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Keywords:

  • anaplastic glioma;
  • irinotecan;
  • thalidomide;
  • progression-free survival

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES

BACKGROUND:

Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination.

METHODS:

Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme-inducing anticonvulsants were enrolled. Treatment was in 6-week cycles with irinotecan at 125 mg/m2 weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression-free survival rate at 6 months (PFS-6), and the secondary endpoints were overall survival (OS) and response rate (RR).

RESULTS:

In 39 eligible patients, PFS-6 for the intent-to-treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment-related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment-related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis.

CONCLUSIONS:

The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing. Cancer 2012;3599–3606. © 2011 American Cancer Society.

Malignant gliomas are aggressive primary brain tumors with a high morbidity and mortality. Although new standards of care have emerged for patients with newly diagnosed1 and recurrent glioblastoma,2 treatment options for patients with anaplastic gliomas (AGs) remain limited. Meta-analyses of clinical trials using conventional cytotoxic chemotherapy for patients with newly diagnosed malignant gliomas have indicated only a modest benefit from the addition of chemotherapy.3 The median survival for patients with AGs was reported to be 33.5 months in a recent large series.4 Ongoing trials are examining the utility of chemotherapy in patients with newly diagnosed AGs in the context of specific molecular markers such as 1p/19q deletion. However, for recurrent AGs, there have been few advances in treatment options. Combination strategies appear to have the highest likelihood of improving outcome in this patient population, given the potential for targeting several aspects of tumor biology.

Angiogenesis inhibition constitutes a valid approach against malignant gliomas, which are highly vascular tumors,5 but is considered to be mainly a cytostatic strategy. Hence, studies have examined the effect of the addition of DNA-damaging agents to provide a cytotoxic signal to enhance the antitumor effect of antiangiogenic agents. Before the introduction of studies with bevacizumab, thalidomide was frequently used as an antiglioma agent for its antiangiogenic and immunomodulatory effects6, 7; however, this agent lacked single-agent activity against malignant gliomas. Irinotecan, a topoisomerase II inhibitor, has been used both as a single agent and in combination against malignant gliomas8-10; however, because it lacked consistently demonstrable single-agent activity, it has been considered as a reasonable cytotoxic backbone for combination therapies against this tumor type.11, 12

To test the hypothesis that the combination antiangiogenic activity of thalidomide and the cytotoxic effect of irinotecan would improve outcome in patients with recurrent malignant glioma, we conducted an open-label phase 2 study of this combination with 2 separate arms involving World Health Organization (WHO) grade IV and grade III gliomas. The results of the arm with patients who had recurrent glioblastoma were previously reported and showed an improvement in the progression-free survival rate at 6 months (PFS-6) compared with historical controls.13 Here, we report the efficacy and toxicity of this combination in the anaplastic glioma arm of the phase 2 study.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES

Eligibility

Adult patients (≥18 years) with a Karnofsky performance status (KPS) score ≥ 70 and histologically proven WHO grade III glioma (anaplastic astrocytoma [AA], anaplastic oligodendroglioma [AO], or mixed anaplastic glioma [AOA]) were enrolled in the study. Patients were required to have disease progression documented by a magnetic resonance imaging (MRI) scan obtained within 14 days of study enrollment. All patients were required to have received prior radiation therapy; treatment for up to 2 prior progressions was allowed. Patients undergoing recent resection for recurrent tumor (including gross total resection) were eligible; given that the primary endpoint was PFS-6, neither measurable or evaluable tumor on neuroimaging was required for study entry. Recovery from surgery and any prior medical therapy for the tumor was required prior to enrollment. Supportive therapy was allowed at the discretion of the treating physician. Treatment with enzyme-inducing antiepileptic agents was not allowed, given the potential for interaction with irinotecan. However, patients whose anticonvulsant was changed to a non–enzyme-inducing antiepileptic drug were eligible for entry after a 1-week “washout” period.14 Adequate bone marrow function as well as normal liver and kidney function, as documented by serum laboratory values, were required.

