Search

2583 Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody (Ab) to human DR5 created by CDR grafting of the murine Ab TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in pts with mCRC. Methods: Pts with mCRC were treated with weekly IV CS-1008 in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (0.2 to 6 mg/kg), followed by a weekly dose of 2 mg/kg. D1 and D36 doses were trace-labeled with 111In, followed by whole-body planar and regional SPECT imaging over 10 days. Primary endpoints: initial biodistribution, pharmacokinetic (PK) and tumor uptake following single infusion; changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints: tumor response; changes in tumor metabolism by FDG-PET; serum apoptosis biomarkers and tumor response markers. Results: 19 pts (median age 64 yrs; M:F 11:8; 2-6 prior chemotherapy regimens) were enrolled as follows: Co 1, n=2; Co 2, n=4; Co 3, n=5; Co 4, n=3; and Co 5, n=5. Tumor uptake was variable: 7 pts had no uptake, 11 pts had uptake in all sites of disease but liver, 1 pt showed liver uptake. Tumor uptake and PK were not affected by dose or repeated drug administration. No anti-CS-1008 Ab responses were detected. DR5 expression in archived samples did not correlate with uptake or response. 111In‐CS‐1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. Mean % change in SUVmax from baseline in lesions with uptake was higher than in those with no uptake. There were 8 SD, 1 PR and 10 PD. Duration of PR was 3.7 months (mo). Mean duration of SD was 4 mo. Disease control rate (SD + PR) in pts with uptake was 58% vs 28% of pts with no uptake. Lesions with no uptake were more likely to progress, with a PD risk of 3.4 times higher than those lesions with uptake. Conclusions: Tumor DR5 expression, assessed by 111In-CS-1008 imaging, revealed real-time heterogeneous DR5 expression and appeared to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Clinical trial information: NCT01220999.

Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway by activating caspases. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody to human DR5 created by CDR grafting of the murine antibody TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in patients with mCRC. Methods: Pts with mCRC who had received at least 1 course of chemotherapy (CT) were treated with weekly IV CS-1008 infusions in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (Co 1: 0.2 and 6 mg/kg; Co 2: 1 and 6 mg/kg; Co 3: 2 and 6 mg/kg; Co 4: 4 and 4mg/kg; Co 5: 6 and 2 mg/kg), followed by a weekly CS-1008 dose of 2 mg/kg. Cycle 1 encompassed 7 wks of therapy (D1 and D36 doses trace-labeled with 111In); additional weekly CS-1008 was scheduled as 4-wk cycles. Primary endpoints were to determine (1) the influence of CS-1008 dose on initial biodistribution, pharmacokinetic (PK) and tumor uptake of 111In-CS-1008 following single infusion; (2) changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints were to determine (1) anti-tumor response; (2) changes in tumor metabolism; (3) serum apoptosis biomarkers and serum tumor response markers. Results: Nineteen pts with a median age of 64 years and 2-6 prior CT lines were enrolled as follows: Co 1, 2 pts; Co 2, 4 pts; Co 3, 5 pts; Co 4, 3 pts; and Co 5, 5 pts. Twelve pts showed tumor uptake of 111In-CS-1008, 3 at each of the 1, 2, 4 and 6 mg/kg D1 dose levels. 111In-CS-1008 uptake in tumor was variable: some pts showed no uptake, in others uptake was observed in all measurable lesions. Liver metastases showed poor uptake of CS-1008. No significant differences were observed in tumor uptake between D1 and D36, and no effect of dose on tumor uptake was seen. DR5 expression in archived samples did not correlate with 111In-CS-1008 uptake, nor with clinical outcome. 111In-CS-1008 biodistribution showed gradual blood pool clearance and no discernible abnormal uptake in normal tissue. CS-1008 PK was not affected by dose or repeated drug administration. At restaging, there were 8 SD, 1 PR and 10 PD. The duration of PR was 3.7 months (mos). The mean duration of SD was 4 mos (range, 2.6-6.7 mos). Among the group of pts who showed CS-1008 uptake in tumor, 58% had clinical benefit (SD or PR), compared with 28% of pts in the group with no tumor uptake. The lesions that showed CS-1008 uptake were less likely to progress even in pts with overall PD at restaging. Conclusions: 111In-CS-1008 uptake in tumor predicts SD or PR. Tumor DR5 expression, assessed by 111In-CS-1008 imaging, reveals real-time heterogeneous DR5 expression, both on a per pt and on a lesion by lesion basis, and appears to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Citation Format: Marika Ciprotti, Niall C. Tebbutt, Fook T. Lee, Sze T. Lee, Dave C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Hui K. Gan, Wendie Hopkins, Bridget Chappell, Nancy Y. Guo, Fiona E. Smyth, Archie N. Tse, Mendel Jansen, Manabu Matsumura, Rira Watanabe, Robert A. Beckman, Jon Greenberg, Andrew M. Scott. A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1174. doi:10.1158/1538-7445.AM2013-1174

