bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between tumor blood flow and serum albumin levels: A positron emission tomography study
Authors: Koetz B. , Bruce J. , Price P.
Published: March 2020

3058

Background: Positron emission tomography (PET) is increasingly used to aid development of drugs targeting the tumor vasculature. Reduced serum albumin levels lead to a decrease in plasma colloid osmotic pressure, reducing the effective intravascular volume. This study examined the relationship between serum albumin levels and tumor perfusion parameters evaluated with PET. Method: PET perfusion studies using oxygen-15-labeled water (H215O) were performed as part of clinical trials in 18 patients with advanced solid tumors. Regional tumor blood flow (mlblood/min/mltissue) and volume of distribution of water (Vdwater;ml/mltissue), an indicator of the fraction of tissue participating in the exchange of water, were measured prior to any intervention and related to serum albumin levels. Two-tailed Pearson’s correlation coefficient was used for statistical analysis. Results: Serum albumin levels ranged from 19 to 44g/l (median 32g/l). Regions of interest were drawn in 7 renal cell cancers, 5 liver metastases, 2 hepatomas, 2 para-aortic lymph node metastases, one mesenteric and one pelvic mass. Tumor blood flow ranged from 0.13 to 1.67mlblood/min/mltissue (median 0.47mlblood/min/mltissue) and tumor Vd water from 0.39 to 1.11ml/mltissue (median 0.69ml/mltissue). A significant correlation between serum albumin level and tumor blood flow (r=0.51, P=.031) could be demonstrated, whereas Vdwater was independent of albumin levels (r=0.29, P=.21). Conclusions: This study demonstrates that tumour blood flow is related to serum albumin levels. Changes in serum albumin levels need to be considered when assessing effects on tumor blood flow with treatments targeting the tumor vasculature, particular if given over several weeks. The fraction of perfused tissue may more accurately assess the vascular effects of cancer treatments. If correction of serum albumin levels could be used for therapeutic benefit will require further research.

No significant financial relationships to disclose.
Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE)
Authors: Perotti A. , Maur M. , Viganò L. , Gallerani E. , Angst R. , Albanell J. , Sessa C. , Laliberte R. , Marsoni S. , Gianni L.
Published: March 2020

3065

Background: AP23573 is a novel mTOR inhibitor with anti-tumor activity in Phase1 and 2 trials. In vitro, AP23573 is at least additive with chemotherapy agents including 5FU. CAPE is activated to 5FU by thymidine phosphorylase which may be highly expressed in tumors and correlates with progression through angiogenic mechanisms controlled by mTOR. Given the potential for a positive interaction, this trial studied the combination of AP23573 and CAPE in adult patients with solid tumors. Methods: Starting doses were: AP23573 25 mg i.v. on Days 1, 8, and 15 of a 28-day cycle, and CAPE 1650 mg/m2 p.o. daily on Days 1–14. Planned PK and PD studies include analysis of plasma VEGF, PBMC, skin, and tumor samples for effects on pathways associated with mTOR and on the metabolism of CAPE and fluoropyrimidines. Dose limiting toxicity (DLT) was defined as: febrile neutropenia; neutrophils <500x106/L for ≥ 5 days; ≥ Grade 3 (CTC) thrombocytopenia; non-haematological toxicities ≥ Grade 2 (diarrhea, cardiac or renal); or missing two consecutive weekly doses due to any toxicity. Results: 15 patients have been treated. Three dose levels of weekly AP23573 (25, 37.5 and 50 mg) were completed without DLT. Treatment-related toxicity was mostly mild or moderate (≤ grade 2), with mucositis/stomatitis the most frequent. Anti-tumor activity included a partial response in a case of endometrial cancer, and stable disease > 4 months in 3 cases (1 renal, 1 uterine and 1 head & neck cancer). AP23573 did not affect the PK of CAPE or 5FU but a trend toward a decreased exposure to the catabolite 5-FuH2 was apparent in the presence of AP23573. In keeping with this observation, the activity of dihydro-pyridine-dehydrogenase gradually decreased to 60% of that before AP23573. This decrease was not associated with reduced tolerability. Conclusions: The combination of AP23573 with CAPE is safe with initial indications of anti-tumor activity. This is the first description of a feasible combination of an mTOR inhibitor with an anti-metabolite. Additional dose levels of AP23573 (75 mg) and CAPE (1850 mg/m2/day) are ongoing and PK and PD studies are continuing.

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Phase 1 clinical trial of KOS-953 + bortezomib (BZ) in relapsed refractory multiple myeloma (MM)
Authors: Chanan-Khan A. , Richardson P. , Alsina M. , Lonial S. , Krishnan A. , Carroll M. , Albitar M. , Hannah A. L. , Johnson R. G. , Anderson K.
Published: March 2020

