tbuckley/cabot-search huggingface dataset:
Intrapatient dose escalation to 800 mg/m<sup>2</sup> pemetrexed is safe and feasible in patients with advanced non-small cell lung cancer (NSCLC) who have had prior chemotherapy
Authors: J. S. Lee, T. C. Hsia, C. H. Yang, D. S. Heo, G. C. Chang, K. Park, S. W. Kim, H. Yildirim, W. H. H. Reece, M. Lehnert
Journal: Journal of Clinical Oncology (2005)

7107 Background: Pemetrexed has proven clinical benefit in advanced NSCLC after prior chemotherapy. The aim of this open-label single-arm phase II study (H3E-AA-S037) is to determine the response rate, feasibility and safety of tailored dosing of pemetrexed in patients (pts) with previously treated advanced NSCLC. Methods: Major eligibility criteria included histologic or cytologic diagnosis of NSCLC; Stage IIIB or IV disease; one prior chemotherapy regimen for palliative therapy of locally advanced or metastatic disease; ECOG performance status 0 or 1; written informed consent. Pemetrexed was administered on day 1 of 21-day cycles. A dose of 500 mg/m2 was given in Cycle 1. The dose was increased to 800 mg/m2 in Cycle 2 if the pt had no hematologic or nonhematologic toxicity in Cycle 1 that exceeded predefined levels. Pts received folic acid, vitamin B12 and dexamethasone. Results: This interim safety analysis was planned to occur when 30 pts had completed at least one cycle of pemetrexed at 800 mg/m2. At this point 90 pts were enrolled (67 males, 23 females; mean age 59 yr, range 32–83; 98% had 1 prior chemotherapy regimen, 2% had 2 prior regimens). The pemetrexed dose was increased to 800 mg/m2 for Cycle 2 in 48/79 pts (61%), not adjusted for 13 pts (16%), reduced for 3 pts (4%), and 15 pts (19%) discontinued before Cycle 2. The remaining 11 pts were still on Cycle 1. 12 pts (15%) delayed Cycle 2 due to toxicity in Cycle 1. Pts have completed between 1 and 8 cycles (median, 2). Grade 3/4 toxicity has been reported for 36 pts (40%) and included neutropenia (2 pts, 2%), febrile neutropenia (1 pt, 1%), thrombocytopenia (2 pts, 2%), pneumonia (2 pts, 2%), infection (3 pts, 3%), dyspnea (8 pts, 9%), anemia (6 pts, 7%), diarrhea (2 pts, 2%), fatigue (2 pts, 2%), vomiting (1 pt, 1%) and rash (1 pt, 1%). There have been two deaths due to infections related to study drug toxicity. Conclusions: Following one cycle of pemetrexed at 500 mg/m2 the majority of pts were able to receive and tolerate an increased dose of 800 mg/m2 in Cycle 2, indicating that intrapatient tailoring of pemetrexed dosing in this patient population is feasible and safe. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly AstraZeneca, Eli Lilly Eli Lilly Eli Lilly Eli Lilly, Eli Lilly Korea, SK Pharma Korea
A phase Ib study of oxaliplatin in combination with fluorouracil (5FU) and leucovorin (LV) in pediatric patients (pts) with advanced solid tumors
Authors: L. Gore, J. Kuttesch, S. P. Hunger, C. Herzog, A. Narendaren, J. Boklan, N. K. Foreman, S. P. Ivy, N. Boucher, T. M. Trippett
Journal: Journal of Clinical Oncology (2007)