Results: Preliminary data are presented for 43 patients (25 M, 18 F), median age 64 years. No dose-limiting toxicities or serious toxicity patterns occurred at any dose level. Drug-related adverse events occurring in 10% of patients were fatigue (28%), decreased appetite (23%), nausea (16%), diarrhea (14%), and anemia (12%); the majority were grade 2. Perturbations in insulin and growth hormone were not observed. Clinically significant changes in serum glucose were rare. The MTD was not reached after completely enrolling patients through the highest dose, 45mg/kg IV q3w. Serum exposure of MEDI-573 increased with increasing dose. Full suppression of IGF-I/-II was achieved with weekly and q3w dosing. No neutralizing antibodies against MEDI-573 were detected. Of 43 patients, 13 (30%) had stable disease with 8 (19%) of 12 weeks duration. The longest exposure was 21 months in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 demonstrated an acceptable safety profile at all doses tested. No dose-limiting toxicity or serious toxicities, including those related to glucose homeostasis, were detected. These preliminary results support further clinical development. This study was funded by MedImmune, LLC.

The epidermal growth factor receptor (EGFR) pathway is a regulator of cellular proliferation and tumour progression. EGFR overexpression occurs with gene amplification and activating EGFR kinase mutations (EGFRmt). Monoclonal antibody 806 (mAb806) is an anti-EGFR antibody which targets tumours with EGFR mutation variant III and overexpression but not cells with low EGFR expression (wild type EGFR, wtEGFR) and normal tissues. To characterise mAb806 binding, we correlated mAb806 expression with EGFRmt, EGFR immunohistochemical (IHC) expression and overall survival (OS). Formalin fixed paraffin embedded tissues were stained using the mAb806 (Ludwig Institute for Cancer Research) and EGFR (Dako, PharmDx kit). A H-score was obtained based on staining intensity and percentage of cells stained. mAb806 H-scores 0-50 were classified as negative (mAb806-) and ≥50 as positive expression (mAb806+). EGFR H-scores were calculated to stratify patients into low (Dako score Disclosure A. Scott: A.S is an inventor of a patent for mAb806, and a consultant to Life Science Pharmaceuticals which has the license for mAb806. All other authors have declared no conflicts of interest.

5587 Background: There is increasing evidence that NCF abnormalities may occur in cancer pts. Data on pre-treatment NCF in HNC pts are lacking. This study reports NCF in pts with newly diagnosed, curable HNC compared to controls. Methods: HNC pts underwent a 2-hour battery of NCF tests prior to radio +/-chemo(bio)therapy. Domains tested were intelligence (IQ), memory, language, attention, processing speed, executive function and manual dexterity. Test performances were transformed into Z-scores using normative data (score < -1 signified deficit). Pts also had self-reported assessments for NCF, quality of life (QOL), fatigue and affect. Data obtained were compared to non-cancer controls who underwent the same tests. Results: Eighty HNC and 30 control subjects were assessed. Objective NCF testing demonstrated that HNC and control cohorts were similar across all domains, except for IQ, with pts having higher scores (mean 0.55 vs 0.12, p=0.03). However, individual analysis showed that 39% of HNC and 43% of control subjects had abnormal Z-scores in ≥ 2 domains. Multivariable analysis of factors associated with ≥ 2 abnormal NCF domains included: low education level, significant smoking history (≥ 10 pack year), previous mild brain injury, gender, and group (pt vs control). Amongst pts, HPV -ve status and non-oropharyngeal tumors were also associated with decreased NCF. Pts reported statistically worse subjective baseline symptoms compared to controls: NCF (mean FACT-COG 33.7 vs 18.2, p=0.002), QOL (FACT H&N 33.8 vs 14.9), fatigue (FACT-F 35.1 vs 15.1), anxiety (HADS 7.0 vs 3.1) and depression (HADS 3.9 vs 1.2), p