3066

Background: KOS-953 (17-AAG in Cremophor) inhibits HSP90 chaperone function, resulting in disruption of protein complexes and proteasomal degradation. Single-agent 17-AAG is active in relapsed/refractory MM patients (pts) (ASH 2005 A#361), with a recommended dose ≥ 275 mg/m2. In vitro, BZ + KOS-953 show additive cytotoxicity of myeloma cells. Objectives: Define phase 2 dose of BZ+KOS-953 in pts with relapsed refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates and explore changes in intracellular signaling proteins in pt PBMCs and MM cells. Methods: Pts received BZ as IV bolus followed by 1-hour infusion KOS-953 twice weekly for 2 out of 3 weeks. Dose escalation occurred in a step-wise manner. PK and collection of surrogates are performed following the 1st and 4th infusion. Pts assessed for response by EBMT criteria. Results: 20 pts were enrolled in 4 cohorts: BZ+KOS-953 (mg/m2): 0.7+100 (n=3); 1.0+100 (n=3); 1.0+150 (n=8); and 1.3+150 (n=6), receiving a total of 103+ cycles (median 5 cycles; range <1 - 17). Demographics: 10F/10M; median age/KPS 64y/90; median # of prior regimens 4 (range 2–16); 75% prior BZ (5 with ≥2 prior BZ); 95% prior thalidomide; 15% prior lenalidomide; 70% prior SCT(s). DLT observed in Cohort 2 (n=1 grade 4 hepatotoxicity in a setting of congestive heart failure secondary to cardiac amyloidosis) and in Cohort 3 (n=1 pancreatitis). Other Grade 3–4 toxicity (1 each): thrombocytopenia with Herpes Zoster recurrence and pneumonia; septic thrombophlebitis. Drug-related toxicity (mild-to-moderate): diarrhea (n=8), fatigue (n=8), constipation (n=7), neuropathy (n=7), ↑AST (n=5), muscle cramps (n=5) and rash (n=4). PK similar to single-agent trial; stationary kinetics noted upon twice weekly dosing. 20S proteasome function (1.3 mg/m2, end of infusion): 50% decrease (similar to predicted values). Response was seen in 6 out of 12 BZ-refractory patients (1 nCR, 5 MR) and 3 out of 4 BZ-naïve pts (1 nCR, 2 MR). Conclusions: Dose escalation continues with no additive toxicity or PK interactions to date. Similar inhibition of the 20S proteasome is observed compared to BZ alone. Encouraging activity is seen in both BZ-naïve and BZ-refractory heavily pre-treated MM pts.

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Phase I trial of a sequence-specific combination of the HDAC inhibitor, valproic acid (VPA), and the topoisomerase II inhibitor, epirubicin, in advanced solid tumors: Clinical results and correlative studies
Authors: Munster P. N. , Marchion D. C. , Bicaku E. , Schmitt M. L. , Padilla B. , Stauffer P. , Garrett C. , Chiappori A. , Sullivan D. M. , Daud A. I.
Published: March 2020

3068

Background: Multiple lines of evidence indicate that histone deacetylase inhibitors (HDACi) potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explored a sequence-specific combination of VPA and epirubicin in solid tumors. A VPA loading dose and 6 oral doses (q12h) were given prior to epirubicin in 3-week cycles. Histone acetylation and topo II expression were evaluated in pre-and post-VPA peripheral blood mononuclear cells and tumor samples. Results: To date, 42 patients [median age 53 (39–78)] have been treated in 12 cohorts: IV VPA loading (mg/kg)/epirubicin (mg/m2): 15/75, 30/75, 45/75, 60/75, 75/75 and 75/100, oral loading: 75/100, 90/100, 100/100, 120/100, 140/100 and 160/100. Tumor types included: breast (10), melanoma (11), lung (6), sarcoma (2), GYN (2), GI (5) and others (6). Dose-limiting toxicities included somnolence (1) and neutropenia (1). No exacerbation of epirubicin-related toxicities was observed. Objective responses were seen across different tumor types in anthracycline-resistant and -refractory tumors, despite a median number of 3 (0–6) prior regimens: Partial response; 7/37 (19%), stable disease/minor response: 16/37 (43%). Patients received a median number of 4 (1–10) treatment cycles. Study treatment was stopped despite a clinical benefit or response in 4/33 patients after reaching maximal epirubicin doses (≤750 mg/m2). VPA peak and trough plasma concentrations increased linearly up to 120 mg/m2. MTD is being defined at 160/100 mg/kg/d VPA. H3 and H4 histone acetylation and topo II expression have been correlated with VPA dose, plasma concentration and response. Conclusion: A sequence-specific combination of VPA and epirubicin is active without exacerbation of epirubicin toxicity. VPA plasma peak and trough levels exceeding concentrations needed for biological effects and in vitro synergy are easily achievable with minimal toxicity. The noteworthy anti-tumor activity seen in this heavily pretreated Phase I population warrants further exploration.

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An open label phase I study of ABR-217620, a fusion protein of the 5T4 antibody moiety and an engineered superantigen, in patients with non-small cell lung, renal cell or pancreatic cancer
Authors: Cohen R. B. , Langer C. J. , Alpaugh R. K. , Dueland S. , Aamdal S. , Hawkins R. E. , Griffiths R. W. , Hedlund G. , Forsberg G. , Kilany S.
Published: March 2020

3083

Background: ABR-217620 (naptumomab estafenatox) is a recombinant fusion protein that consists of the 5T4Fab moiety genetically fused to the engineered superantigen variant SEA/E-120. This fusion protein is a new generation tumor-targeted superantigen based on the previously described ABR-214936 (anatumomab mafenatox). ABR-217620 was designed to reduce antigenicity and toxicity. The 5T4 antigen is expressed on more than 95 % of tumors from patients with non-small cell lung (NSCLC), renal cell (RCC) and pancreatic cancer (PC). In clinical PET studies 124I-labeled ABR-217620 has been shown to localize to 5T4 positive tumors. Methods: The compound was administered as a 5 min bolus infusion for 5 consecutive days. Patients with disease control at day 28 were offered a second cycle of therapy. Dose escalation has been performed using a Bayesian model starting at 0.5 μg/kg/day. The primary endpoint is determination of MTD. Secondary endpoints include characterization of side effects, immunological response, efficacy and pharmacokinetics. Results: 31 patients to date have been treated (19 NSCLC, 8 RCC, 4 PC). 3 patients have had dose limiting toxicities (fever, hypotension and nausea, grade 3) at doses between 23 and 28 μg/kg/day. The side effects were resolved quickly. Based on the experience from ABR-214936, these side effects were expected, but the MTD is ∼ 200 times higher. ABR-217620 leads to a dose dependent systemic increase of cytokines including IL-2 and IFN-γ after infusion. It also leads to an expansion of the superantigen reactive T cell population. 16/29 evaluable patients investigated had SD while 13 patients had PD. In contrast to ABR-214936, the first cycle of ABR-217620 treatment can be given without factoring in the titer of preformed anti-superantigen antibodies. Conclusions: ABR-217620 treatment had predicted and manageable side effects with fever, hypotension and nausea being dose limiting toxicities. Treatment with ABR-217620 resulted in a restricted systemic activation of the immune system. A large fraction of the patients have had stable disease.