Patients were required to provide informed consent and to comply with the System for Thalidomide Education and Prescribing Safety Program (S.T.E.P.S.) developed by Celgene Corporation (Summit, NJ) to ensure pregnancy testing, birth control, and education about thalidomide teratogenicity. Exclusion criteria included diagnosis of other cancers (unless in complete remission and off therapy for at least 3 years) except for nonmelanoma skin cancer and in situ carcinoma of the cervix. In addition, pregnant and lactating patients, patients with serious medical conditions, patients with high-grade peripheral neuropathy (grade 2 or higher), and patients previously treated with irinotecan were excluded (prior treatment with thalidomide was permitted). All patients provided informed consent prior to entry into this protocol, which was approved by the Institutional Review Board of the University of Texas MD Anderson Cancer Center.

Treatment Plan

A treatment cycle was defined as 6 consecutive weeks of treatment. Thalidomide was administered daily throughout the cycle starting at 100 mg/day for the first week and was escalated weekly by 100 mg to a target dose of 400 mg/day provided it was tolerated well. Irinotecan was administered at a dose of 125 mg/m2 by intravenous infusion over 90 minutes weekly for 4 weeks followed by a 2-week rest period. Given the known thromboembolic risk of thalidomide therapy, patients who were not already on anticoagulants received low-dose warfarin therapy (1 mg daily) as prophylaxis against thromboembolism. Dose modification in subsequent cycles was dependent on toxicity which was graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (NCI-CTC); any toxicity graded ≥3 by these criteria required a treatment hold for at least 2 weeks. Therapy was then restarted at a lower dose once the toxicity resolved (reduction by 100 mg for thalidomide to a minimum of 100 mg and 25 mg/m2 less per dose for irinotecan to a minimum of 75 mg/m2). The agent selected for dose reduction was dependent on the type of toxicity observed.

Study-Related Evaluations

A history and physical examination was performed at baseline and prior to every cycle. A complete blood count with differential and platelet counts was performed at baseline and repeated every 2 weeks. Serum chemistry was obtained at baseline and repeated before each treatment cycle. A brain MRI documenting tumor progression and a dynamic contrast-enhanced MRI scan were obtained at baseline and after each cycle of therapy. A quantitative sensory test was performed at baseline on all patients and after every 2 cycles for detection of early signs of peripheral neuropathy. Women of reproductive age were required to have a pregnancy test before each treatment cycle. Prophylactic use of colony-stimulating factor was not permitted.

Response Criteria

The primary endpoint of the study was PFS-6, defined as the time interval between the date of registration and the date of progression, irreversible neurological deterioration, or death while on study. On the basis of criteria proposed by MacDonald et al,15 bidimensional measurement of the enhancing lesion was used to define radiological response; a partial response (PR) was defined as >50% decrease of the baseline sum of measurable contrast-enhancing lesion with no new lesions present, whereas a complete response (CR) required complete resolution of all contrast-enhancing lesions and absence of any new lesions. Stable disease (SD) was defined as no change on the MRI scan. Disease progression was defined as >25% increase in the sum of all measurable lesions, clear worsening of evaluable disease, or new lesions. However, if neuroimaging data could not be obtained, progression was defined by confirmed reports of death or neurologic deterioration. Data from patients in whom this information could not be obtained were censored at the date of last follow-up.

Evaluation of Toxicity

Definition and grading of toxicity was according to the NCI-CTC version 3. Toxicity was assessed on an ongoing basis throughout the trial. When the trial accrued 50% of the total planned number of patients, an interim analysis for toxicity was performed. Because no unexpected or excessive toxicity was seen, the trial continued to full accrual.

Statistical Design

This open-label phase 2 study used a single-stage design, and the results were compared with historical data obtained from a database of 150 patients with recurrent anaplastic gliomas.16 The hypothesis tested was H0: P < P0 versus H1: P > P1, where P was the probability of remaining alive and progression-free at 6 months, assuming an alpha (false positive rate) ≤ 10%, and beta (false negative rate) ≤ 10%. The proportion of patients who remained alive and progression-free at 6 months in the historical population was 31%. Based on this, P0 was set to 30% to discard a treatment that may be significantly worse than the aggregate value from the control population, and P 1 was set to 50% (for an absolute improvement of 0.2 and a relative improvement of 1.7). These parameters led to a 1-stage design with a total of 39 patients (declaring success if more than 15 patients had PFS ≥ 6 months) with a false positive rate of 11% and false negative rate of 9%. To accomplish the secondary objectives, the distribution of time to progression or death (PFS) and time to death were calculated with the Kaplan-Meier method. The proportion of patients in each of the response categories (CR, PR, SD) as well as the response rate (CR and PR) was also computed.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES

Patient Characteristics

Between November 2003 and October 2008, 42 patients with AG were registered in this trial of whom 39 were included in the final analysis, given that 3 had ineligible histologies. Of these, 23 patients had AA and 13 had AO, whereas the remaining 3 had other histologies. The patients ranged in age from 20 to 73 years (median, 43 years) and had KPS ranging from 70-100 (median, 90). The patient characteristics are indicated in Table 1.

Table 1. Patient Characteristics
CharacteristicValue
  1. Abbreviation: KPS, Karnofsky performance status.

Age, median (range), y43 (20-73)
KPS score, median (range)90 (70-100)
SexNo. of patients (%)
 Men24 (62)
 Women15 (38)
KPS 
 10011 (28)
 9011 (28)
 8011 (28)
 706 (16)
Histology 
 Anaplastic astrocytoma23 (59)
 Anaplastic oligodendroglioma13 (34)
 Anaplastic ependymoma1 (2)
 Mixed glioma, anaplastic2 (6)

Treatment Efficacy

Of the 39 eligible patients, 33 had disease progression at the time of analysis with a Kaplan-Meier median PFS of 13 weeks (95% confidence interval [CI]: 6%, 28%) (Fig. 1A). The PFS-6 for the intent-to-treat population was 36% at 6 months (26 weeks) (95% CI: 21%, 53%). Fourteen patients were alive and progression-free at 6 months from the time of registration to the study. Twenty-six patients had died at the time of analysis. Kaplan-Meier median overall survival (OS) was 72 weeks (95% CI: 51 weeks, 144 weeks). OS was 74% at 6 months and 62% at 1 year (Fig. 1B). Clinical outcome for the whole cohort is summarized for PFS and OS (Table 2). There were 23 patients with AA, 13 with AO, and 3 with other histologies. Notably, median PFS was 14 weeks for AA and 11 weeks for the others, but the difference was not significant (hazard ratio = 0.8; 95% CI: 0.4, 1.7; P = 0.60). Median OS was 60 weeks among patients with AA and 82 weeks among others (hazard ratio = 1.2; 95% CI: 0.5, 2.6; P = 0.71) (Table 3). Best response was CR seen in 2 of 39 patients (5.12%), PR in 2 of 39 patients (5.12%), SD in 18 of 39 patients (46.15%), and progressive disease in 15 of 39 patients (38.46%) (Fig. 2). The response rate (CR+PR) was 4 of 39 patients (10%; 95% CI: 3%, 24%). Characteristics of patients with prolonged PFS are shown in Table 4.

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Figure 1. Kaplan-Meier plots for (A) progression-free survival and (B) overall survival. Dotted lines represent 95% confidence interval.

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Figure 2. Magnetic resonance imaging scans of selected patients with (upper and middle panels) partial responses and (lower panel) complete response.

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Table 2. Progression-Free and Overall Survival for the Entire Cohort
 Median Survival, wk (95% CI)6 mo1 y2 y3 y
PFS13 wk (6, 28)36%20%18%
OS72 wk (51, 144)74%62%32%28%
Table 3. Histology-Specific Clinical Outcome Measures
 AA (N = 23)AO+AOA (N = 16)Hazard Ratio95% Confidence IntervalP
  1. Abbreviations: AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; AOA, mixed anaplastic glioma; OS, overall survival; PFS, progression-free survival.

Median PFS14 wk11 wk0.80.4-1.7.60
Median OS60 wk82 wk1.20.5-2.6.71
Table 4. Characteristics of Patients Who Were Alive and Progression-Free for at Least 6 Months
Patient Age, yProgression- Free Survival, wkOverall Survival, wkSubsequent Treatment (Last Known Status)
  1. Overall survival was measured from date of registration to present trial.

452660Carboplatin+bevacizumab (death)
392761Dose-dense temozolomide; imatinib+hydroxyurea (death)
6230736-Thioguanine, CCNU, capecitabine and chloroquine (death)
253151Isotretinoin (death)
20461806-Thioguanine+temozolomide+capecitabine+celecoxib; bevacizumab+isotretinoin (death)
4351152Dose-dense temozolomide; bevacizumab; CCNU+procarbazine (death)
4568103Temozolomide+isotretinoin; resection (death)
4691179Reirradiation, resection (pending treatment decisions)
41115164Vorinostat+carboplatin+isotretinoin; Dose-dense temozolomide (hospice due to leptomeningeal disease)
46123142Sorafenib+erlotinib; CPT-11+bevacizumab (death)
59227227None (progression-free)
55301301None (progression-free)
48385385None (progression-free)
20410410None (progression-free)

Toxicity and Treatment Tolerance

All patients who received any duration of treatment were assessed for toxicity. The most common toxicities in this study included fatigue, hematological and gastrointestinal events, and serum electrolyte disturbances. Patients who experienced grade 3 or higher hematological toxicities comprised 14 with leukopenia, 20 with neutropenia, 17 with lymphopenia, and 2 with thrombocytopenia (Table 5). Dose reduction was required in 7 patients due to severe neutropenia, 3 with lymphopenia, and 3 with leukopenia. One patient developed neutropenic fever and 1 developed sepsis. Grade 3 or higher nonhematological toxicities comprised fatigue in 18 patients, diarrhea in 9, constipation in 6, nausea and vomiting in 5, hypophosphatemia in 4, and hyponatremia in 3. Six patients had deep vein thrombosis of whom 2 also had pulmonary embolism. Grade 1 and 2 toxicities included nausea, dehydration, dizziness, myelotoxicity, elevated aminotransferase levels, and abnormal electrolyte levels. Four patients died of possible treatment-related causes: 1 had pulmonary embolism, 2 died after experiencing severe diarrhea and dehydration likely related to irinotecan, and 1 died of urosepsis during treatment.

Table 5. Treatment-Related Toxicity (Grade 3 or Higher)
Type of ToxicityNo. of Patients (%)
  1. Abbreviation: DVT, deep vein thrombosis from date of registration into the trial to the date of death or of analysis.

Hematological 
 Leukopenia14 (33.3)
 Neutropenia20 (47.6)
 Lymphopenia17 (40.4)
 Thrombocytopenia2 (5)
Nonhematological 
 Fatigue18 (42.8)
 Diarrhea9 (21.4)
 Constipation6 (14.2)
 Nausea/vomiting5 (11.9)
 Hypophosphatemia4 (9.5)
 Hyponatremia3 (7.1)
Grade 4 toxicity 
 DVT6 (7.2)
 Pulmonary embolism (in patients with DVT)2 of 6