3000 Background: FAK has an important role in cancer invasion and metastasis. FAK and phospho-FAK (pFAK) are increased in advanced cancer and are correlated with poor prognosis. GSK2256098 is a potent and specific small molecule inhibitor of FAK. Methods: This is a first-time in cancer pts, dose escalation study (NCT01138033) to identify the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity. Part 1 used a modified accelerated titration procedure switching to standard 3+3 design based on toxicity during the first 21 days of treatment. Pts were treated with GSK2256098 orally twice daily (BID) with food. Safety was established in cohorts of 1-6 pts. After MTD determination, Parts 2 and 3 were opened to further evaluate safety, PK and PD. Serial PK samples were obtained over 24 h on Days 1 and 15. Pre- and post-dose skin, hair and tumor tissue biopsies were analyzed for pFAK. Results: 57 pts with advanced solid tumors have been treated at escalating doses ranging from 80 mg to 1500 mg BID: median age=58.8 (range 21-84). The most common tumor types include: mesothelioma (23), ovary (7), colon (3), kidney (3), and pancreas (3). MTD was determined to be 1000 mg BID. DLTs were Gr 2 proteinuria (1000 mg), Gr 2 nausea, vomiting, fatigue (1250 mg) and Gr 3 asthenia (1500 mg). Most frequent toxicities were nausea (32 pts, 56%), diarrhea (31 pts, 54%), vomiting (25 pts, 44%), decreased appetite (18 pts 32%) and asthenia (11 pts, 19%). The majority of toxicities were Gr 1-2; Gr 3 drug-related events included hypertriglyceridemia (n=2), hyperlipasemia (2), asthenia (1), increased amylase (1), and loss of consciousness (1). Few dose reductions and interruptions have occurred. Minor responses/stable disease (SD) were observed in pts with mesothelioma (-12%, 27 wks), melanoma (-26%, 54 wks), and naso/pharyngeal cancer (-31% target lesion, 30 wks) and SD in renal cell (48+ wks). In preliminary analysis of single-dose PK, exposure generally increased in a dose-proportional manner, and the geometric mean t½ was 4.2 h. Accumulation was not observed with repeat dosing. Conclusions: GSK2256098 is well tolerated with evidence of clinical activity. PK supports BID dosing.

5522 Background: There is evidence that cancer and/or its treatment can impair thinking abilities. To date, there have been no longitudinal studies exploring NCF in HNC pts. We present a prospective NCF assessment in HNC pts treated with C/B-RT. Methods: Baseline information including pt demographics, primary tumor site, stage, smoking/alcohol history, systemic therapy details and RT dosimetry were collected. All pts underwent a 2-hour battery of NCF testing at baseline and at 1-year (yr). Domains evaluated included memory, motor skills, intelligence, language, attention, processing speed and executive function (EF). Performances on the various tests were transformed to Z-scores using normative data. NCF decline was defined as a Z-score decrease of ≥-1 and improvement as a Z-score increase of ≥+1. Pts also had subjective assessments of anxiety, depression, NCF and quality of life (QOL) using the Hospital Anxiety and Depression Scale and FACT questionnaires. QOL was considered significantly altered if FACT...

