tbuckley/cabot-search huggingface dataset:
A phase I study of bevacizumab in combination with sunitinib in advanced solid tumors
Authors: M. M. Cooney, J. Garcia, J. Brell, R. Dreicer, K. Beatty, T. Mekhail, R. Bukowski, J. Zwiebel, S. C. Remick, B. I. Rini
Journal: Journal of Clinical Oncology (2007)

15532 Background: Bevacizumab is a humanized monoclonal antibody that binds to all biologically active isoforms of human vascular endothelial growth factor (VEGF). Sunitinib is a potent tyrosine kinase inhibitor of VEGFR-2, PDGFR, KIT, and FLT3. This phase I trial of bevacizumab and sunitinib was undertaken to determine the maximal tolerated dose (MTD), dose-limiting toxicity (DLT), and to evaluate for any tumor response for this novel combination. Methods: Patients (pts) with advanced solid tumors, ECOG performance status 0 or 1, and having adequate organ function were eligible. Patients received bevacizumab IV on days 1, 15, and 29 of a 42 day cycle. Sunitinib was given for 28 days with a 14 day rest. DLT was defined as any grade 4 toxicity, grade 3 cardiac event, hypertension not controlled to &lt; 160/90 mmHg with medication, or proteinuria &gt; 3.5 gm/24 hours. Results: Nine patients, 6 male and 3 female, with tumor types including renal carcinoma (2), bladder (2), pancreatic, testicular, melanoma, gastric, and neuroendocrine were enrolled. The median patient age was 55 years (range 37 to 83). Median number of prior systemic therapies was 2 (range 0 to 3). A total of 15 cycles have been administered (cycles range 1 to 4). Grade 1 or 2 toxicities that occurred with a &gt; 20% incidence included anorexia, bleeding, diarrhea, dyspnea, fatigue, fever, hypomagnesemia, nausea, pain, vomiting, and weight loss. Grade 3 toxicities included hypertension (3 pts), fatigue and hypokalemia (2 pts) and one episode each of hand-foot syndrome, and hypophosphatemia. At the dose level bevacizumab 3 mg/kg and sunitnib 25 mg/day no DLTs were observed. One patient experienced DLTs of grade 4 hypertension and headache at the dose level of bevacizumab 5 mg/kg and sunitinib 37.5 mg/day. This dose level has expanded to six patients and toxicity assessment is continuing. One patient with papillary renal carcinoma has an unconfirmed partial response and three patients have experienced stable disease. Conclusions: Enrollment and toxicity evaluations are ongoing. DLTs of headache and hypertension have occurred. This trial will determine the maximal tolerated dose of this novel anti-angiogenic combination for future renal cell carcinoma studies. Supported by the NCI/Clinical Therapeutic Evaluation Program Grant U01 CA62502. No significant financial relationships to disclose.
Phase II randomized trial on dose-escalated sorafenib (S) versus best supportive care (BSC) in patients with advanced hepatocellular carcinoma (HCC) with disease progression on prior S treatment.
Authors: T. Pressiani, L. Rimassa, C. Boni, R. Labianca, S. Fagiuoli, A. Ardizzoni, P. Foa, E. Cortesi, C. Porta, F. Artioli, L. Latini, C. Carnaghi, R. F. Lutman, G. Torzilli, M. Tommasini, R. Ceriani, G. Covini, L. Giordano, N. Locopo, A. Santoro
Journal: Journal of Clinical Oncology (2011)