9548 Background: Platinums have significant activity in a wide variety of pediatric tumors, and oxaliplatin exhibits synergy with 5FU and LV in adults with colorectal cancer in FOLFOX regimens. The primary objectives of this study are to determine the maximum tolerated dose (MTD) of the modified FOLFOX6 regimen in pediatric tumors. Secondary objectives include safety, PK pharmacokinetic (PK) and PET scan efficacy analyses. Methods: Pts age &lt;21 years with advanced cancers and adequate organ function are eligible. Patients are stratified by tumor type (CNS or non-CNS) to better delineate the potential neurotoxicity in patients with altered neurologic function. Pts received oxaliplatin starting at 85 mg/m 2 and LV 400 mg/m 2 over 2 hours on day 1 followed by a 5FU bolus of 400 mg/m 2 then 2,400 mg/m 2 continuous infusion over 46 hours, every 2 weeks (3 courses = 1 cycle), with integrated PK sampling in a limited dose escalation design. Standard 3+3 dose escalation, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. The MTD is expanded to 15 patients to confirm and further characterize tolerability and toxicity. Results: To date, 15 very heavily pre-treated patients (7 M, 8 F) have received 25 cycles (range 1–4, median 2) of treatment at 2 dose levels. One of 8 pts at dose level 2 (oxaliplatin 100 mg/m 2 ) developed DLT (delay in repeat treatment &gt; 14 days due to grade 3 platelets). Treatment has been well tolerated. The most frequently reported related grade 3–4 adverse events (AEs) are reversible leukocytes (29%), neutropenia (43%), platelets (35%) and lymphopenia (21%). 31 of 90 courses (34%) have been delayed for neutropenia and thrombocytopenia. Anti-tumor activity to date includes a confirmed partial response lasting 15 weeks in a patient with osteosarcoma, and prolonged stable disease in 5 other pts with brain tumors (2), hepatoblastoma (2) and sarcoma (1). Conclusions: The modified FOLFOX6 regimen has significant but reversible myelosuppression in heavily pre-treated pediatric patients, but is tolerable and has promising activity in several tumor types. Cohort expansion continues at 100 mg/m 2 of oxaliplatin. PET scan and pharmacokinetic analyses will be presented. No significant financial relationships to disclose.
Advanced-stage anaplastic large-cell lymphoma in children and adolescents: Results of ANHL0131, a randomized phase III trial with standard APO (doxorubicin, prednisone, vincristine) versus consolidation with a regimen including vinblastine: A report from the Children's Oncology Group.
Authors: J. M. Kraveka, S. S. Weitzman, L. Smith, J. C. Lynch, M. Chang, M. Kinney, S. L. Perkins, J. H. Laver, T. G. Gross, H. J. Weinstein
Journal: Journal of Clinical Oncology (2010)

9511 Background: Anaplastic large cell lymphomas (ALCL) comprise 10-15% of childhood non-Hodgkin lymphomas. Children with advanced-stage (Murphy III and IV) ALCL have a 2-year survival in the range of 70-80%. Vinblastine (VBL) as a single agent has resulted in durable responses in children with relapsed ALCL. Methods: ANHL0131 examined whether a consolidation regimen adding VBL to the standard APO (doxorubicin, prednisone and vincristine) regimen would result in superior event-free survival (EFS). The study was open to Murphy stage III/IV with CD30+ ALCL under age 21. Induction was identical for both arms. Patients were randomized to either receive standard APO therapy with vincristine every 3 weeks during consolidation or a regimen substituting weekly VBL for vincristine (APV). Total length of therapy was 1 year. Stringent criteria were followed to monitor and reduce VBL if increased toxicity was observed. The initial starting dose was 6 mg/m2 and was subsequently reduced to 4 mg/m2. Results: 118 eligible patients were enrolled from January 2004 to November 2008. Analysis was performed using data through May 2009 with a median follow-up of 2.2 yrs (range 0 - 4.9 yrs). The 2 yr EFS for all patients was 79% (95% CI of 71-88%) and the 2 yr OS was 89% (95% CI of 83-95%). For those randomized to APO the 2 yr EFS was 80% (95% CI of 68-91%) and the 2 yr OS was 91% (95% CI of 83-99%). The 2 yr EFS was 79% (95% CI of 67-91%) and the 2 yr OS was 87% (95% CI of 77-97%) for APV (analysis included starting doses of 6, 5, and 4 mg/m2). There have been 8 deaths and 10 failures in the APO Arm and 7 deaths and 10 failures in APV. The APV arm was associated with more toxicity. For those who completed therapy, 29/32 (91%) receiving APV experienced grade 3 or higher neutropenia during consolidation, which was significantly higher than the rate on APO with 16/36 (44%) experiencing Grade 3 or higher neutropenia (p<0.0001). Conclusions: The addition of vinblastine following APO induction did not result in a statistically significant improvement in EFS or OS for children with advanced stage ALCL. No significant financial relationships to disclose.
A retrospective study on the relationship between normal tissue complication probability and computed tomography grading of radiation-induced lung injury for the patients with non-small cell lung cancer treated by three-dimensional conformal radiotherapy
Authors: J. Xing, J. B. Li, J. M. Yu, F. Shi, M. Xu, J. Lu, T. Y. Fan, S. F. Guo, S. Y. Tian, C. Q. Liang, Q. Shao
Journal: Journal of Clinical Oncology (2008)