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Assessment of response using FDG-PET and CT in a phase I study of AMN107 alone or in combination with imatinib (IM) in patients with imatinib-resistant (IM-R) gastrointestinal stromal tumors (GIST)
Authors: Van Den Abbeele A. D. , Barnes A. S. , De Vries D. J. , Yap J. T. , Reichardt P. , Casalli P. G. , Von Mehren M. , O’Neel J. , Hayes W. , Demetri G. D.
Published: March 2020

3087

Background: Although IM induces durable clinical benefit in pts with metastatic GIST, resistance to this single agent may emerge over time and new approaches are needed. AMN107 is a new agent rationally designed to inhibit in a structurally different manner the tyrosine kinase activities of KIT, PDGFR, and Bcr-Abl. Since AMN107 has demonstrated the ability to inhibit the proliferation of both IM-sensitive and IM-R GIST cells in vitro, a clinical trial was begun to test this agent with rapid assessment of impact using FDG-PET. Methods: Pts with IM-R GIST were treated with AMN107 alone (400 mg p.o. bid), or a combination of IM (400 mg p.o. bid) and inter-cohort dose escalations of AMN107 (200 mg qd, 400 mg qd, and 400 mg p.o. bid). FDG-PET and CT were performed at baseline and after 1 and 4 wks on therapy. Maximum standardized uptake values (SUVmax) were measured in 11 pts in up to 5 lesions with the greatest FDG uptake/pt (n=46 lesions). For each patient, the summation SUVmax (sSUVmax) of all lesions was calculated at each time point. Percentage change in SUVmax and sSUVmax was calculated at wks 1 and 4 compared to baseline. Metabolic response was assessed using EORTC thresholds for % SUVmax change (PR≤ -25% <SD< +25%≤ PD). The longest diameters of all lesions analyzed by PET were measured on corresponding CT images, summed at each time point, and the % change was calculated at wks 1 and 4 compared to baseline. CT response was assessed using conventional RECIST thresholds. Results: At 1 wk, PET imaging of 11 evaluable pts documented metabolic PR in 3/11, SD in 7/11, and PD in 1/11. After 4 wks on therapy, 2 pts whose PET was stable after 1 wk had converted to metabolic PR, and all other imaging results were unchanged. The CT response for all 11 pts was SD after 1 and 4 wks on therapy. Conclusions: These findings suggest that a metabolic response to AMN107, or the combination of AMN107 plus IM, is seen with FDG-PET while CT anatomic response remains SD at 1 and 4 wks.

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Phase II study of Sorafenib (BAY 43–9006) in hormone-refractory patients with prostate cancer: A study of the Central European Society for Anticancer Drug Research—EWIV (CESAR)
Authors: Steinbild S. , Mross K. , Morant D. , Köberle D. , Dittrich C. , Strumberg D. , Hochhaus A. , Hanauske A. , Burkholder I. , Scheulen M. E.
Published: March 2020

3094

Background: Sorafenib (BAY 43–9006) is a novel, orally active multi-kinase inhibitor with anti-angiogenic and anti-proliferative activity, blocking both Raf/MEK/ERK pathway and receptor tyrosine kinases VEGFR-2 and PDGFR. Activity of sorafenib in hormone-refractory progressive patients (pts) with prostate cancer (PC) was investigated in a Phase II clinical study. Methods: Pts received sorafenib 400 mg bid by continuous oral dosing. Pts with progressive disease during hormonal treatment and no prior chemotherapy therapy for advanced prostate cancer, and either one uni-dimensional measurable lesion according to RECIST-criteria or increasing PSA values reflecting a hormone-refractory situation, were eligible for study entry. Tumor PSA-based response was defined as: increase of PSA from baseline or lowest measured value by 100% = progressive disease (PD); decrease of PSA by >50% in two consecutive measurements = responder; PSA levels in between the two definitions above = stable disease (SD). Primary study objective was the proportion of patients with time to progression of ≥12 weeks (PP-TTP-12) using target lesions and PSA based response evaluation. At least 45 evaluable pts were required to detect an increase in PP-TTP-12 from 20 to 40% in a one stage design. Secondary endpoints were overall response and survival, and toxicity according to Common Toxicity Criteria (CTC v3.0). Results: A total of 55 pts with PC were enrolled between October 2004 and June 2005. The majority of pts (40/55, 72.7%) were treated for at least 6 weeks. Among the 42 pts evaluable for PP-TTP-12, 2 pts (4.8%) had a response and 15 pts (35.7 %) showed SD ≥12 weeks and 25 pts (59.5 %) showed PD. The one-sided binomial test of the null-hypthesis of PP-TTP-12 = 20% can be rejected at a significance level of 5% (p= 0.0019). All 55 pts were included in the evaluation of adverse events. Drug-related serious adverse events (diarrhea (1), constipation (1), fatigue (1), skin (1) cardiac (2) were seen in six patients. Conclusions: These results of a PSA-based evaluation indicate that sorafenib has some clinically useful activity in PC. Further investigations are necessary to evaluate the clinical benefit. Final results will be presented.