4115 Background: S is the only targeted agent that has been shown to improve survival in advanced HCC. It is not known whether a rebound phenomenon occurs after discontinuation of treatment after radiological progression (PD), or if continuation of treatment beyond this endpoint further delays tumor progression. The present trial was proposed to address this question. Methods: This phase II randomized trial evaluated the feasibility and efficacy of increased-dose S (600 mg bid) after PD (RECIST criteria) on S 400 mg bid (standard dose). The primary aim was PFS from PD. Patients (pts) with histologically proven advanced HCC unsuitable for loco-regional therapies, Child-Pugh class A/B cirrhosis, were randomized 1:1 to increased-dose S + BSC vs BSC. Written informed consent was obtained from all pts. S was continued until disease progression or unacceptable toxicity. Results: From April 2007 to July 2008, 300 pts were prospectively treated with S 400 mg bid. At documented PD, 101 pts (34%) were randomized: 49 pts (48.5%) to increased-dose S (600 mg bid) + BSC and 52 pts (51.5%) to BSC. Baseline characteristics: male (83%), Child-Pugh status A (93%), no extra hepatic spread (58%). In the S arm 41/49 (84%) pts were evaluable for drug exposure: 19 pts (46%) required no dose reduction, 15 pts (37%) received 75-99% of the planned dose, 3 pts (7%) 50-74% and 4 pts (10%) less than 50%. The table shows efficacy results. Conclusions: Increased-dose S in HCC patients progressing on standard dose S is feasible. These promising results on PFS suggest that increased-dose S may be used as a control arm in phase II-III trials evaluating new drugs as second line therapy in HCC. S + BSC BSC Log-rank p value HR SvsBSC (95% CI) Median PFS (months) (range) 3.9 (0.3-40.5) 2.6 (0.5-18.6) 0.07 0.66 (0.41-1.04) 3-month PFS (%) 69 46 Median OS (months) (range) 6.1 (0.3-40.5) 6.0 (0.5-26.3) 0.14 0.73 (0.47-1.11) 1-year OS (%) 42 30 Median TTP (months) (range) 4.0 (0.6-40.5) 2.0 (1.2-16.3) 0.04 0.54 (0.30-0.97)
Resistance to methotrexate due to gene amplification in a patient with acute leukemia.
Authors: M D Carman, J H Schornagel, R S Rivest, S Srimatkandada, C S Portlock, T Duffy, J R Bertino
Journal: Journal of Clinical Oncology (1984)

A patient is described with acute myelocytic leukemia refractory to conventional therapy, who also became highly resistant to methotrexate (MTX) after repeated courses of this drug. Leukemia cells from this patient were found to contain an elevated level of dihydrofolate reductase (DHFR) activity, with no change in the affinity of the enzyme for MTX. A sensitive "dot blot" assay revealed a fourfold increase in the gene copy number of DHFR. Southern blot analysis with a human DHFR cDNA probe confirmed this increase in the gene copy number, and demonstrated a similar restriction pattern with Eco R1, Hind III, and Pst 1 as seen with a highly amplified human leukemia cell line, K562. Additional DHFR fragments were detected, not seen in the K562 blot, suggesting the presence of pseudogenes, or a result of gene rearrangements occurring as part of the amplification process. Resistance to MTX in this patient was therefore ascribed to gene amplification and overproduction of DHFR.
Platinum and taxane intraperitoneal chemotherapy after secondary cytoreductive surgery for recurrent ovarian carcinoma
Authors: L. G. Seamon, S. Seward, D. Richardson, J. M. Fowler, D. E. Cohn
Journal: Journal of Clinical Oncology (2007)

16043 Background: Intraperitoneal chemotherapy (IP) after primary optimal debulking for advanced stage epithelial ovarian carcinoma improves survival. The objective of this research is to describe our experience with IP taxane and platinum chemotherapy after optimal secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer. Methods: We retrospectively reviewed charts from January 2006 to January 2007 and identified approximately 30 patients who received IP chemotherapy for optimally debulked advanced ovarian carcinoma. Of these patients, 8 were treated at first recurrence with cytoreductive surgery followed by second-line IP chemotherapy with intravenous docetaxel (70 mg/m 2 ) and IP cisplatin (75–85 mg/m 2 ) on day 1 and IP paclitaxel (60 mg/m 2 ) on day 8, every 21 days. Results: The median disease free interval from completion of initial chemotherapy to recurrence was 19 months. All patients who underwent secondary cytoreductive surgery were considered optimally debulked (less than 1 cm residual disease), with 6 patients having no residual disease. One patient required rectal resection and another patient had ileocecal resection without a protective ostomy. All patients had insertion of an intraperitoneal venous access device for infusion of IP chemotherapy at the time of cytoreduction. While four patients have completed all 6 cycles of IP chemotherapy, one patient completed only 3 cycles due to catheter related toxicity requiring removal of the port (abdominal pain). This patient did not undergo concurrent bowel surgery. In addition, two patients have completed 3 cycles and two patients are currently scheduled to begin IP chemotherapy. Only two patients experienced grade 3 or 4 neutropenia. No other grade 3 or 4 toxicities were identified. A median of 5 cycles (range 2–5 cycles) was required to achieve a CA125 nadir. Complete clinical response was obtained in all patients at a median follow up of 9 months (range 4–10 months). Conclusions: In optimally debulked, platinum-sensitive patients following secondary cytoreductive surgery for recurrent ovarian cancer, intraperitoneal taxane and platinum chemotherapy is feasible with acceptable toxicity and provides another option for treatment. No significant financial relationships to disclose.
Risk of intracranial hemorrhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients
Authors: G. Srivastava, V. Rana, S. Taylor, M. Debnam, Y. Huang, L. Feng, D. Suki, D. Karp, D. Stewart, Y. Oh
Journal: Journal of Clinical Oncology (2007)

7671 Background: Brain metastases confer significant morbidity and a poorer survival in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-targeted antiangiogenic therapies (AAT) have demonstrated benefit for patients with metastatic NSCLC and are expected to directly inhibit the pathophysiology and morbidity of brain metastases, yet patients with brain metastases have been excluded from most clinical trials of AAT for fear of intracranial hemorrhage (ICH). This is a low suspected risk, but needs to be quantitated to plan clinical trials of AAT for NSCLC brain metastases. Methods: Data from MD Anderson Cancer Center Tumor Registry and electronic medical records from January 1998 to March 2006 was interrogated. 2143 patients with metastatic NSCLC registering from Jan 1998 to Sept 2005 were followed till March 2006. 776 patients with and 1367 patients without brain metastases were followed till death, date of ICH, or last date of study, whichever occurred first. Results: The incidence of ICH seemed to be higher in those with brain metastasis compared to those without. However, the rates of symptomatic ICH were not significantly different. All ICH patients with brain metastasis had received radiation therapy for them and were not anticoagulated. Most of the brain metastasis-associated ICH's were asymptomatic, detected during radiologic surveillance. The rates of symptomatic ICH, or cerebrovascular accidents were similar and not significantly different between the two groups. The following table depicts the rates of CVA and/or ICH in metastatic NSCLC patients. Conclusions: In metastatic NSCLC patients, the incidence of spontaneous ICH appeared to be higher in those with brain metastases compared to those without, but was very low in both groups nonetheless without a statistically significant difference. These data suggest minimal risk of clinically significant ICH for NSCLC brain metastasis patients and justifies for them clinical trials of AAT. No significant financial relationships to disclose. [Table: see text]
Detection of liver metastases in small-cell lung cancer: a comparison of peritoneoscopy with liver biopsy and ultrasonography with fine-needle aspiration.
Authors: S W Hansen, F Jensen, N T Pedersen, A G Pedersen, H H Hansen
Journal: Journal of Clinical Oncology (1987)

Liver evaluation of 131 patients with small-cell lung cancer (SCLC) was performed both by peritoneoscopy (PS) with liver biopsy and by ultrasonography (US) with fine-needle aspiration. A total of 33 patients (25%) had liver involvement, 82% detected by US and 76% detected by PS. The difference was due to 27 incomplete investigations by PS and two incomplete investigations by US. In 104 patients in whom both investigations were "successful," PS confirmed 86% and US confirmed 79% of the patients with liver metastases. In each of the investigations, 7% (PS) and 14% (US) of patients had false-negative conclusions as compared with histologic evidence obtained by the other method. US found six patients with extrahepatic intraabdominal disease, while PS found none. S-lactic dehydrogenase (s-LDH), SGOT, and s-alkaline phosphatase were found to be too unspecific to indicate liver metastases unless all three tests were normal or abnormal. It is recommended that US should be used as the initial procedure when staging patients with SCLC, and that PS can be considered complementary in patients with negative US.
Phase I study of combination chemotherapy with amrubicin and paclitaxel in relapsed small cell lung cancer
Authors: J. Tanaka, H. Yoshizawa, R. Ito, Y. Hayashi, H. Kuriyama, H. Tanaka, H. Kagamu, F. Gejyo
Journal: Journal of Clinical Oncology (2007)

18206 Background: Amrubicin (AMR) and paclitaxel (PTX) are promising agents for advanced non-small cell and small cell lung cancer (SC). However, the combination of these drugs for relapsed SC has never been reported. The aim of this study was to determine the maximum tolerated dose (MTD) of AMR and PTX, thus to investigate the recommended dose (RD) of this combination chemotherapy for relapsed SC patients. Methods: Relapsed SC patients after 1 or 2 regimens with age younger than 70 and good performance status (PS) were eligible. The treatment consisted of AMR (escalating from 30 to 40 mg/m 2 by 5 mg/m 2 increment) as a one- shot iv on days 1 through 3, and PTX (escalating from 70 to 90 mg/m 2 by 10 mg/m 2 increment) as a 60-minute infusion on days 4 and 11, repeated every 21 days. The dose-limiting toxicities (DLTs) were defined as grade 3/4 non-hematological toxicities, grade 4 thrombocytopenia, and grade 4 leukocytopenia / neutropenia for 4 days or more. Results: Nine relapsed SC patients were enrolled. All of them were sensitive-relapsed cases with mean age of 60.1 and PS of 0 - 1, and received one or more cycles of chemotherapy (mean: 2.7 cycles). Six patients were treated at level 1 (AMR 30mg/m 2 , PTX 70 mg/m 2 ) with two of them on DLT of grade 4 neutropenia for 4 days or more. Three patients were treated at level 2 (AMR 35 mg/m 2 , PTX 70 mg/m 2 ) with all of them on DLTs; grade 4 neutropenia for 4 days or more, grade 3 febrile neutropenia, and grade 3 pneumonia. Overall response rate was 63%. Conclusion: The MTD was identified to be level 2, and the RD for this regimen with AMR and PTX was considered to be 30 mg/m 2 and 70 mg/m 2 , respectively. Treatment was well tolerated and the preliminary activity observed warrants further investigation. A phase II study is currently under investigation for relapsed and refractory SC patients. No significant financial relationships to disclose.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of a small molecule inhibitor of Poly ADP-Ribose Polymerase (PARP), KU-0059436 (Ku) in patients (p) with advanced tumours
Authors: P. C. Fong, J. Spicer, S. Reade, A. Reid, L. Vidal, J. H. Schellens, A. Tutt, P. A. Harris, S. Kaye, J. S. De Bono
Journal: Journal of Clinical Oncology (2006)

3022 Background: PARP is a DNA strand break and base damage repair enzyme. Ku inhibits PARP-1 and 2 with a mean IC 50 of 2nM. Inhibition of PARP leads to defective DNA repair and induces selective cytotoxicity in cells with defective homologous recombination repair through, for example, loss of BRCA 1/2 function (Farmer et al, Nature 2005 Apr 14;434(7035):917–21). This is a first in man Phase I trial of Ku. PD studies included functional evaluation of PARP-1 activity in surrogate and tumor tissue. Methods: Ku was administered once a day for 14 of every 21 days to p with advanced solid tumors refractory to standard treatment. Cohorts of 3–6 p were treated, with a starting dose of 10 mg/day. The dose was doubled in the absence of drug related grade 2 CTC-AE toxicity. Drug related toxicity in cancer patients known to carry a BRCA mutation is being compared to toxicity in other patients. Results: To date 12 p (6 male; median age 55y, range 25–73) with solid tumours have received 25 courses (range 1–8), with 1 p being a known BRCA1 mutation carrier (dose level 40mg). Dose levels evaluated to date include 10, 20, 40, and 80mg per day. Minimal toxicity has been observed to date, with only intermittent grade 1 nausea being reported. PK data to date, up to 40mg per day, supports dose proportionality with a mean elimination half-life of 6.91 hours (Range: 5.3–9.5), a mean clearance of 4.1 L/h (Range: 1.3–9.4) and a mean volume of distribution of 39.8 L (Range: 16.3–86.9). PD studies indicate inhibition of PARP functional activity in peripheral blood mononuclear cells with increasing inhibition observed with increasing dose of Ku. Initial studies in tumor biopsies performed pre-treatment and on day 8 revealed PARP inhibition of &gt;50% at 40 mg/day. A p with metastatic soft tissue sarcoma and progressing disease pretreatment achieved stable disease for 24 weeks. Conclusions: Dose escalation continues with more BRCA carriers planned. PARP inhibition in both surrogate and tumor tissue is achievable with minimal toxicity in cancer patients, and has not resulted in any short term toxicity in a BRCA mutation carrier. [Table: see text]
Prognostic significance of (18) F-fluorodeoxyglucose positron emission tomography after treatment in patients with limited stage small cell lung cancer
Authors: J. Engel, A. A. Onitilo, J. Demos, B. Mukesh
Journal: Journal of Clinical Oncology (2008)

7591 Background: Small cell lung cancer (SCLC) represents 15%-25% of all lung cancers. Despite favorable response rates after initial treatment, SCLC is likely to recur and long term prognosis is dismal. The ability to accurately measure response to therapy is critical in order to determine which patients might benefit from further treatment and which patients might be spared additional treatment and the potential for additional treatment-related side effects. After treatment, functional imaging with (18) F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) alone or in combination with computerized tomography (CT) may help distinguish between necrotic or fibrous tissue and residual disease, and thus be a useful tool in guiding further treatment and prognosis. Methods: This study was a retrospective chart review of patients with SCLC treated between January 1, 1992, and July 31, 2007. Results: A total of 21 patients with limited stage SCLC were identified as having a PET scan after treatment. The median duration between the last chemotherapy to PET scan was 37 days (13 to 125 days). PET scan results were positive in 11 (52.4%) patients and negative in 10 (47.6%). Median follow-up for all patients was 36.8 months, ranging from 6.8 to 65.9 months. Median survival time for all patients was 19.2 months (95% confidence interval [CI], 10.2 to >65.8 months). The estimated median survival time for PET negative patients was higher than the PET positive patients (29.2 vs. 10.3 months, P = 0.09). Estimated median progression-free survival for all patients was 8.1 months (95% CI, 4.3 to 11.9 months). Only about 5% of patients with SCLC treated in this time period underwent post-treatment PET scans. Conclusions: From this study, we conclude that post-treatment PET/PET-CT scanning has prognostic significance and currently post-treatment PET scanning may be underutilized. No significant financial relationships to disclose.
Docetaxel and capecitabine for previously treated metastatic colorectal cancer
Authors: T. E. O’Brien, E. Newton, J. Trey, E. Crum
Journal: Journal of Clinical Oncology (2006)

13579 Background: Docetaxel (D) induces human colon cancer cell lines to upregulate thymidine phosphorylase, an enzyme which activates capecitabine (C) to its cytotoxic form. This provided rationale for adding low dose D to C in patients with colorectal cancer (CRC). Although this combination has been established in metastatic breast cancer, it has not been evaluated in CRC. Because of concerns of toxicity in a pretreated population, we performed a phase I trial in patients with previously treated CRC. Methods: Eligibility: At least 1 prior treatment for metastatic disease; ECOG PS 0–1; adequate organ function. Design: Phase I, dose escalation. D, IV, days 1 &amp; 8, and C, PO BID days 5–18, repeated q21days. Dose Level 1: D=15mg/m 2 , C=1000mg/m 2 ; Level 2: D= 15 mg/m 2 , C= 1100 mg/m 2 ; Level 3: D= 20 mg/m 2 , C= 1100 mg/m 2 ; Level 4: D=20mg/m 2 , C=1250mg/m 2 . Results: 13 patients have thus far been treated. 11 are evaluable for toxicity and 10 for response (1 at dose level 4 was taken off study due to non-compliance before completion of cycle 1; another died of progressive cancer before completing cycle 1 at dose level 4; another is evaluable for toxicity but not yet for response). 9 with colon, 4 with rectal primary sites. Median follow-up= 5 mo (1–19 mo). Med age= 59 (30–75); #prior regimens for met disease 1–2, all of which were 5-FU based. Toxicities No dose limiting toxicities (DLT) until Dose Level 4. Dose Level 1: 1/3 developed grade 2 diarrhea and hand-foot syndrome and delayed grade 3 hand-foot; Dose Level 2: 2/3 developed grade 2 toxicities (hand-foot in one and diarrhea in the other); Dose Level 3: 1/3 developed delayed grade 2 hand-foot; Dose Level 4: 1 patient with delayed grade 2 hand-foot and grade 1 eye tearing; another developed DLT (grade 4 stomatitis/dehydration). Response 6/10 patients progressed after 2 cycles; 2 pts had stable disease, one lasting 4.6 mo; 2 patients had a partial response, one of which lasted 9 mo. The latter case had refractory disease to FOLFOX 4 but a 78% reduction in her liver metastases to D+C. Conclusions: The combination of low dose docetaxel, used as chemosensitizing agent, with capecitabine in this pretreated group of patients with metastatic CRC appears to be well tolerated, with no DLTs seen until Dose Level 4, and has modest activity. MTD determination awaits further accrual. No significant financial relationships to disclose.