2562 Background: The expected benefit of the experimental over the standard arm (δ) in a RCT is estimated based on current evidence and investigators’ experience. Overestimation of δ can lead to in...

e15153 Background: The efficacy of second-line targeted therapy (SLT) in patients with metastatic RCC who have progressed on first-line VEGFR TKI is of clinical relevance but remains to be fully de...

Introduction: There is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA). Methods: We retrieved all phase I trials testing monotherapy with an MTA published in English after January 1st, 2000. In each trial, all items used to define DLTs were recorded. Results: Reports of 155 phase I trials evaluating 111 different MTAs were reviewed. The median DLT assessment period was 28 days [range: 7-56]. Among the 155 trials, the most common category of hematologic toxicity was “hematologic toxicity, not otherwise specified (NOS)”. Similarly, the most common category of non-hematologic toxicity was “non-hematologic toxicity, NOS”. A total of 8 other categories of hematological items and 46 categories of non-hematologic organ-specific items were employed to define DLTs in the 155 trials reviewed. Organ-specific items were reported in 111 trials (72%). Mean number of organ-specific items per trial increased from 2.03 in the 2000-2005 timeframe to 2.79 in the 2006-2010 timeframe (p=0.02). The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE grading system. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. A number of other factors were increasingly found to influence the determination of DLT. Specifications about minimum duration and degree of reversibility were incorporated into the definition of a non-hematologic DLT in 13% and 12% of trials respectively. The need to delay treatment and to reduce dose-intensity because of toxicity was incorporated in the definition of DLT in 19% and 8% of trials respectively. The definition of DLT varied with administration schedule, with (near-)continuous dosing regimen often defining DLTs at lower severities. Definition of DLT did not differ according to classes of agents, to first-in-human versus not first-in-human studies or to dose escalation method used. Twenty three percent of the organ-specific DLTs defined in the trials in which non-hematologic DLTs occurred were actually encountered, suggesting an added value of these organ-specific DLTs to the generic definition. In 28 of the 155 trials (18%), toxicities were eventually considered to be DLTs even though they were not initially defined as such. Conversely, in 13 of the 155 trials (8%), toxicities were not reported as DLTs even though they were initially defined as such. Conclusions: The definition of DLT is heterogeneous across phase I cancer clinical trials of MTA administered as monotherapy and depended on the drug administration schedule. While our results do no support the standardization of the definition of DLT, we provide recommendations aiming at reducing the heterogeneity observed in the definition of DLT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1690. doi:10.1158/1538-7445.AM2011-1690

e19629 Background: There is increasing evidence that cancer and/or its treatment can impair thinking abilities. We recently reported on cognitive functioning (CF) in LA-SCCHN pts 1-2 yrs post RT or...

6031 Background: To improve the quality of results reported in randomized clinical trials (RCTs), international registration has been recommended. We performed a review of oncology RCTs published o...

6122 Background: The CONSORT guidelines (2001) aimed to improve the reporting of RCTs. This study examined the adequacy of data provided in oncology RCTs in selected journals (Ann Oncol/BJC/Breast ...

6068 Background: Evidence suggests cancer-related treatments affect cognition. To our knowledge, no studies have systematically investigated cognitive impairment in head and neck cancer (HNC) patients (pts). We assessed ten relapse-free HNC pts after curative-intent radiotherapy (RT), half of whom received cisplatin (Cp). Methods: Pts completed a 2-hr battery of tests/questionnaires assessing objective cognitive function (CF), subjective CF, quality of life and affect. Objective measures of CF were transformed to Z-scores (mean=0, standard deviation=1) using age normative data. A negative value for the Difference Score (DS=Z-score minus IQ score) in each tested domain indicates cognitive deterioration as IQ is a pre-morbid estimate of pts’ CF. A Global Deficit Score (GDS) was obtained by averaging the DS of all tested CF domains. Results: Pt demographics were: M:F=8:2; mean age=58 yrs(range 47–66); mean smoking pack yrs=15(0–45); mean drinks/week=7(0–25); mean IQ Z-score=+1.2(-1.0 to +2.0), mean school yrs=15 (6–18) and mean time post treatment=20 mo(9–41). All pts completed the battery within 2 hr. Nine participants appeared to have impaired CF based on negative DS and GDS scores ( Table 1 ). Exploratory univariate analyses showed trends that higher RT dose and Cp use were associated with increased impairment but cytokines, anemia, hormonal status and affective state were not. Conclusions: This feasibility study suggests cancer-related treatment affects cognition in HNC survivors. A longitudinal study is underway. [Table: see text] No significant financial relationships to disclose.