No significant financial relationships to disclose.
Direct cost-survival analysis of therapies for metastatic colorectal cancer
Authors: Wong Y. , Meropol N. J. , Sargent D. , Goldberg R. , Beck J. R.
Published: March 2020

3515

Background: Patients with metastatic colorectal cancer (mCRC) treated with 5Fluorouracil plus leucovorin (5FU/LV) have a median life expectancy (LE) of approximately12 months. The addition of irinotecan, oxaliplatin, bevacizumab and cetuximab has increased LE significantly. Although they have been widely adopted, little is known about the financial impact of these new drugs. Methods: Using published reports and aggregate data from NCCTG 9741, we developed a Markov Model which assumes forward progression through up to three lines of therapy compared to 5FU/LV alone. Patients who do not die of toxicity (tox) transition through supportive care prior to death. State changes are based on progression and dose-limiting toxicity. Drug costs are based on Average Sales Price. No other direct or indirect costs are included. Dose modifications for toxicity are defined as 80% of standard doses. Sensitivity analyses (SA) were performed on key variables. Results: LE, total drug costs, and cost-effectiveness (CE) ratios compared to single line-5FU/LV and FOLFOX for 9 commonly used treatement sequences are presented below. SA show that results are sensitive to progression rates,drug costs and length of time on supportive care. Changes in 1st line tox rates have a greater impact on final results than changes in 2nd or 3rd line therapy tox rates. Conclusions: Using drug costs alone, this model shows sequential combination therapy including all available agents to cost $2000-$2800K/week life gained ($100-$145K/year) compared to both 5FU/LV and FOLFOX. For clarity only 9 strategies are presented, but the model presented will contain multiple sequences consisting of 1–3 lines of therapy. Refined tox data, associated costs and quality of life adjustments are needed for realistic comparisons among specific combinations. Combination therapy may have CE ratios similar to other currently accepted intensive medical interventions. These data can help inform discussions of how the cost of care impacts patients, providers, and societies.

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Preliminary safety of bevacizumab with first-line Folfox, Capox, Folfiri and capecitabine for mCRC—First B.E.A.Trial
Authors: Berry S. R. , Cunningham D. , Michael M. , Dibartolomeo M. , Rivera F. , Kretzschmar A. , Mazier M. , Lutiger B. , Vancutsem E.
Published: March 2020

3534

Background: In a phase III pivotal trial in patients (pts) with metastatic colorectal cancer (mCRC), bevacizumab (BEV) increased overall survival by 30% when added to first-line IFL chemotherapy (CT). Safety data from controlled BEV trials have been described, and indicate that certain serious adverse events (SAE), primarily gastrointestinal (GI) perforations and arterial thromboembolic events (TE) occurred more often in pts who received CT with BEV than those who received CT alone. First BEAT was opened to evaluate safety events of BEV in a broader pt population using a variety of CT regimens. Methods: First BEAT started in June 2004 and aims to enrol up to 2000 mCRC pts in 41 countries. Eligible pts starting with first-line CT (physician’s choice) are treated until progression with BEV (5mg/kg q2w [5FU based CT] or 7.5mg/kg q3w [capecitabine based CT]). SAEs include deaths, new and prolonged hospitalizations, life-threatening as well as medically significant events and are reported within 24 hours. There BEV-relatedness is assessed by investigators. Results: By Dec 20, 2005, 1915 pts had been enrolled in 40 countries. 1603/1915 pts (male 58%; median age 59 years [29% were > 65 years]; PS 0–1 99%) had baseline data available for analyses. Median follow-up was 6.7 months (mean 7.3); 1509 pts had been followed-up for >60 days. The most common first-line CT regimens used with BEV were FOLFOX (28%), CAPOX (17%), FOLFIRI (25%) and capecitabine (8%). Among the 1603 pts that had started treatment with BEV, 638 SAEs were reported in 394 pts (25%). 60-day mortality was 2.4%. The most common SAE were diarrhoea 2.7% and pyrexia 2.2% and were usually not attributed as related to BEV. Related SAEs were reported in 132 (8%) pts. venous TE 1.7%, pulmonary embolism 1.1%, bleeding 1.0%, GI perforation 0.9%, arterial TE 0.8%, hypertension 0.5% wound healing complications 0.3% were usually classified as related SAEs. Conclusions: In this ongoing, large community-based study, the safety profile of BEV in first line mCRC pts receiving a variety of CT regimens, namely FOLFOX, CAPOX, FOLFIRI and capecitabine, appears consistent with that observed in large phase III randomised studies. Updated safety data, including grade 3/4 CTC toxicities, will be presented.

