bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of q3W R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer
Authors: Rodon J. , Patnaik A. , Stein M. , Tolcher A. , Ng C. , Dias C. , Kurman M. , Greig G. , Kurzrock R. , Rubin E. 
Published: March 2020

3590 Background: Insulin-like growth factor receptor (IGF-1R) is a tyrosine kinase cell surface receptor overexpressed in cancer cells which mediates the mitogenic and anti-apoptotic actions of IGF, playing a key role in malignant transformation. The safety and pharmacokinetics of 3-weekly administration of R1507, a human monoclonal antibody selective for IGF-1R, were explored in this phase I dose escalation study in patients with advanced solid tumors or lymphomas. Materials and Methods: Multiple ascending doses of R1507 were administered as a 1 hour infusion every 3 weeks until the development of dose-limiting toxicity (DLT) or progressive disease. Inclusion criteria: ECOG PS 0–1, adequate hematologic, hepatic, and renal function, CD4 count >200/μl. Exclusion criteria: infection, immunosuppressive agents, diabetes mellitus, uncontrolled systemic disease, NYHA III/IV CHF. DLT defined as ≥ grade 2 hypersensitivity reaction; ≥ grade 3 non-hematologic toxicity; ≥ grade 2 cardiac toxicity; ≥ grade 3 hematologic toxicity = 7 days, or dose delay > 1 week due to toxicity. Blood samples were collected following 1st dose for non compartmental PK analysis and for future analysis of IGF-1R levels. Results: 21 patients (pts) (M:F 14:7) were enrolled in 1 of 4 dose levels (dose range 1–16 mg/kg). Mean pt age 57 yrs (range: 30–81), mean prior treatments 4.6 (range: 1–9). Mean treatment cycles 2.6 (range: 1- 6). Six pts remain on study. Adverse events (AE) included infection (6 pts), fatigue (4); rash, fever, arthralgia, cough, diarrhoea, abdominal and back pain (3 each). No DLT or serious AEs attributed to study drug were reported. Activity: 10 pts showed stable disease (median 33 days). PK: Clearance (CL) decreased from 812 mL/Day (Coefficient of Variation [CV] =19.9%) in the 1 mg/kg group to 418 mL/Day (CV=46.7%) in the 16 mg/kg group; Volume of distribution was in the range of 4.4 - 5.4 L (CV=10.9–34.8%). T1/2 increased from 4 to 9 days. Conclusions: Treatment with R1507 is tolerable at the dose of 16mg/kg q3W. Treatment-related toxicities are mild and clinically manageable. Decrease in CL across doses levels suggests a saturable elimination pathway. T1/2 value of ∼8 days supports a weekly dosing for future trials. [Table: see text]
Phase I and pharmacokinetic (PK) study of PTK787/ZK222584 (PTK/ZK) plus capecitabine (cape) in patients (Pts) with advanced cancer
Authors: Schilsky R. L. , Geary D. , Skoog L. , Desai A. , Valickas J. , Masson E. , Laurent D. , Pendowski C. , Vokes E. , Ratain M. 
Published: March 2020