13005 Background: Whilst oligodendroglial tumours are chemosensitive, the data about Temozolomide in high grade oligodendrogliomas are almost exclusively in recurrent tumours. Methods: 40 untreated patients of a planned 50 with high grade oligodendrogliomas were enrolled in a Phase II trial of Temozolomide. Eligible patients had confirmed oligodendrogliomas/astrocytomas and adequate organ function. Patients were excluded for prior chemotherapy or radiotherapy. Once recovered from surgery, patients were treated with 6 monthly cycles of Temozolomide (200 mg/m2 for five days), with post-chemotherapy radiotherapy at investigator discretion. Patients were assessed for loss of heterozygosity (LOH) of 1p and 19q, which are markers of chemosensitivity. The primary endpoint was disease-free progression at six months. Results: Patients were accrued within 42 months with 17 women (42.5%) and 37 (92.5%) having a performance status (ECOG) 0–2. Eight patients did not complete the full 6 cycles (6 progressed during chem...

6072 Background: Due to their anatomical complexity, the interactive effects of multiple treatment modalities, the difficulties in differentiating scar tissues versus residual disease and second cancers versus tumor recurrence, LA-HNSCC represent a challenging disease for the reporting of endpoints and the tracking of failures. Methods: We retrieved all randomized trials that began accrual on or after 1978, and enrolled previously untreated nonmetastatic HNSCC patients receiving primary (chemo)radiotherapy. The reporting of endpoints and the tracking of failures in these trials were analyzed. Failures were defined as events meeting a pre-specified endpoint definition. Results: Forty trials involving 13,892 patients fulfilled our inclusion criteria. A total of 125 endpoints were identified: primary versus secondary = 34:91, survival-based (e.g., overall survival [OS]) versus surrogate (e.g. locoregional control [LRC]) = 47:78. In 6 trials, no primary endpoint was identified. LRC and OS accounted for 70% of primary endpoints. All but one trial reported at least one secondary endpoint, with a median of 2 per trial (range: 0–5), and as many as 17 different types of secondary endpoints were reported. Among 72 endpoints tracking locoregional failures, 21/72 (29%) did not define locoregional failure, while 46/72 (64%) specified the absence of complete response as a failure. Whether salvage surgery or elective node dissection was performed or not was reported in less than half of the trials. Furthermore, it was usually not specified if residual disease found during these procedures would account for failure or not. The means (i.e. clinical and/or radiological examinations) to ascertain failures and the protocol-specified timing to track failures were reported in 41% and 67% of surrogate endpoints, respectively. The tracking of other types of failure beyond the first failure is not reported by any of the trials. The reporting of second cancers was found in 15/40 (38%) trials, whereas the duration of follow-up was quantified in 31/40 (78%) trials. Conclusions: These results demonstrate the vast heterogeneity in endpoint reporting and tracking of failures in clinical trials of LA-HNSCC. No significant financial relationships to disclose.

Background The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an IgG1-humanized antibody, huA33, in colorectal tumours. Methods Twelve patients were infused with radiolabelled huA33 at 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in tumour antigen (GPA33) expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined. Results The I-huA33 uptake in whole tumour sections was (mean ± SD) 5.13 ± 2.71 × 10−3% injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n = 5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17 × 10−3%ID, p = 0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10 × 10−9 vs 3.82 ± 3.67 × 10−9%ID/cell, p = 0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between 131I-huA33 uptake in tumour on a cellular basis and tumour vascularity. Conclusions In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targets viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding.