Efficacy and safety of ingenol disoxate gel in field treatment of actinic keratosis on full face, scalp or large area (250 cm2) on the chest: results of four phase 3 randomized controlled trials.

INTRODUCTION: Actinic keratosis (AK) is a skin condition arising from chronic exposure to ultraviolet light and may lead to the development of malignancies. This trial aimed to evaluate efficacy and safety of ingenol disoxate gel (IngDsx, 0.018% for face/chest [FC]; 0.037% for scalp [S]), versus vehicle. METHODS: Four identical phase 3 trials in patients with AK on the full face/up to 250cm2 of chest or full balding scalp, with an initial 8-week period and 12-month follow-up, were conducted. FC and S trials were pooled for analysis. The primary endpoint was complete clearance at Week 8. RESULTS: Across trials, 616 patients were randomized to FC and 626 to S, with 410 and 420 assigned to receive IngDsx, respectively. In the FC and S trials, 25.9% and 24.5% of patients in the IngDsx group, respectively, achieved the primary endpoint. IngDsx was relatively well tolerated. During extended follow-up, there were more identified non-melanoma skin malignancies in the IngDsx group than vehicle group; HR: 2.38 (95% CI: 1.28, 4.41). CONCLUSION: Treatment with IngDsx was superior to vehicle on all clinical endpoints, patient-reported and cosmetic outcomes. During the 12-month follow-up, slightly increased skin malignancies in the treatment area were identified, potentially due to unintentional detection bias.

The prevalence of programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer in an unselected, consecutive population.

Little is known about prevalence of PD-L1 expression in tumor cells of unselected patients with all stages of non-small cell lung cancer. The objective of this study is to assess the prevalence of PD-L1 positivity in patients with non-small cell lung cancer, to analyze the association between PD-L1 positivity and patients' clinicopathological characteristics, and to assess the use of immune-oncologic treatment in eligible patients. All non-small cell lung cancer patients diagnosed in a 10-month period in an unselected population of 1.7 million Caucasian inhabitants were evaluated with the PD-L1 IHC 22C3 pharmDx kit. A total of 819 patients were diagnosed with non-small cell lung cancer. Samples analyzable for PD-L1 expression were obtained from 97% of patients. In a multivariate analysis with cut-off at tumor proportion score ≥50%, lower stage was associated with lower prevalence of PD-L1 positivity with an odds ratio of 0.31 for stage I vs. stage IV. A significant difference in PD-L1 expression between squamous-cell carcinoma and adenocarcinoma was observed with odds ratio for adenocarcinoma 1.8. With cut-off tumor proportion score ≥1%, attenuated effects of the same direction were seen. For neither cut-off did type and location of material used for PD-L1 analysis, age, sex, smoking history, or performance status have statistically significant impact on the PD-L1 expression. Fifty four percent of the patients who were eligible for immune-oncologic treatment were actually treated in first-line with pembrolizumab monotherapy. In conclusion, 97% of the patients had material analyzable for PD-L1. If a patient in need of immuno-oncologic treatment has shifted stage, a negative or low positive PD-L1 test performed on a biopsy taken in a lower stage might not mirror the PD-L1 expression in the new metastatic lesion. Therefore, a re-biopsy should be considered.

Efficacy and safety of ingenol mebutate gel in field treatment of actinic keratosis on full face, balding scalp, or approximately 250 cm2 on the chest: A phase 3 randomized controlled trial.