3595 Background: PTK/ZK is a small molecule inhibitor of the vascular endothelial growth factor receptor family. Cape is a standard treatment for pts with breast and colon cancer, tumors for which angiogenesis inhibition is beneficial. Therefore, we conducted a phase I study of the combination to determine the maximally tolerated doses (MTD), toxicities and PK interactions. Methods: Eligible pts had advanced cancer with no standard treatment option, Karnofsky performance status (KPS) > 70, and normal organ function. Pts with bone marrow or CNS involvement or who had more than 4 prior chemotherapy regimens were excluded. A dose escalation (dosesc) phase was conducted to determine the MTD followed by a dose expansion (dosexp) phase to assess PK interactions. PTK/ZK was given as a single oral daily doser without interruption and cape was given orally twice daily for 14 of 21 days. Results to Date: 43 pts (30 male, 13 female), median age 61 y (34–78 y) and median KPS 95 (70–100) were enrolled in the dosesc phase. 37 had prior chemotherapy; 5 had radiation only. Diagnoses included colorectal cancer (10), head/neck (7), sarcoma (5), renal (4), stomach/pancreas (3 each) and others (11). 29/43 pts were evaluable for MTD determination and received a total of 145 cycles. Doses of PTK/ZK-cape (mg-mg/m2) were: 750/2,500; 1,000/2,500; 750/2,000; 1,000/2,000; 1,250/2,000. DLT occurred in 1/6 pts (gr 3 fatigue) at 750/2,500; 2/2 pts (≥gr 3 fatigue, hypertension [HTN]) at 1,000/2,500; 0/3 pts at 750/2,000; 2/12 pts (≥ gr 3 dizziness, HTN and seizure) at 1,000/2,000 and in 1/6 (gr 3 proteinuria) pts at 1,250/2,000. 1,250 mg was the highest PTK/ZK dose planned. Other common toxicities in the dosesc phase were hand-foot syndrome (HFS, 93%) and HTN (28%). In the dosexp phase 26 pts (14 M, 12 F) have thus far received 73 cycles at the MTD (1,250/2,000). Median age is 65 y (26–79 y) and median KPS is 80 (70–100). 28/73 cycles were delayed or interrupted for toxicity with gr ≥3 toxicities (# cycles): HFS (7), fatigue (5), increased LFTs (5), HTN (3), DVT/PE (4). 23 pts (17 in dosesc and 6 in dosexp) had response or stable disease longer than 12 weeks. Final results and PK data will be presented. Conclusion: PTK/ZK and cape can be combined without unexpected toxicities. No significant financial relationships to disclose.
Survival following recurrence in patients with adjuvant colon cancer: Findings from the 20,800-patient ACCENT dataset
Authors: O’Connell M. J. 
Published: March 2020

4009 Purpose: To examine 4 possible prognostic factors in patients (pts) with recurrent (rec) stage II and III colon cancer: time from randomization to rec (< 1 yr, 1–2 yrs 2–3 yrs 3–4 yrs, 4+ yrs), initial stage (II vs III), initial adjuvant treatment (adj rx) (5-FU based vs no rx control), and era pt entered onto study (1978–1985, 1986–1992, 1993–1999). Methods: The Adjuvant Colon Cancer Endpoints (ACCENT) dataset, including individual pt data from 18 trials and over 20,800 pts testing 5-FU based adj rx for pts with stage II and III colon cancer, was analyzed using univariate and multivariate Cox proportional hazards models, stratified by study. The QUASAR trial (Lancet, 2000) was excluded due to non protocol specified follow-up for rec. No data was available on rx subsequent to rec, or tumor characteristics at time of rec. Results: 5,713 of 17,381 (32.9%) of pts experienced rec. Median survival following rec was 13.4 months. Primary results from univariate models are shown in the table . Time from randomization to rec was highly prognostic of survival following rec (p<0.0001); this result was primarily driven by pts with initial stage III disease. Longer survival following rec was also seen in pts with initial stage II vs III disease (p<0.0001), with a 15% 6 year OS in initial stage II pts, pts entered more recently onto trials (p< 0.0001), and pts initially treated with surgery alone vs 5-FU adj rx (p=0.0005). All relationships were maintained in multivariate models. Conclusions: Time from initial rx and initial stage are important prognostic factors in pts with rec colon cancer. Survival following rec increased modestly from 1980–1995 possibly due to improvements in surgery, chemotherapy, supportive care, or unknown selection effects. Pts who rec following adj rx have poorer prognosis than those untreated, which may be a selection effect (only more aggressive tumors escape adj rx), or a sensitivity effect (those without adj rx retain sensitivity to 5-FU in the rec setting). [Table: see text] No significant financial relationships to disclose.
Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with metastatic colorectal cancer (MCRC)
Authors: Rothenberg M. L. , Navarro M. , Butts C. , Bang Y. , Cox J. V. , Goel R. , Gollins S. , Siu L. L. , Cunningham D. 
Published: March 2020