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES

Recent advances in treatment options have redefined the therapeutic approach against glioblastoma however, there has been little progress in the treatment of patients with anaplastic (WHO grade III) gliomas. AGs constitute a heterogeneous population of tumors including AA, AO, and AOA, which have distinct clinical outcomes partly associated with markers such as 1p/19q deletion and O6-methylguanine-DNA methyltransferase promoter methylation, which have prognostic significance at initial diagnosis although their influence on clinical outcome when the tumor recurs is less evident.17 In patients with recurrent AGs (excluding AO) who were either chemotherapy-naive or treated with nitrosourea-based regimens, temozolomide on a 5-day/28-day schedule showed activity, with a PFS-6 of 46% and a median PFS of 5.4 months,18 establishing this as the standard of care. However, for temozolomide-refractory AGs, there is no consensus regarding optimal therapy; such patients are often appropriate candidates for clinical trials.

Angiogenesis inhibition offers a novel approach against treatment-refractory malignant gliomas, which are driven by neoangiogenesis and in combination with conventional chemotherapy has the potential to improve outcome in these patients.5 Although vascular proliferation is not a histologic characteristic of AGs, unlike in glioblastoma, we hypothesized that the requirement of recurrent AGs for neoangiogenesis would justify this approach in patients with these tumors. A similar rationale was used by Short et al, who treated patients with recurrent high-grade glioma with single-agent thalidomide at a daily dose of 100 mg and reported a PR rate of 6% and a median survival of 2.5 months from the start of treatment.6 Similarly, Fine et al also examined the effects of single-agent thalidomide but at a much higher final dose of 1200 mg daily, in patients with recurrent malignant gliomas (WHO grade III and IV) and reported a PR rate of 6% and SD rates of 33%; PFS data was not reported.7 Overall, results of these studies were considered indicative of the limited activity of thalidomide as a single agent against malignant gliomas.

Single-agent therapy with irinotecan also appeared to have only modest efficacy against recurrent AGs. Chamberlain et al reported that irinotecan as a single agent had minimal activity in patients with temozolomide-refractory AGs; patients with recurrent AO with 1p/19q deletion had a PFS-6 of 33%,19 whereas those with recurrent AA had a comparatively better PFS-6 of 40%.8 In addition to demonstrating the minimal efficacy of irinotecan in these patients, the results also suggest that, despite their possible prognostic role in newly diagnosed AGs, markers such as 1p/19q deletion may not predict treatment response in the recurrent setting, although this requires further confirmation given some reports to the contrary in temozolomide-naive recurrent gliomas.20

Combination strategies using thalidomide and cytotoxic agents have been reported in high-grade gliomas, but the limited number of patients with AG included in these studies makes it difficult to assess their efficacy.21 To address this deficiency, our study included separate arms for grade III and IV gliomas. We previously reported the results of the glioblastoma arm in which the combination of irinotecan and thalidomide showed promising activity with improvement of PFS-6 compared with historical controls.13 Here, we examined the activity of the combination in the AG arm of the study in adults with recurrent tumor. In this study, 14 patients were alive and progression-free at 6 months with an overall PFS-6 in the intent-to-treat population of 36%; the study hence did not meet its primary endpoint, because these results were below the protocol-specified limits for declaring success. The median OS of 61 weeks seen in this study is better than historically reported values of 39 to 47 weeks for WHO grade III gliomas; however, the improved survival cannot be reliably attributed to the regimen used given that the majority of our patients were treated with other regimens, including other chemotherapeutic agents or reirradiation.

