cancer centers that met the Communities Working Group criteria were invited to participate in in-depth interviews. Notable strategies for increased REMG accrual to cancer trials were reported across five broad themes: commitment and center leadership, investigator training and mentoring, community engagement, patient engagement, and operational practices. Specific notable practices included increased engagement of health care professionals, the presence of formal processes for obtaining REMG patient/caregiver input on research projects, and engagement of community groups to drive REMG participation. Centers also reported an increase in the allocation of resources to improving health disparities and increased dedication of research staff to REMG engagement. CONCLUSION:: We have identified notable practices that facilitate increased participation of REMGs in cancer trials. Wide implementation of such strategies across cancer centers is essential to ensure that all populations benefit from advances in an era of increasingly personalized treatment of cancer