4031 Background: Capecitabine is an oral fluoropyrimidine that has demonstrated similar efficacy to 5-FU/LV in the 1st-line treatment of MCRC. Most patients now receive multi-agent chemotherapy and FOLFOX4 has become a popular regimen in this setting. We conducted a phase III study comparing XELOX with FOLFOX4 in patients who had received prior treatment with irinotecan in combination with bolus and/or infusional 5-FU/LV for MCRC. The primary endpoint of the study was time-to-tumor progression (TTP). With 610 patients, this study had 80% power to detect non-inferiority of the XELOX vs. FOLFOX, defined by a progression hazard ratio (HR) of <1.3. Methods: Patients were treated with XELOX (oxaliplatin 130mg/m2 i.v., capecitabine 1,000mg/m2 bid oral x 14 days, q3w) or FOLFOX4 (as described previously). Results: The study recruited 627 patients (the intent-to-treat - ITT - group). Baseline characteristics were well balanced. The primary objective of the study was met with a progression HR of 0.97 for the XELOX group (95% CI, 0.83–1.14). Median TTP was 4.8 months for XELOX- and 4.7 months for FOLFOX4-treated patients. Overall survival was also similar between the groups with a death HR of 1.03 for the XELOX group (95% CI, 0.87–1.23). Median survival was 11.9 months for XELOX- and 12.6 months for FOLFOX4-treated patients. Grade 3/4 toxicities occurred in 60.1% of XELOX- and 72.4% of FOLFOX4-treated patients. The most common treatment-related grade 3/4 adverse events (XELOX vs. FOLFOX4) were: diarrhea (20 vs. 5%), neutropenia (5 vs. 35%), fatigue (5 vs. 8%), paresthesia (9 vs. 8%), nausea/vomiting (6 vs. 5%). The rate of grade 3 hand-foot syndrome was 3.5% with XELOX and 0.6% with FOLFOX4. The 60-day all cause mortality was 3.9% in XELOX- and 4.2% in FOLFOX4-treated patients. Conclusions: These results demonstrate that second-line treatment with XELOX is non-inferior to FOLFOX4 in terms of PFS. Results for overall survival and response rates were also similar between the two groups. The safety profile was similar to previous studies, with no unexpected toxicities. Study supported by Hoffmann-La Roche. No significant financial relationships to disclose.
Phase I/II study of neoadjuvant bevacizumab with radiation therapy and 5-fluorouracil in patients with rectal cancer: initial results
Authors: Willett C. , Duda D. , Boucher Y. , di Tomaso E. , Clark J. , Blaszkowsky L. , Czito B. , Bendell J. , Jain R. 
Published: March 2020

4041 Background: A phase I/II study of neoadjuvant bevacizumab with 5-fluorouracil and radiation therapy in patients with locally advanced rectal cancer was undertaken to determine whether inhibition of VEGF is safe and has clinical benefits by enhancing chemo- radiation therapy. Methods: 22 patients with endoscopic ultrasound or surface coil MRI staged T3/T4 non-metastatic rectal cancer were enrolled from 2001–2006. All patients completed 4 cycles of neoadjuvant therapy including: 1) bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 2) peripheral venous infusion 5-FU (225 mg/m2/24 hours) administration each treatment week of cycles 2 - 4; 3) external beam irradiation delivery (50.4 Gy in 28 fractions over 5.5 weeks); and 4) surgery 7 to 9 weeks after completion of all neoadjuvant therapy. Correlative studies were undertaken before and during the trial. We collected serial tumor biopsies, PET-FDG scans, and analyzed blood and urine for potential biomarkers. Results: Mean pre-therapy tumor size was 4.7 cm (2–9 cm). Post-treatment surgical specimens usually had well-demarcated shallow ulcerations with a mean diameter of 2.4 cm (0.7–6 cm). In response to the neoadjuvant regimen, all patients had significantly (p<0.01) decreased FDG-uptake by PET. Histologic examination showed no residual primary cancer in 5 patients (ypT0). Of 17 patients with residual disease, microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 in 3 patients, ypT2 in 4 patients, ypT3 in 10 patients). Downstaging was seen in 12/22 tumors. 8 patients had microscopic nodal metastases. Bevacizumab alone and combined treatment were both associated with increased plasma VEGF and PlGF levels in 18/18 patients (P<0.01 at all 4 timepoints compared to baseline). Viable CECs were decreased by VEGF blockade at day 3 (P<0.01 compared to baseline), and peak CEC levels during treatment was correlated with histologic tumor response (2.77 [1.18–3.18] for T3 patients, n=9 versus 1.14 [0.82–1.53] for T0-T2 patients, n=12; p=0.05). Conclusions: Addition of bevacizumab at a dose of 5 mg/kg to standard chemo-radiation is safe in patients with locally advanced rectal cancer. Bevacizumab is active and the combined regimen yields promising results. [Table: see text]
Phase II study of preoperative chemoradiation (CRT) with cetuximab, irinotecan and capecitabine in patients with locally advanced resectable rectal cancer
Authors: Hong Y. S. , Kim D. Y. , Lee K. S. , Lim S. B. , Choi H. S. , Jeong S. Y. , Kim J. H. , Im S. A. , Kim T. W. , Jung K. H. 
Published: March 2020