BACKGROUND: Ingenol mebutate (IngMeb) 0.015% or 0.05% is approved for actinic keratosis (AK) areas of 25 cm2 or less; some patients require treatment of larger fields. OBJECTIVE: To determine efficacy and safety of IngMeb 0.027% in areas of AK of up to 250 cm2 during an 8-week initial assessment period and extended 12-month follow-up. METHODS: This phase 3, randomized, double-blind, vehicle-controlled trial (NCT02361216) enrolled adult patients with 5 to 20 AK lesions on the face/scalp (25-250 cm2) or chest (approximately 250 cm2). Patients received once-daily IngMeb or vehicle for 3 consecutive days on the full face, full balding scalp, or approximately 250 cm2 on the chest. The primary endpoint was complete AK clearance (AKCLEAR 100; week 8). Additional endpoints included partial AK clearance (AKCLEAR 75), recurrence, patient satisfaction, cosmetic outcome, and safety. RESULTS: IngMeb was superior to vehicle for complete AK clearance (21.4% vs 3.4%, P < .001) and AK clearance of 75% or greater (59.4% vs 8.9%, P < .001) at week 8. Probability of sustained clearance during the 12-month follow-up was 22.9% for patients treated with IngMeb. Increased treatment satisfaction and cosmetic outcomes were observed with IngMeb versus vehicle. No unexpected safety signals were identified. LIMITATIONS: Localized skin responses hindered maintenance of double-blinding. CONCLUSIONS: IngMeb 0.027% was superior to vehicle for treatment of AK areas of up to 250 cm2. The safety profile of IngMeb was as expected.

Efficacy Endpoints in Clinical Trials in Actinic Keratosis.

INTRODUCTION: Actinic keratosis is regarded as a chronic disease of the skin and, although fluctuating, is chronically progressive. Approval of new products for the treatment of actinic keratosis requires the use of a standard methodology in clinical trials which emphasize complete clearance of all actinic keratoses in a treatment field in a defined time span and the evaluation of long-term efficacy in terms of recurrence rate among completely cleared patients. METHODS: Analysis of data from six previously published clinical trials in patients with actinic keratosis. RESULTS: There was poor agreement over a period of 1 month in the complete clearance endpoint. This variation in assessment renders recurrence in cleared patients invalid as the estimate of long-term efficacy. Furthermore, complete clearance was shown to depend heavily on the number of baseline actinic keratoses. CONCLUSION: The main endpoints presently in use for the assessment of short- and long-term efficacy of actinic keratosis field-directed therapy, namely, complete clearance and recurrence rate, are obsolete and should be replaced by the percentage reduction in actinic keratosis count or the absolute actinic keratosis count. FUNDING: LEO Pharma A/S.

Pharmacokinetics and Safety of Ingenol Disoxate Gel Administered Under Maximum-Use Conditions to Patients With Actinic Keratosis.

BACKGROUND AND OBJECTIVES: Ingenol disoxate (LEO 43204) is a field therapy in development for the treatment of actinic keratosis (AK) on areas between 25 and 250 cm2. We evaluated the systemic exposure and safety of ingenol disoxate under maximum-use conditions. METHODS: This was a phase I, open-label, non-randomized, multicenter trial. Patients ≥ 18 years of age with ≥ 15 clinically typical, visible, discrete AK lesions in a treatment area on the full face or approximately 250 cm2 on the arm or scalp were treated once-daily for 3 consecutive days with ingenol disoxate 0.018, 0.1, or 0.037% gel, respectively. RESULTS: The trial included 58 patients. Median age (range) of patients was 68 years (42-89) [face, N = 18], 66 years (43-88) [arm, N = 21], and 67 years (37-83) [scalp, N = 19]. The highest quantifiable ingenol disoxate level was observed in the arm group (0.33 nM, area under the concentration-time curve from time zero to the last data point [AUCtlast] 3.12 nM·h). Mean composite local skin response scores peaked at Day 4 and declined towards baseline by Day 15 in all treatment groups. Most adverse events (AEs) were of mild or moderate intensity; the most common treatment-related AEs were application-site pain (face, 88.9%; arm, 57.1%; scalp, 100.0%) and application-site pruritus (face, 50.0%; arm, 52.4%; scalp, 42.1%). CONCLUSION: Very low systemic exposure to ingenol disoxate was observed when applied to the face, arm, or scalp in patients with AK under maximum-use conditions. No new safety signals were identified. TRIAL REGISTRATION: NCT02424305.

Safety and Efficacy of Escalating Doses of Ingenol Mebutate for Field Treatment of Actinic Keratosis on the Full Face, Full Balding Scalp, or Chest.