[Table: see text]
Bevacizumab improves outcomes of patients with metastatic colorectal cancer (mCRC) treated with IFL with or without bevacizumab (BV) independent of baseline risk
Authors: Kabbinavar F. , Zurlo A. , Irl C. , Hurwitz H.
Published: March 2020

3539

Background: It has been reported that patients with mCRC obtain benefit from BV independent of baseline risk factor status. Analysis of 3,825 patients treated with 5-FU/LV in 19 randomised trials conducted by Koehne et al. [Ann Oncol 2002;13:308–17] showed that four baseline prognostic variables can be used to categorise patients into three prognostic groups with different overall survival (OS). We have retrospectively applied this model to data from a phase III trial of first-line IFL with placebo or BV (AVF2107g). Methods: Data on ECOG performance status (PS), tumour site, alkaline phosphatase (AP) levels and white blood cell counts (WBC) were prospectively collected for the 813 patients randomised in AVF2107g. These data were retrospectively used to categorise patients in the IFL/placebo (n=411) and IFL/BV (n=401; data not available for 1 patient) arms into three risk groups: Low - ECOG PS 0/1, one tumour site; intermediate - ECOG PS 0/1, >1 tumour site, AP level <300U/L, or ECOG PS >1, low WBC count, one tumour site; high - ECOG PS 0/1, >1 tumour site, AP level >300U/L, or ECOG PS >1, high WBC count, >1 tumour site. Median OS and PFS in these groups were calculated. Results: OS (Table) and PFS were significantly longer in the IFL/BV groups compared to the IFL/placebo groups, as well as in the lower compared to the higher risk groups in both arms. Conclusions: The analysis supports previous analyses showing that adding BV to IFL improves OS independent of baseline patient risk. Furthermore, high-risk patients, who are less likely to benefit from IFL, benefit from IFL/BV. The model developed by Koehne et al may be applicable to regimens other than 5-FU/LV and validates the efficacy of BV first line in mCRC.

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Phase II study of FOLFOX, bevacizumab and erlotinib as initial therapy for patients with metastatic colorectal cancer (MCRC)
Authors: Meyerhardt J. A. , Stuart K. , Zhu A. , Fuchs C. , Bhargava P. , Earle C. , Blaszkowsky L. , Lawrence C. , Battu S. , Ryan D. P.
Published: March 2020

3545

Background: Cytotoxic chemotherapy with targeted therapy against the vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) has become a standard approach in MCRC, though combining VEGF and EGFR inhibition with chemotherapy as initial treatment is not well established. We conducted a phase II study of the combination of infusional 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX), bevacizumab, and erlotinib in chemotherapy naïve patients with MCRC. Methods: Eligible patients had measurable MCRC, no prior systemic therapy for MCRC or at least one year since completion of adjuvant therapy (only 5-FU and leucovorin acceptable), performance status 0–1. The regimen consisted of 14-day cycles of FOLFOX started on day 1 (oxaliplatin 85 mg/m2, bolus 5-FU 400 mg/m2, leucovorin 400 mg/m2 and 46-hour infusion 5-FU 2.4 g/m2), day 1 bevacizumab 5 mg/kg and erlotinib 150 mg daily. This isa single stage trial with goal of 35 patients. The primary endpoint was progression-free survival (PFS). Results: Between Jan and Dec 2005, 31 patients have been enrolled with the following characteristics: male/female, 19/12; PS ECOG 0/1, 15/16; median age 58, range 38–81. Of the 28 patients who completed at least 1 cycle, the most common grade 3/4 adverse events include: 8/28 (29%) diarrhea, 8/28 (29%) neutropenia, 5/28 (18%) rash, 4/28 (14%) fatigue, 3/28 (11%) nausea/vomiting, 3/28 (11%) neuropathy. 22/28 (78%) of patients had at least 1 grade 3/4 toxicity. 14/31 patients remain on trial, 13/31 (42%) came off for toxicity or withdrew consent due to treatment-related toxicities, 4 withdrew consent for other reasons. Efficacy data is not available at time of submission but will be more mature by June 2006. Conclusions: The combination of FOLFOX, bevacizumab and erlotinib appears to have moderate toxicity, with ∼40% of patients coming off trial due to side effects. Further characterization of the tolerability profile will be necessary when interpreting the efficacy of the combination. We expect full accrual as well as reasonable point estimates of PFS by June 2006. Supported by: Sanofi-Synthelabo, a member of the Sanofi-Aventis group, Genentech

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Neoadjuvant chemotherapy including bevacizumab in potentially curable metastatic colorectal cancer
Authors: Gruenberger B. , Scheithauer W. , Tamandl D. , Puhalla H. , Kornek G. , Zielinski C. , Gruenberger T.
Published: March 2020

3546

Background: the addition of targeting therapies to combination chemotherapy have dramatically improved outcome in metastatic colorectal cancer (mCRC). Special issues have been raised regarding the sequence of bevacizumab (bev) administration and surgery in mCRC. Methods: a pilot series of non-optimal resectable mCRC patients was initiated including a neoadjuvant protocol with bevacizumab 5mg/kg every two weeks plus XELOX (capecitabine 3500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1 of a 2-week cycle) for six cycles (3 months). The sixth cycle did not include bev resulting in a gap of 5 weeks between last bev and surgery. Additional 6 cycles were started 5 weeks after surgery. Primary end points were feasibility of the regimen, possibility of curative surgical approach and morbidity of the surgical procedure including liver resection. Results: we have enrolled 22 patients of whom 12 are evaluable for all primary endpoints today. Median age of the patients was 61.5 years (± 8.8), 83% had a lymph node positive primary, 67% had synchronous liver metastases (LM), 33% had bilobar LM. The neoadjuvant treatment regimen was safely administered resulting in 2 CR, 8 PR and 2 SD; XELOX was dose reduced to 75% due to HFS, diarrhoe or PNP ≥ 3 in 3 patients (25%). Potentially curative surgery was performed in all but one patient (92%) including liver resection in 11 patients, involving additional resection of the primary in 3 patients. No patient required perioperative blood transfusions, morbidity consisted of one bile leak from the resection edge and one wound infection. No patient experienced bleeding complications or showed postoperative liver dysfunction. Median postoperative hospital stay was 7 days (± 1.7). All patients started adjuvant treatment within 5 weeks. Liver regeneration as evaluated during staging CTs confirmed no abnormalities. Conclusions: these data suggest that bevacizumab can be administered prior and after potentially curative surgery including liver resection without appearing to adversely effect surgical wound healing, bleeding or liver regeneration. However we would like to emphasize that patients need to be treated by an experienced multidisciplinary team including a liver surgeon qualified in dealing with chemotherapy altered livers.