4045 Background: Preoperative CRT with irinotecan and capecitabine is effective and safe in rectal cancer. Cetuximab, an EGFR- targeted agent, is synergistic with chemotherapy and radiotherapy. We conducted this study to determine efficacy and safety of cetuximab, irinotecan, and capecitabine as a combined preoperative CRT in patients with locally advanced resectable rectal cancer. Methods: This is a non-randomized, open-label, multicenter phase II study with cetuximab 400mg/m2 on D-6 (1 week before radiation) followed by cetuximab 250mg/m2 and irinotecan 40mg/m2 once a week (D1, 8, 15, 22, & 29) and capecitabine 1650mg/m2/day for weekdays only during radiation. Radiotherapy was given to a total dose of 50.4 Gy/28 fractions starting on D1. Main eligibility criteria were histologically proven rectal adenocarcinoma; T3–4 lesions; age 18 - 75 years; ECOG PS 0 - 2; no prior chemotherapy or EGFR targeted therapy. Total mesorectal excision was planned to be performed 4–8 weeks after completion of CRT. Results: Between May 2006 and Dec 2006, 40 patients were enrolled; median age 56.5 years (34 - 72); M/F 32/8; PS 0–1/2 38/2; cT3/T4 36/4; cN0/N+ 8/32; median tumor location from anal verge 5.5cm (0 - 8.0); moderately-differentiated adenocarcinoma 29. At present, 21 patients completed preoperative CRT and were evaluable for toxicity. Grade 3/4 toxicities included leucopenia (2, 9.5%), neutropenia (1, 4.8%), anemia (1, 4.8%) and diarrhea (1, 4.8%). Grade 2 hypersensitivity reactions and skin rashes were observed in 2 (9.5%) and 9 patients (42.9%), respectively and no grade >1 hand-foot syndrome was observed. Of 10 patients who underwent surgery (all R0 resection) till now, 9 were treated with sphincter saving procedure. Pathologic T0 and N0 were observed in 3 and 7 patients, respectively. Pathologic complete responses were observed in 2 patients and another 2 patients had only minimal microscopic residual tumor. Conclusions: Preoperative CRT with cetuximab, irinotecan and capecitabine showed promising preliminary pathologic responses with mild toxicity profiles. Study enrollment has now been completed and further results of efficacy and safety will be presented. No significant financial relationships to disclose.
A prospective randomized phase III trial of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with stage II colon cancer
Authors: Schippinger W. , Samonigg H. , Greil R. , Tschmelitsch J. , Steger G. , Jakesz R. , Gnant M. , Hofbauer F. , Rabl H. , Thaler J. 
Published: March 2020

4052 Background: Whereas several studies showed adjuvant chemotherapy to improve survival of patients with stage III colon cancer, survival benefit from adjuvant treatment in patients with stage II disease is a matter of controversy. Methods: Patients with curatively resected stage II colon cancer (T3–4, N0, M0) according to UICC were randomized to either adjuvant chemotherapy with 5-FU/LV (100 mg/m2 LV + 450 mg/m2 5-FU weekly, w 1–6, in 8 w cycles x 7) or surveillance only. Primary endpoint was overall survival (OS) with 636 patients originally planned to demonstrate a difference in OS of 10% with 85% power and alfa =0.05 in a final analysis 7 years after study initiation. After accrual of 535 patients between 11/1993 and 6/2003, recruitment was stopped ahead of schedule for low accrual rates. Results: 505 patients were eligible and evaluable for analyses. After a median follow-up of 96 months, 56 (21.8%) patients have died in the 5-FU/LV arm and 58 (23.4%) in the surveillance arm. There was no statistically significant difference in OS between the two treatment arms (HR 1.137, 95% CI 0.787–1.641, p=0.4947, chi square), thus the primary endpoint of the study was not met. Disease relapse was documented in 35 (13.6%) patients of the chemotherapy arm and in 48 (19.4%) patients of the control arm. The relative risk for disease relapse was higher for patients in the surveillance arm compared to patients in the 5-FU/LV arm, however, this difference was statistically not significant (HR 1.506, 95% CI 0.974–2.328, p=0.0657, chi square). Subgroup analysis including in the chemotherapy arm only patients who received at least one cycle of 5-FU/LV (n=250), showed a statistically significantly lower risk for relapse in patients treated with 5- FU/LV (HR 1.559, 95% CI 1.001–2.429, p=0.0477, chi square). Conclusions: Results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, adjuvant chemotherapy did not significantly improve DFS and OS. No significant financial relationships to disclose.
Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases
Authors: Miller G. , Biernacki P. , Kemeny N. , Gonen M. , Downey R. , Jarnagin W. R. , D’Angelica M. , Fong Y. , Blumgart L. H. , DeMatteo R. P. 
Published: March 2020