Background: Actinic keratosis (AK) can affect large skin areas. Ingenol mebutate (IngMeb) gel (0.015% and 0.05%) is approved for topical treatment of AK in a single contiguous area of ~25 cm2.

Objective: The study sought to determine the maximum tolerated dose (MTD), efficacy, and tolerability of IngMeb applied to AK on a contiguous area less than equal to 250 cm2.

Methods: Part 1 determined the MTD of IngMeb at 7 concentrations for 2 or 3 days. Part 2 assessed efficacy and tolerability at the MTD and one dose lower for 2 or 3 days vs vehicle.

Results: Four dosing regimens with an acceptable benefit-to-risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Complete clearance at 8 weeks was achieved by 21.3% to 39.1% of IngMeb-treated patients vs 0% to 3.2% treated with vehicle. Composite local skin response scores peaked on the day after the last application, rapidly declined, and were near baseline at 2 weeks. Adverse events were predominantly mild or moderate.

Limitations: The study evaluated a limited number of doses in a population of only white patients.

Conclusion: IngMeb gel was effective and well tolerated as field treatment of AK on the full face, full scalp, and up to 250 cm2 on the chest.

J Drugs Dermatol. 2017;16(5):438-444.

Paired Comparison of PD-L1 Expression on Cytologic and Histologic Specimens From Malignancies in the Lung Assessed With PD-L1 IHC 28-8pharmDx and PD-L1 IHC 22C3pharmDx.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for anti-PD-1 immunotherapy in non-small cell lung cancer. Different immunohistochemistry (IHC) assays have been developed on histologic material with different cutoffs for positivity. More than one third of the patients are diagnosed on cytology alone. We hypothesized that cytologic cell block material is suitable for PD-L1 analysis. MATERIALS AND METHODS: Eighty-six paired samples of malignancies from the lung where cytologic cell block and histologic material were available from the same lesion were stained with PD-L1 IHC 28-8pharmDx and PD-L1 IHC 22C3pharmDx. Scorings of like material (cytology or histology) stained with different assays were analyzed in order to evaluate the analytical agreement between assays. Scoring of different materials stained with like assays were analyzed in order to evaluate the agreement between cytology and histology. RESULTS: A high degree of agreement was found between 28-8pharmDx and 22C3pharmDx, whether applied to histologic or cytologic cell blocks, with Pearson R of 0.95. The Pearson R between 2 rounds of assessment of the same assay on the same type of material was also 0.95. The agreement between histologic and cytologic specimens was high with Pearson R 0.87 to 0.89 and overall agreement between 85% and 95%. There was no bias toward lower prevalence of positivity with cytology than with histology. Disagreement was related to heterogeneity of the histologic tumor sample. CONCLUSION: PD-L1 assessment is feasible on cytologic material with the tested assays using cutoffs for positivity similar to those used on histologic material.

Regression Analysis of Local Skin Reactions to Predict Clearance of Actinic Keratosis on the Face in Patients Treated With Ingenol Mebutate Gel: Experience from Randomized Controlled Trials.

Ingenol mebutate gel, a topical field treatment for actinic keratosis (AK), elicits inflammatory application-site reactions in most patients. This analysis explored the relationship between the intensity of local skin reactions (LSRs) and AK clearance, measured by the reduction in AK count from baseline in 218 patients who were treated for AK on the face in the pivotal Phase 3 studies. The analysis modeled the AK count at week 8, adjusted for baseline count, with the composite LSR score at 1 day after the last treatment application for each patient as a predictor to estimate the mean and 90% prediction interval for the percent reduction in AK count. The predicted mean percent reduction in AK count was higher in patients with higher composite LSR scores. Lower composite scores demonstrated a variable, less predictive percentage reduction in efficacy. Therefore, a large inflammatory reaction from ingenol mebutate gives a more reliable prognosis for improved AK clearance.

J Drugs Dermatol. 2017;16(2):112-114.

Biological Effects of Ingenol Mebutate Gel in Moderate to Severe Actinic Fields Assessed by Reflectance Confocal Microscopy: A Phase I Study.

Ingenol mebutate represents a topical treatment for fields with actinic keratosis (AK). The biological effects of ingenol mebutate in AK, subclinical (SC)-AK, and reference-skin were assessed and graded by in vivo reflectance confocal microscopy (RCM) and histology. Patients with AK and SC-AK lesions in one 25 cm2 field on hands or forearms, and with an area of reference skin on the inner upper arm, were included. The two fields were each treated with ingenol mebutate 0.05% gel (n=16), or vehicle (n=8), on 2 consecutive days; clinical and RCM assessments were performed on days 1, 2, 3, 8, and 57, and biopsies on day 3. Local skin responses were more pronounced in AK fields (6.1 (mean) ± 2.6 (SD)) compared with reference skin (3.5 ± 1.5). The clinical AK lesion reduction was 43.8% and 6.3% with ingenol mebutate and vehicle, respectively. RCM and histology evaluations showed that ingenol mebutate induced a significant pronounced cell death and immune response in AK and SC-AK lesions, compared with reference skin. Ingenol mebutate induced RCM-measured reduction in (investigator-1/investigator-2): AK lesions (34/28%), SC-AK lesions (72/56%), and solar elastosis in AK fields (mean, -0.22/-0.25). In conclusion, ingenol mebutate showed selective pronounced biological responses in AK and SC-AK as compared with reference skin.

J Drugs Dermatol. 2016;15(10):1181-1189.

Relationship between severity of the local skin reactions and the rate of local skin reaction resolution in patients treated with ingenol mebutate gel.

BACKGROUND: Ingenol mebutate gel is a topical field treatment for actinic keratosis (AK). The treatment elicits application-site reactions in most patients. This analysis evaluated the relationship between the severity of reactions and the speed of their resolution. METHODS: Patients in Phase III studies were treated for AKs on the face (n=218), scalp (n=56), and trunk and extremities (n=209). All of the patients were treated with either ingenol mebutate gel 0.015% once daily for three consecutive days (face/scalp) or ingenol mebutate gel 0.05% once daily for two consecutive days (trunk/extremities). Local skin reactions (LSRs) were assessed on a 5-point scale from 0 to 4 in six categories, yielding composite scores in the range of 0 to 24. RESULTS: The composite LSR score on the day after the last application of ingenol mebutate gel was an important predictor of the speed of resolution of LSRs. The rate of resolution was greatest for AKs treated on the face, followed by the scalp, and then the trunk and extremities. All patients were expected to have minimal LSR scores for the face and scalp at 2 weeks, and for the trunk and extremities at 4 weeks. CONCLUSION: The absolute reduction in LSR scores was proportional to the composite LSR score on the day after the last application of ingenol mebutate gel treatment. The rate of resolution for LSRs was dependent on the anatomic site treated as well as the day 4 composite score.

Squamous cell carcinoma and keratoacanthomas are biologically distinct and can be diagnosed by light microscopy: a review.

Keratoacanthomas (KAs) are self-limiting squamoproliferative lesions usually seen on sun damaged skin. These tumours are in many ways enigmatic, and the relation between KAs and squamous cell carcinoma is still a contested topic. In this review the biology and histology of KAs will be discussed, and based on morphology, clinical outcome and recent genetic analysis of the tumour types, we conclude that KAs and SCCs are two distinct biological entities which can usually be distinguished by conventional microscopy. The sentinel observation of rapid and frequent appearance of KAs after BRAF treatment of malignant melanoma patients has paved the way for a more general understanding of the pathogenesis leading to the appearance of KAs in patients with inflammation in the skin. In BRAF treated patients, the KAs are a consequence of paradoxical activation of the MAP kinase pathway. Similarly, any external trauma or pharmaceutical interventions resulting in inflammation in the skin will activate the MAP kinase pathway. Such inflammation-mediated MAP kinase activation in the skin will result in the development of KAs through the same pathway as demonstrated for BRAF treated patients. It is characteristic that skin tumours following short acting inflammatory stimulation of severely sun damaged skin develop almost exclusively into KAs, whereas it is exceedingly rare that such inflammatory conditions lead to formation of SCCs. The understanding that inflammatory reactions in sun-damaged skin may activate pathways specifically leading to the formation of KAs may spare the patient the discomfort and disfigurement of needless overtreatment.

The prevalence of EGFR mutations in non-small cell lung cancer in an unselected Caucasian population.

EGFR mutation frequencies in unselected Caucasian populations are unknown. This study assesses the prevalence of EGFR mutations in an unselected population-based cohort, and the correlation between mutation and gender, age, ethnicity, smoking habits, and pathological data. NSCLC patients diagnosed in a well-defined Danish population were included. The type of the diagnostic material, and data on smoking were registered. The mutation analyses were investigated by Therascreen EGFR RGQ-PCR Kit or Sanger sequencing. A total of 658 men and 598 women were included. 6.2% were never smokers, 38.9% were ex-smokers, and 54.9% were current smokers. One thousand one hundred and sixty-one (92.4%) patients had sufficient material for mutation analysis. Cytological material was used for 38% of the mutation analyses. 5.4% had mutation in the EGFR gene (4.3% men/6.7% women). 87% were activating mutations. 8.0% of adenocarcinomas, and 1.9% of squamous cell carcinomas were mutated. 29.4%, 4.4% and 2.9% of never, ex- and current smokers were mutated (p < 0.001). No difference in mutation rate was observed between patients with cytology only, histology only or both cytology and histology available. 5.4% of the patients had EGFR mutation. Adenocarcinomas were mutated more often (8.0%) than squamous cell carcinomas (1.9%). Mutations were found in never smokers as well as in former and current smokers. No difference in gender and age regarding mutation status was observed. EGFR mutations analysis was possible in almost all patients with no difference between cytology and histology specimens.

Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results.

INTRODUCTION: Cryosurgery is the most common treatment for actinic keratosis (AK) in the United States. Efficacy with cryosurgery is variable, and is a modality for treating individual, visible lesions while failing to treat subclinical lesions. METHODS: FIELD Study 1 (NCT01541553) is a phase 3, multicenter, randomized, double-blind study that evaluated the short- (11-week) and long- (12-month) term efficacy and safety of sequential AK treatment using cryosurgery with liquid nitrogen followed by ingenol mebutate gel, versus cryosurgery followed by vehicle. RESULTS: Overall, 329 patients were randomized to ingenol mebutate 0.015% gel (n=167) or vehicle (n=162) 3 weeks after cryosurgery. Baseline characteristics were balanced across groups. At week 11, complete clearance rate (100%) in the treatment area was higher for ingenol mebutate gel compared with vehicle (60.5% vs 49.4%, respectively; P=.04). Mean percentage reduction in number of AKs versus baseline was also numerically higher for ingenol mebutate gel (82.7% vs 75.6%). A general reduction from baseline lesion count was observed 3 weeks after cryosurgery. Treatment after cryosurgery was well tolerated. CONCLUSIONS: Short-term (11-week) AK clearance rates on the face or scalp with ingenol mebutate gel after cryosurgery were higher than with cryosurgery alone.

ERCC1 and Ki67 in small cell lung carcinoma and other neuroendocrine tumors of the lung: distribution and impact on survival.

BACKGROUND: Excision repair cross-complementation group 1 (ERCC1) is a key component of the platinum-DNA repair mechanism. Ki67 is associated with the clinical course of several malignancies. The associations of ERCC1 and Ki67, clinical features and survival in small cell lung carcinoma (SCLC), typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LCNEC) were determined. MATERIALS AND METHODS: We included a consecutive series of 186 patients with SCLC treated with platinum-based chemotherapy and surgically treated patients with TC (n = 48), AC (n = 15) and LCNEC (n = 27). ERCC1 and Ki 67 were measured by immunohistochemistry and scored using published criteria. RESULTS: The expression of ERCC1 was different among the different tumor types (p < 0.001). For patient with limited disease as well as extensive disease SCLC, no association of ERCC1 expression with survival was observed (p = 0.59). However, only 10% of SCLC tumors expressed ERCC1. For TC and AC, ERCC1 positive patients had better survival than ERCC1 negative patients. ERCC1 had no prognostic impact for LCNEC. A difference of the percentage of Ki67 LI was observed for the different tumor types (p < 0.001). The difference between TC and AC was significant (p = 0.02), as was the difference between low grade (TC+AC) and high grade NE (LCNEC + SCLC) (p < 0.001). For all included patients, a correlation between Ki67 and ERCC1 was observed (RSquare = 0.19, p < 0.001). CONCLUSION: ERCC1 expression in SCLC treated with platinum-based chemotherapy has no impact on survival. High expression of ERCC1 in TC might represent a clue to the failure of platinum-based therapy in these patients. ERCC1 expression has prognostic impact in lung carcinoids. Ki 67 might be considered as a supplementary test to the histopatologic classification of NE tumors.

Different impact of excision repair cross-complementation group 1 on survival in male and female patients with inoperable non-small-cell lung cancer treated with carboplatin and gemcitabine.

PURPOSE: The excision repair cross-complementation group 1 (ERCC1) status was assessed in patients receiving carboplatin and gemcitabine for inoperable non-small-cell lung cancer (NSCLC). We analyzed the association between the ERCC1 status and the overall survival after the chemotherapy. PATIENTS AND METHODS: We retrospectively identified 163 patients with inoperable NSCLC and sufficient tumor tissue for ERCC1 analysis, who had received carboplatin and gemcitabine as first-line treatment. Immunohistochemistry was used to assess the expression of ERCC1. RESULTS: One hundred sixty-three patients were included. Seventy (42%) were ERCC1 positive. Patients treated with carboplatin and gemcitabine and having ERCC1-negative tumors had a significantly increased survival when compared to patients with ERCC1-positive tumors (median survival, 12.0 months v 8.2 months; P = .02). This difference was mainly seen in men, where those with ERCC1-negative tumors had a significantly increased survival compared to men with ERCC1-positive tumors (median survival, 11.8 months v 7.9 months; P = .005). Conversely, women who were ERCC1 negative did not have a survival advantage over ERCC1-positive women. CONCLUSION: We confirmed previous reports that ERCC1 expression is predictive for outcome in patients treated with carboplatin and gemcitabine. Patients with ERCC1-negative tumors had an increased survival compared to patients with ERCC1-positive tumors and this difference was mainly attributable to a survival difference among men.

Reclassification of neuroendocrine tumors improves the separation of carcinoids and the prediction of survival.

INTRODUCTION: The classification of neuroendocrine lung tumors has changed over the last decades. Reliable diagnoses are crucial for the quality of clinical databases. The purpose of this study is to determine to which extent the use of different diagnostic criteria of neuroendocrine lung tumors has influenced the classification of these tumors. The prognostic information of tumor, node, metastasis descriptors was also evaluated. METHODS: We retrieved 110 tumors from the period 1989 to 2007. All tumors were reclassified according to the World Health Organization classification of 2004. Tumor, node, metastasis descriptors were evaluated. RESULTS: By reclassification, the diagnoses on 48 tumors (44%) were changed. More diagnoses were changed in the older part of the material. A significantly different survival was shown for all patients in relation to tumor size (p < 0.0001). An endobronchial component was seen in 54%, 31%, and 11% of typical carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma, respectively with no impact on survival (p = 0.90). For all included patients the survival was significantly worse for patients having metastasis to N1 nodes as compared with N0 (p = 0.03). However, the number of removed lymph nodes were insufficient for definitive determination of the prognostic impact of node metastases. Regarding the revised diagnoses, a significant difference in survival between typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma was noted (p < 0.005). CONCLUSION: Tumors must be rediagnosed before entering a central database. Tumor and node seem to be useful predictors of survival.

A Phase I study of CHS 828 in patients with solid tumor malignancy.

CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1-5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 +/- 1.3 h and half-life was 2.1 +/- 0.52 h (mean +/- SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.