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Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing low (1–9%) or negative (<1%) levels of epidermal growth factor receptor (EGFr)
Authors: Hecht J. , Mitchell E. , Baranda J. , Malik I. , Richards D. , Navale L. , D’Avirro P. , Amado R.
Published: March 2020

3547

Background: Panitumumab is a fully human monoclonal antibody directed against EGFr. We investigated the antitumor activity of panitumumab in pts with mCRC who failed prior therapy and had low or negative EGFr tumor expression. Methods: In this multicenter, phase 2 study of 150 planned pts, pts had documentation of disease progression (PD) during or after adequate doses of fluoropyrimidine, irinotecan, and oxaliplatin (centrally confirmed refractory disease [CCRD]), 2–3 prior regimens, ECOG score 0–2, and low or negative EGFr staining (by IHC) in evaluable tumor cells. Pts received panitumumab at 6 mg/kg Q2W until PD or drug intolerability. Tumor assessments (modified WHO, blinded central review) were taken periodically from wk 8 until PD. Endpoints were objective response (OR) through wk 16 (+ ≥ 4 wk confirmation; primary) and OR throughout study, response duration, progression-free survival (PFS) time, survival time, and safety (secondary). Results: In this interim analysis (6/05), 88 pts were enrolled and had ≥ 1 dose of panitumumab (safety set); 23 pts had ≥ 20 wks before the cutoff and CCRD (efficacy set). The efficacy set consisted of 16M/7W, median age of 65 (range: 46, 85) yrs, 83% white, 100% with ECOG ≤ 1, 74% colon cancer and 26% rectal cancer; all received ≥ 2 prior regimens (equivalent characteristics for safety set). 2/11 (18%) pts with EGFr-negative tumors and 1/12 (8%) with low EGFr staining had a partial response. Duration was up to 16 wks. 7/23 (30%) of all pts had SD. Median (95% CI) PFS was 7.9 (7.0, 23.0) wks. In the safety set, all pts had a treatment-related adverse event; 19% grade (gr) 3; 2% gr 4. Integument and eye toxicities were: 92% skin, 17% eye, 28% nail, 8% hair, and 2% chelitis. 20 (23%) had diarrhea (1 gr 3); 7 (8%) had hypomagnesemia (2 gr 3/4). Three pts had an infusion reaction-1 gr 3 (led to panitumumab discontinuation) and 2 gr 1/2. In 65 pts with both a baseline and post-baseline sample, no human anti-human antibodies to panitumumab were detected. Updated data will be presented. Conclusions: Responses to panitumumab were seen in pts with mCRC with both low and negative EGFr levels. Efficacy appears similar to that in other studies with panitumumab in pts with higher EGFr tumor levels.

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Cetuximab plus irinotecan for metastatic colorectal cancer (mCRC): Safety analysis of 800 patients in a randomized phase III trial (EPIC)
Authors: Abubakr Y. , Eng C. , Wong L. , Pautret V. , Scheithauer W. , Maurel J. , Kroening H. , Lutz M. , Zubel A. , Sobrero A.
Published: March 2020

3556

Background: EPIC is a randomized phase III study comparing cetuximab plus irinotecan to irinotecan in second-line metastatic, EGFR-expressing mCRC patients (pts) (target N=1,300 pts). Following an independent Data Safety Monitoring Board (DSMB) review of 400 pts., the pooled safety data was presented at ASCO 2005 (#3580). The DSMB has recently reviewed safety data on the first 800 patients. Methods: Patients with EGFR-expressing mCRC who had failed first-line oxaliplatin in combination with a fluoropyrimidine and an ECOG performance status ≤ 2 were randomized to either Arm A (cetuximab 400 mg/m2 followed by 250 mg/ m2 weekly and irinotecan 350 mg/ m2 q 3 weeks) or to Arm B (irinotecan 350 mg/ m2 q 3 weeks). A pooled safety analysis is presented. Results: Eight hundred patients were randomized from May 2003 to March 2005 in Europe, Australia, Asia, and the US: 309 women and 491 men, with a median age of 61 years (range 21–90) and ECOG performance status (PS) of: 0= 53%, 1= 42%, 2= 5%. Seventeen pts received no study therapy and are excluded from the analysis. A total of 3,629 chemotherapy cycles were administered to the 783 pts with a median of 4 cycles per pt (range 1–23). Four (0.5%) subjects experienced severe infusion reactions: 2 grade 3 and 2 grade 4, none were fatal. In this pooled analysis, 59 deaths occurred within 30 days of last study therapy: 45 disease-related, 5 study drug related, 6 due to other causes, and 3 with unknown etiology. A summary table of adverse events (AE’s) is included. Conclusions: The DSMB raised no concerns after reviewing the safety data from 800 pts. In this pooled analysis characteristic toxicities of cetuximab and irinotecan do not appear to be increased, incidences and severities are similar to the earlier safety report based on the initial 400 patients. The study is currently nearing completion of accrual.