7555 Background: To explore the relationship between computed tomography grading of radiation-induced lung injury and normal tissue complication probability (NTCP) in the patients with non-small cell lung cancer (NSCLC) treated by three-dimensional conformal radiotherapy (3D-CRT). And to find out the liminal value of NTCP for the evaluation of the treatment plan and the prediction of radiation-induced lung injury. Methods: 169 NSCLC patients treated by 3D-CRT and followed by CT scan for more than six months after 3D-CRT were selected, and all the patients were divided into five grades (grade 0∼4) based on the CT image appearance of radiation-induced lung injury. The NTCP values and the clinical pathologic characters were reviewed to analyzed. Results: Regardless of the whole lung or the ipsilateral lung, there was statistically significant difference of NTCP value in different CT grades, and the mean value of NTCP increased along with upgrade of CT grades. There were not statistically significant difference of the NTCP values of the contralateral lung for the patients in the different CT grades. On statistical analysis, the NTCP values of the whole lung or the ipsilateral lung correlated tightly with CT grading of radiation-induced lung injury and there was relatively strongest relationship between the NTCP of the ipsilateral lung and the CT grades (η=0.522). On statistical analysis, if the whole lung NTCP≥0.10, the positive predictive value of radiation-induced lung injury of the ipsilateral lung is 94.29%, the specificity is 96.61%. The positive rate of CT appearance was significantly higher in the chemoradiotherapy group than in the radiotherapy group (72.73% vs. 45.83%, P=0.001). In different subgroups of Conclusions: An association between NTCP value and CT grading of radiation-induced lung injury has been demonstrated in the literature. Therefore, the NTCP value can be selected as the reference for evaluation and optimization of the treatment planning to decrease development of radiation-induced lung injury after 3D-CRT for patients with NSCLC. No significant financial relationships to disclose.
A Randomized trial of long term dalteparin low molecular weight heparin (LMWH) versus oral anticoagulant (OA) therapy in cancer patients with venous thromboembolism (VTE).
Authors: MN Levine, Ay Lee, RI Baker, C Bowden, AK Kakkar, M Prins, F Rickles, JA Julian, S Haley, M Kovacs, M Gent
Journal: Blood (2002)
Performance of CCP assay in an updated series of biopsy samples obtained from commercial testing.
Authors: E. David Crawford, Neal Shore, Peter T. Scardino, John W. Davis, Jonathan D. Tward, Lowndes Harrison, Brent Evans, Lisa Fitzgerald, Steven Stone, Michael K. Brawer
Journal: Journal of Clinical Oncology (2015)

64 Background: The cell cycle progression (CCP) score is an RNA-based expression assay which has improved the prediction of prostate cancer aggressiveness in nine separate retrospective cohorts. In this analysis, we characterized the patient population and CCP score performance in commercial testing. Methods: Formalin-fixed prostate biopsy samples from 4,261 patients were submitted by 930 physicians to Myriad Genetic Laboratories for CCP test analysis. Patient clinicopathologic data was obtained from the test request form. The CCP score was calculated based on RNA expression of 31 cell cycle progression genes normalized to 15 housekeeping genes. Patients were sorted in to AUA risk categories and assigned a relative classification of cancer aggressiveness based on the CCP score. Results: Of the 4,261 samples that contained sufficient carcinoma (&gt;0.5mm linear extent), 4,218 (99.0%) provided quality RNA for analysis. The CCP score distribution ranged from -2.9 to 3.4. Correlation with Gleason score was r=0.35 and the correlation with PSA was r=0.16. Based on the CCP score, 36.8% of men had a less aggressive cancer and 21.2% of patients had a more aggressive cancer than expected based on clinicopathologic prediction. Conclusions: The CCP test can improve risk stratification for men with prostate adenocarcinoma independent of other clinicopathologic variables. Fifty-eight percent of men tested in the commercial assay were assigned to a different risk category than predicted by their clinicopathologic features.
Gemcitabine (GEM) and liposomal doxorubicin (PLD) in recurrent/metastatic breast carcinoma: A phase II study
Authors: V. Adamo, G. Ferrandina, M. Spada, F. Ferrau’, G. Condemi, L. Di Lullo, D. Lorusso, R. Rossello, C. Garipoli, G. Scambia
Journal: Journal of Clinical Oncology (2005)

790 Background: Aim of the study was to assess the efficacy and safety of the combination gemcitabine (GEM) and liposomal doxorubicin (PLD) in patients (pts) with measurable recurrence/metastasis from breast cancer (BC). Methods: A phase II study with a two-stage design was planned with an early stopping in case of <10 responses in 27 pts. If >9 responses were observed the accrual was increased up to 81 pts with the regimen considered active if at least 30 responses were observed among 81. This design provided a 80% chance of correctly classifying the treatment as inactive if the true probability of response was <30%, and a 95% probability of correctly classifying the treatment as active, if the true response rate was 45%. GEM 800 mg/m2 d1,8, and PLD 25 mg/m2 d1, q28, were administered until progression or unacceptable toxicity. Results: 28 pts were evaluated for safety and 23 pts for efficacy. Median age was 59 years (37–76), and ECOG Performance Status was 0/1/2 in 23/4/1 pts. Multiple visceral involvement was present in 23 pts (82.1%), and 2 pts (7.1%) had isolated liver metastases. Complete response was documented in 4 pts (17.4%), and partial response was observed in 6 pts (26.1%), with an overall response rate of 43.4. Median duration of response was 9 weeks (range=6–18). Stable disease was documented in 11 pts (47.8%), with a median duration of 12 weeks (range=9–21). Median progression free survival was 27 weeks. A total of 168 cycles with a median of 6 cycles (range=1–12) were analysed. Median cumulative GEM dose was 12,000 mg (range=1,200–28,600) and median cumulative PLD dose was 240 mg (range=40–440). Dose reduction and delay of treatment were required in 8.9% and 2.4% of cycles, respectively. Main toxicities were as follows: G3 anemia and G3 neutropenia occurred in 1.2% and 7.7% cycles, respectively. G3 thrombocytopenia occurred in 1.2% cycles, G3 PPE in only 1 case, and G3 mucositis in 2.9% cycles. Severe allergic reaction occurred in one patient, while severe pulmonary toxicity in 1 patient. G4 hepatotoxicity in 1 case. The combination GEM/PLD showed a favourable toxicity profile and promising activity in terms of overall response rate and stabilization of disease. The second step of patient enrolment is warranted. No significant financial relationships to disclose.
Identification of occult brain metastases amenable to stereotactic radiosurgery by motexafin gadolinium (MGd) based treatment planning MRI: Results of a phase II trial of MGd and whole brain radiotherapy (WBRT) with stereotactic radiosurgery (SRS)
Authors: M. P. Mehta, A. Dagnault, P. Chabot, J. Suh, E. Chang, M. Fortin, R. Timmerman, J. Grecula, L. Eubank, M. F. Renschler
Journal: Journal of Clinical Oncology (2007)

2037 Background: Motexafin gadolinium (MGd) is a novel anti-cancer agent that selectively localizes in tumors and is detectable by MRI. Previous studies of patients (pts) with brain metastases (BM) demonstrated the detection of occult lesions after MGd administration not visible with gadolinium MRI contrast. The purpose of this study was to evaluate if MRI scanning after MGd improves SRS treatment-planning and treatment outcome by identifying and better defining lesions that can be treated with the SRS boost. Methods: Pts with 1–4 BM (&lt; 4 cm diameter, or, if multiple, &lt; 3cm) received WBRT (37.5 Gy) and MGd, 5 mg/kg/day during weeks 2–3 of WBRT, plus MGd, 5 mg/kg prior to treatment planning MRI and prior to SRS (21 Gy for lesions = 2 cm, 18 Gy for lesions 2.1–3.0 cm, and 15 Gy for lesions 3.1–4.0 cm). MRI was obtained within 4 weeks prior to enrollment with standard contrast, and after WBRT for SRS treatment planning with MGd and standard contrast. Patients were followed for neurologic progression and survival. Results: 45 patients with either lung cancer (76%), breast cancer (11%), melanoma (7%), or other cancers (7%), a median age of 58 years (range 42–74), and a median of 2 BM (range 1–4) were evaluable. In 9 of 42 patients (21%) with MRI data available, the MGd-based treatment planning MRI demonstrated at least one occult lesion not visualized on the screening MRI. The MGd-based treatment planning MRI detected 1 occult lesion in 6 pts, 2 occult lesions in 1 patient, and 3 occult lesions in 2 patients. Median survival for evaluable pts is 10 months; median time to neurologic progression or radiologic progresssion is not reached at 15 months. Grade 3+ neurotoxicity was limited to 1 pt with tumor necrosis and 1 pt with motor weakness. Most common Grade 3+ adverse events were pneumonia (9%) and DVT (9%). Conclusions: MGd-based treatment planning MRI for SRS identified occult BM that are amenable to SRS and are undetected with standard gadolinium contrast agents in 21% of the pts enrolled in this phase II trial. Treatment with MGd, WBRT and SRS to all lesions visualized resulted in improved survival and local control compared with historical results. [Table: see text]
Performance characteristics of common immunologic biomarkers used in clinical trials
Authors: V. Goodell, B. Macleod, M. Slota, M. L. Disis
Journal: Journal of Clinical Oncology (2006)

620 Background: Standardization of cell-based immunologic monitoring is becoming increasingly important as methods for measuring cellular immunity become more complex. We assessed the ability of 2 cell-based assays widely used in immune monitoring, the ELISPOT assay and a modified limiting dilution assay based on titrated thymidine incorporation, to predict T cell responses to a HER-2/neu protein vaccine in breast cancer patients. We also assessed the ability of these assays to predict T cell response to tetanus toxoid and CMV, and analyzed the correlation between results from the ELISPOT and modified limiting dilution assays. Methods: 27 Stage II, II, and IV HER-2/neu positive breast cancer patients were vaccinated against the HER-2/neu protein and tt. PBMC were collected before and after vaccination. Samples were analyzed by mLDA and ELISPOT for T cell response to HER-2/neu (a low level response), response to tt (moderate level) and T cell response to CMV (high level). Results: Correlation analysis indicates that there is a strong, significant association between results from the ELISPOT assay and the mLDA for HER-2/neu specific T cell response (Rs=0.547, p=0.02). ROC curves plotted to assess the diagnostic performance of the mLDA and ELISPOT assay indicate that T cell proliferation measurements are a significant indicator of T cell response to the HER-2/neu vaccine (p=0.05), as well as responses to tt (p=0.01) and CMV (p=0.016), respectively. Precursor frequency, as measured by ELISPOT, is a significant indicator of high level T cell response to CMV (p=0.03), but not of a moderate tt response (p=0.09), or HER-2/neu (p=0.09) T cell responses. Conclusion: The mLDA achieves greater assay accuracy in measuring low level T cell responses to HER-2/neu and moderate responses to tt than the ELISPOT assay. No significant financial relationships to disclose.
A phase I dose-escalation study of 5-day intermittent oral lapatinib therapy with biomarker analysis in patients with HER-2–overexpressing breast cancer
Authors: A. J. Chien, G. Auerback, H. S. Rugo, M. Melisko, P. N. Munster, E. Khanafshar, K. G. Ordovas, E. F. Petricoin, K. M. Koch, M. M. Moasser
Journal: Journal of Clinical Oncology (2009)

e14530 Background: Although current HER2 targeting agents have made measurable impact on the treatment of HER2overexpressing breast cancer, their effects have been modest. Recent evidence has redefined the target of interest as the HER2-HER3 signaling dimer and identified inherent signal buffering capacity that protects it against partial inhibitors of HER2 function. In preclinical studies, HER2 catalytic function and HER2-HER3 signaling can be suppressed, but this requires higher fully inactivating doses of HER- family tyrosine kinase inhibitors (TKIs) leading to apoptotic tumor cell death. We hypothesize that TKIs may be much more clinically effective if used at much higher and fully inactivating doses. Such high dosing may only be tolerable if given intermittently rather than continuously. Methods: To test this hypothesis clinically, we conducted a phase 1 dose-escalation study of a 5-day course of lapatinib (Lp) in women with advanced HER2-overexpressing breast cancer. Lp was administered on days 1–5 of a 14 day cycle. Starting Lp dose was 1750 mg/day and was escalated in cohorts of 3 until the maximum tolerated dose (MTD) was defined. The first cycle of Lp therapy was bracketed by tumor fine needle aspirations and serologic studies, performed at baseline and on day 5. Functional signaling pathway biomarker analysis was performed on tumor lysates using Reverse Phase Protein Microarrays to assay the inactivation of HER2-HER3 signaling. Plasma Lp concentration was assayed at all dose levels and cardiac function was rigorously monitored. Tumor core biopsies were performed on a subset of patients at the MTD to determine tissue Lp levels. Results: 17 patients have been treated to date. No grade 4 or serious adverse events (AEs) attributable to Lp have been noted. 1 patient experienced dose-limiting toxicity at dose level 6 (7000 mg/day) consisting of grade 3 diarrhea despite maximal anti-diarrheal support. There have been no cardiac AEs. The most common AEs include grade 2 diarrhea, nausea, vomiting, acne. Conclusions: The MTD and systemic exposure of Lp can be considerably increased throsugh intermittent dosing. [Table: see text]