Various combination chemotherapy regimens have been tested in the recurrent AG patient population. In an approach similar to the one reported in this study, Kesari et al reported a median PFS of 14 weeks, PFS-6 of 26%, and median OS of 41.5 weeks in a subset of patients with recurrent AG treated with a metronomic chemotherapy combination regimen consisting of 2 oral cytotoxic (cyclophosphamide and etoposide) and 2 antiangiogenic (thalidomide and celecoxib) agents.22 In addition, a PFS-6 of 44% and median PFS and OS of 24.5 weeks and 54 weeks, respectively, were reported by Walbert et al in the subset of patients with recurrent AG who were treated with 6-thioguanine, lomustine (or temozolomide), celecoxib, and capecitabine and was considered promising for treatment of AGs.23 The combination of imatinib and hydroxyurea yielded a PFS-6 of 24% in temozolomide-refractory patients with AGs.24 A PFS-6 of 24% and a median survival of 43 weeks were reported in a study using poly-ICLC (carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA), an immune modulator, in patients with AGs, with the authors concluding that the agent was ineffective against this disease.25 In a phase 2 study of irinotecan and carmustine in malignant gliomas, the median time to progression was 16.9 weeks and the median OS was an unexpectedly low 25.7 weeks (likely due to the small patient number and 2 early deaths) for recurrent AA and AO.26 Overall, these combination regimens yielded a PFS-6 of 24% to 44% of patients with recurrent AGs.

Bevacizumab, which is approved for treatment of recurrent glioblastoma, has also been tested in AGs, either as a single agent or in combinations; various previous studies have reported radiographic response rates ranging from 31% to 67%,27-29 PFS-6 rates of 32% to 68%,27, 29-32 and median OS of 9.1 to 16 months.29, 31-33 Although these results appear superior compared with other regimens, it is uncertain whether the results represent true response and PFS rates, considering bevacizumab can induce alteration of the permeability of the blood–brain barrier and be associated with nonenhancing progressions.

The most frequent adverse effects seen in this study were myelotoxicity, gastrointestinal disturbances, and fatigue, which are expected toxicities of the agents used. Notably, 15.4% (6 of 39 patients) of the patients experienced thromboembolism despite the protocol-mandated requirement for low-dose warfarin.34, 35 The frequency of venous thromboembolism in this study was comparatively lower than the 24% to 26% reported in other studies,36, 37 suggesting that low-dose warfarin may have a protective effect against venous thromboembolism in this population. Furthermore, the use of warfarin was not associated with symptomatic or asymptomatic intracranial or intratumoral bleeding.

The PFS-6 and OS noted in this study suggest modest activity for this combination in unselected patients with WHO grade III gliomas, which although better than historical controls, did not meet the statistical threshold to declare this drug combination of sufficient promise to warrant additional testing in a larger sample size, especially given the significant adverse events noted. However, several patients experienced prolonged PFS and OS, suggesting that a subset of patients may derive significant benefit from this regimen, although initial identification of such a subset is challenging. This regimen could provide another salvage option for treatment of patients with WHO grade III gliomas who have exhausted standard treatment options but who remain candidates for additional therapies. We are currently conducting a phase 1/2 trial of irinotecan combined with lenalidomide, a thalidomide analogue, in patients with WHO grade III and IV gliomas. Given the higher potency of lenalidomide seen in preclinical studies, we anticipate a better clinical efficacy of this combination in both grades of malignant gliomas.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES

This investigator-initiated study was supported by research grants and drug supply from Celgene Corporation and Pfizer Incorporated.

CONFLICT OF INTEREST DISCLOSURE

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES

The following authors report disclosures: Charles A. Conrad has received research funding support from Archer Pharma. John de Groot has been a consultant for Bristol-Myers Squibb, has received research funding support from AstraZeneca, Adnexus, and Sanofi-Aventis, and has done advisory and review for Genentech and VBL Therapeutics. Mark R. Gilbert has received honoraria from Genentech, Merck Sharp & Dohme, and Abbott Laboratories. Vinay K. Puduvalli has been a consultant for Novartis, has received research funding support from Merck Sharp & Dohme, Genentech, Pfizer, and Eli Lilly & Co., and has received honoraria from Novartis. W. K. Alfred Yung has been a consultant for Novartis, Merck Sharp & Dohme, and Eden Therapeutic Inc., has received research funding support from Novartis, and has received honoraria from Novartis, Merck Sharp & Dohme, and Eden Therapeutic, Inc. The remaining authors have no disclosures to report.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURE
  8. REFERENCES