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cT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiation (CRT) is warranted
Authors: Guillem J. G. , Diaz-Gonzalez J. , Minsky B. , Rodriguez-Bigas M. , Jeong S. , Coco C. , Hernandez J. L. , Valentini V. , Riedel E. , Pucciarelli S.
Published: March 2020

3568

Background: Although CRT has emerged as the preferred treatment for T3 and/or lymph node (LN) positive rectal cancer, Sauer et al (NEJM 2004) demonstrated that 18% of patients deemed suitable for preop CRT via endorectal ultrasound (ERUS) were overstaged and therefore received unnecessary preoperative CRT. Since data also suggest that LN negative rectal cancer s/p TME may not need adjuvant therapy, it is reasonable to consider the omission of radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CRT ERUS/MRI staging in order to explore the validity of a non-radiation approach for cT3N0 disease. Methods: 188 ERUS/MRI staged T3N0 rectal cancer patients from 6 insitutions in the US, Europe and Asia received preoperative CRT (5-FU based and 45–52.5 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined. Results: Tumors were located a median of 5 centimeters from the anal verge. Sphincter-preserving surgery was performed in 135 (81%) patients. Overall pCR was 19%. Median number of LN sampled was 9 (range 0–38). Rate of positive LN was significantly associated with T-stage: pT0: 3%, pT1: 7%, pT2: 20%, pT3–4: 36%(p=0.001). 41 patients (22%) had pathologically positive mesorectal LN. There was no significant difference in rate of positive LN between those staged by ERUS and MRI(25% vs 16%, p=0.19). Conclusions: Accuracy of preoperative ERUS/MRI for identifying mid to distal T3N0 rectal cancer is limited, as 22% will have undetected mesorectal LN involvement despite CRT. Therefore, ERUS/MRI staged T3N0 patients should continue to receive preoperative CRT. Although 19% are overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CRT, which is associated with inferior local control, higher toxicity, and poor functional outcome.

No significant financial relationships to disclose.
Genome-wide expression profiling and tissue array analysis for prediction of recurrences in stage II-III colorectal cancer (CRC)
Authors: Boige V. , Svrcek M. , Michiels S. , Pocard M. , Laville V. , Drusch F. , Sabourin J. , Dessen P. , Ducreux M. , Lazar V.
Published: March 2020

3572

Background: Despite substantial progress in molecular pathogenesis of colon cancer (CC), no reliable biomarkers of outcome have yet been identified in patients with resected stage II-III CC. Methods: We analyzed genome-wide mRNA expression profiles in 20 stage II or III left side CC from 10 patient who developed metastasis (M+) and 10 disease free patients followed up for at least 4 years (M-) using high-density oligonucleotide microarrays (Agilent technology). RNA from tumor tissue (T) was hybridized against normal tissue (NT) from the same patient and each experiment was replicated 4 times (with 2 dye-swaps). The goal was to select genes both differentially expressed between T and NT and between M+ and M-. A tissu-array was constructed using 212 stage II and III resected CRC (164 CC, 64 rectal cancers) and their matched NT. For survival analysis, immunohistochemistry (IHC) data was dichotomized at the median value. Results: Analysis of microarray data yielded 27 genes that had a 2-fold difference between the expression in T and NT in at least 5 out of 20 patients and for which the average expression was significantly different between M+ and M- (p<0.01, t-test). Among the 6 most differentially expressed genes between M+ and M- in T, 4 of them were found to be involved in interferon γ pathway and could be evaluated by IHC: CXCL9, CXCL13, PPARγ, THSD. In order to assess macrophage and natural killer (NK) cell infiltration, CD68 and CD57 were also analyzed. Intensity was measured by semi-quantitative scores for the first 4 genes and by the number of infiltrating cells for the others. CXCL9, PPARGγ, CXCL13, CD57 and CD68 were significantly underexpressed in T as compared to NT (p<0.0001, paired t-test). The logrank test stratified by cancer site indicated that high IHC expression of CD57 possessed a significantly better recurrence-free survival (RFS) than those low expression (p=0.004). Multivariate Cox analysis identified tumor site (p=0.001), node stage (p<0.001) and CD57 (p=0.002) as independent predictors of RFS. Conclusions: NK cell infiltration within colorectal cancers is associated with prolonged recurrence-free survival in stage II and III CRC.

No significant financial relationships to disclose.
Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first line treatment in advanced or metastatic colorectal cancer (CRC)
Authors: Massuti B. , Gómez A. , Sastre J. , Tabernero J. M. , Chaves M. , Carrato A. , Abad A. , Aparicio J. , Díaz-Rubio E. , Aranda E.
Published: March 2020

3580

Background: OX plus CI 5-FU is one of the standard chemotherapy regimens for first-line treatment in patients (p) with advanced CRC. Phase II trials have shown XELOX as a convenient combination, with a high activity and a favourable safety profile. This study is a phase III trial comparing both schedules. Methods: Multicenter, randomized and open labeled study was designed to include p withadvanced/metastatic CRC adenocarcinoma, measurable disease, PS ≥70% and adequate bone marrow, renal and hepatic functions. Previous adjuvant chemotherapy was allowed. Primary endpoint is time to progression (TTP). The study was designed to determined non-inferiority when the median time to progression in the XELOX arm was not lower than 5.5 months (hazard ratio no larger than 1.27). A sample size of 348 p (174 per arm) was necessary (0.05 level test; 80% power). Treatment: P were randomly assigned to receive either Arm A: oral XEL 1000 mg/m2 twice daily from day 1 to day 15, plus OX 130 mg/m2, iv, 2h, day 1 (in 3-week treatment cycles) or Arm B: biweekly 85 mg/m2, OX, iv, 2h, plus weekly CI 5-FU 2250 mg/m2, in 48h (TTD schedule). Treatment was continued, until progressive disease, unacceptable toxicity or consent withdrawal. Results: 340 (170/170) p have been included in the interim analysis over 348 enrolled, (M/F, 61%/39%), median age: 65.6 years (32.3–81.6), PS 90–100%: 62%. Primary tumour sites were colon (66.4%), rectum (28.3%) and both (5.3%). Median relative dose intensity was 90% for XEL and 92% for OX in arm A and 78% for OX and 78% for 5-FU in arm B. Efficacy: overall response rate in each arm (A/B) was 37.1/43.0% (p=0.824). With a median follow up of 12.6 months, median TTP was 8.8/9.6 months (p=0.130). Main grade 3–4 toxicity per p in each arm (A/B) was: paresthesia (17.7/15.9%), asthenia (12.4/17.1%), diarrhea (14.1/23.6%), neutropenia (8.3/10.0%) and vomiting (4.1/7.6%). Mature data on TTP and OS will be presented at the meeting. Conclusions: Efficacy and safety results suggest a similar toxicity profile, response rate and TTP for both regimens.

No significant financial relationships to disclose.
A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)
Authors: Fakih M. G. , Pendyala L. , Toth K. , Creaven P. , Soehnlein N. , Litwin A. , Trump D.
Published: March 2020

3592

Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted.

No significant financial relationships to disclose.
Patupilone in chemotherapy-pretreated patients with advanced colorectal cancer (CRC) receiving nutritional support and intensive diarrhea management: A phase I multicenter trial
Authors: Casado E. , Tabernero J. , Melichar B. , Bridgewater J. , Bennouna J. , Delord J. , Sopala M. , Sklenar I. , Cheung W. , Johri A.
Published: March 2020

3593

Background: In previous clinical studies, a positive effect was noted in patients with CRC heavily pretreated with chemotherapy who received the novel microtubule stabilizer patupilone (EPO906; epothilone B) once-weekly or q3wk; however, susceptibility to diarrhea was high and response rates were modest. This dose-escalation trial examined the safety/efficacy of 3 patupilone regimens in chemotherapy-pretreated patients with CRC who received nutritional support and intensive diarrhea management. Methods: Patients with histologically confirmed CRC, without ileo- or colostomy or history of abdominal/pelvic irradiation, and who relapsed or were refractory after ≤4 prior chemotherapy regimens received nutritional support, intensive diarrhea management if needed, and patupilone as IV bolus q3wk or 1-or 5-day continuous IV (CIV) q3wk at doses of 6–10 mg/m2. Additional inclusion criteria: ≥1 measurable lesion; age ≥18 years; WHO performance status <2; no hepatic, renal, or hematologic impairment. Nutritional supplementation: ω-3 fatty acids, pre- and probiotics, antisecretory factor, and glutamine. Diarrhea management: appropriate clinical care, loperamide, opium tincture, codeine, and octreotide. Dose escalation was per protocol following a 3+3 design. The primary objective of this trial was to determine the maximum tolerated dose of the 3 patupilone treatment schedules in these patients. Results: Forty-four patients were enrolled: bolus, n = 22; 5-day CIV, n = 3; 1-day CIV, n = 19. Mean age 58.8 years; 95% Caucasian; 54% men. In the 5-day CIV arm, enrollment was closed at the 6.5-mg/m2 dose level since 2 dose-limiting toxicities (severe diarrhea) were reported. With bolus and 1-day CIV, the current doses are 10 and 9 mg/m2, respectively. The most common adverse events in the 43 patients evaluable for safety were diarrhea (70%), asthenia (23%), and nausea (21%). Grade 3 diarrhea occurred in 9 patients (21%). Overall response: 4 partial responses and 13 stable disease. Conclusions: Preliminary results suggest that patupilone monotherapy administered q3wk + intensive diarrhea management may prove beneficial in patients with CRC who progressed after 2–3 chemotherapy regimens.

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A randomized phase II non-comparative study of Ispinesib given weekly or every three weeks in metastatic colorectal cancer. A California Cancer Consortium Study (CCC-P)
Authors: El-Khoueiry A. B. , Iqbal S. , Singh D. A. , D’Andre S. , Ramanathan R. K. , Shibata S. , Yang D. Y. , Lenz H. J. , Synold T. , Gandara D. R.
Published: March 2020

3595

Background: Ispinesib(SB-715992) is a polycyclic, nitrogen-containing heterocycle that inhibits the mitotic kinesin spindle protein (KSP). KSP is essential for mitotic spindle assembly and function during mitosis, and is a rational target of anti-cancer therapy. This phase II study used two different dosing schedules; the primary objective was to determine the response rate (RR) and the secondary objectives were to determine time to tumor progression (TTP), progression free survival (PFS), overall survival (OS) and toxicity. Methods: Patients (pts) were randomized to receive (Arm A) ispinesib 7 mg/m2 every week for 3 weeks, every 28 days or (Arm B) 18 mg/m2 every 21 days. Response was assessed every 6 weeks. Chemotherapy was administered until disease progression or intolerance. Results: A total of 64 pts were accrued. The median number of cycles was 2 for both arms. Five pts had stable disease and 48 had progressive disease. PFS was 49 days in Arm A (44 to 51) and 37 days in Arm B (35 to 42 days). The most common grade 3/4 toxicities in arms A and B respectively included neutropenia (3 and 20), nausea and vomiting (3 and 1), neurologic (1 and 2). Of these, only 1 pt had febrile neutropenia and 1 pt had peripheral sensory neuropathy. The toxicity data is not available on 2 patients. Eleven pts are not evaluable for response yet. Conclusions: Ispinesib did not demonstrate significant activity in heavily pretreated patients with advanced/metastatic colorectal cancer at the dose and schedule employed in this trial. Correlative studies are in progress. Supported by NO1 CM17101

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No significant financial relationships to disclose.