4059 Background: Surgical resection of isolated hepatic or pulmonary colorectal metastases prolongs survival in selected patients. However, the benefits of resection and appropriate selection criteria in patients who develop both hepatic and pulmonary metastases are ill-defined. Methods: Data were prospectively collected from 131 patients with colorectal cancer who underwent resection of both hepatic and pulmonary metastases over a 20-year period. Median follow-up was 6.6 years from the time of resection of the primary tumor. Patient, treatment, and outcome variables were analyzed using log-rank, Cox regression, and Kaplan-Meier methods. Results: The site of first metastasis was the liver in 65% of patients, lung in 11%, and both simultaneously in 24%. Multiple hepatic metastases were present in 51% of patients and multiple pulmonary metastases were found in 48%. Hepatic lobectomy or trisegmentectomy was required in 61% of patients while most lung metastases (80%) were treated with wedge excisions. Median survival from resection of the primary disease, first site of metastasis, and second site of metastasis was 6.9, 5.0, and 3.3 years, respectively. After resection of disease at the second site of metastasis, the 1, 3, 5, and 10 year disease-specific survival rates were 91, 55, 31 and 19%, respectively. An analysis of prognostic factors revealed that survival was significantly longer when the disease-free interval between the development of the first and second sites of metastases exceeded one year, in patients with a single liver metastasis, and in patients younger than 55 years. Conclusions: Surgical resection of both hepatic and pulmonary colorectal metastases is associated with prolonged survival in selected patients. Patients with a longer disease free interval between metastases and those with single liver lesions had the best outcomes. [Table: see text] No significant financial relationships to disclose.
Hepatic resection following rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy
Authors: Aloia T. , Levi F. , Wicherts D. A. , Haas de R. J. , Paule B. , Bralet M. , Bouchahda M. , Azoulay D. , Castaing D. , Adam R. 
Published: March 2020

4061 Background: The impact of cetuximab-containing chemotherapy on resectability of previously unresectable colorectal liver metastases (CLM) is unknown, especially in patients resistant to first-line chemotherapy. This study was performed to determine the cetuximab resectability rate, and to examine the outcomes of these heavily pretreated patients after hepatic resection. Methods: From February 2004 to April 2006, we evaluated 151 patients with unresectable CLM resistant to initial chemotherapy and subsequently treated with cetuximab-containing regimens. 133 patients (88%) were completely treated at our institution and 18 patients (12%) received systemic therapy elsewhere. Resectability rates, perioperative outcomes, survivals, and histopathological analysis of the tumoral and non- tumoral liver were assessed. Results: 27 patients were operated after a median of 6 cycles of cetuximab + irinotecan (20/27), oxaliplatin (4/27), or both (1/27). 18 of these patients (67%) had failed at least 2 lines of prior chemotherapy. 25 patients underwent hepatectomy, including 9 of 133 patients completely treated at our institution (resectability rate: 7%) and 16 of 18 referred patients. Postoperative mortality was 3.7% (1/27), with a complication rate of 50%. Complete tumor necrosis was observed in 2 patients (8%). Histopathological liver abnormalities were found in 9 patients (36%), without any specific lesion related to cetuximab. After a median follow-up of 16 months (range 6–39), all but one resected patients were alive, 10 of whom were disease-free. Conclusions: For CLM refractory to conventional chemotherapy, combination chemotherapy with cetuximab significantly increased resectability rates with no appreciable increase in operative mortality or liver injury. Longer follow-up is awaited to confirm the encouraging results of this new oncosurgical strategy. No significant financial relationships to disclose.