tbuckley/cabot-search huggingface dataset:
A phase I multicenter study of the combination of temozolomide and pazopanib in advanced pancreatic neuroendocrine tumors (PNET).
Authors: Aparna Kalyan, Sheetal Kircher, Crystal Shereen Denlinger, Jordan Berlin, Mary F Mulcahy, Steven J. Cohen, E. Gabriela Chiorean, Mark Zalupski, Al Bowen Benson, Halla Sayed Nimeiri
Journal: Journal of Clinical Oncology (2015)

TPS492 Background: Everolimus and sunitinib targeted therapy have proven efficacy in advanced PNET, with ORR 5-9% and PFS HR &lt; 0.5 compared to placebo.Additionally, a single arm phase II study showed promising activity with temozolomide and capecitabine combination with an ORR of 70%. Rationale:PNETs are distinguished by their vascularlity and up-regulation of VEGF factors. In the preclinical setting, the combination of temozolomide and sunitinib appears to act synergistically by altering the tumor microenvironment enhancing activity of temozolomide. Pazopanib has shown activity in a single arm phase II study in advanced PNETs with a 6-month PFS rate of 80% and ORR of 17%. There is sufficient preclinical and clinical evidence suggesting that the combination of an anti-angiogenic agent with temozolomide is more efficacious, hence, our rationale for the current study. Methods: Objectives: (1) Determine the MTD and toxicity profile of temozolomide + pazopanib. (2) Describe the PK profile of this combination. (3) Observe the ORR. Trial Design:Open label Phase I study to determine the MTD and safety profile employing a 3+3 dose-escalation model of the combination of temozolomide and pazopanib in patients with advanced PNET who have received between 1-4 prior therapies. Cohort 1: temozolomide at 150 mg/m 2 on Days 1-7 and 15-21, and pazopanib 400 mg orally once daily continuously throughout cycle of 28 days. Once MTD is determined, PK sampling will be performed in 6 additional patients enrolled at the MTD. To date, eleven patients have been enrolled in cohort 1 and cohort -1. Cohort -1 is currently accruing at the reduced dose level of temozolomide 100mg/m 2 and pazopanib 400mg daily for the duration of the cycle. The trial is funded to proceed to a single arm phase II with exploratory end points: (1) Correlation of MGMT expression by IHC to ORR and PFS (2) tumor blood flow (perfusion CT imaging) relationship with ORR. (This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline.) Clinical Trial information: NCT01465659. Clinical trial information: NCT01465659.
Treatment optimization by high-dose imatinib: Randomized comparison of imatinib 800 mg versus imatinib 400 mg ± IFN in newly diagnosed BCR-ABL positive chronic phase (CP) CML: The German CML-study IV.
Authors: R. Hehlmann, M. Lauseker, S. Jung-Munkwitz, J. E. Schubert, C. Haferlach, S. W. Krause, A. Gratwohl, J. Hasford, A. Hochhaus, S. Saussele
Journal: Journal of Clinical Oncology (2010)

6517 Background: Initial imatinib therapy has never been optimized. Methods: Therefore, in the CML Study IV imatinib 800 mg (IM 800) was compared with imatinib 400 mg ± IFN (IM 400, IM+IFN) in newly diagnosed, not pretreated CML for molecular and cytogenetic remissions at 12 months, overall (OS) and progression-free survival (PFS) and toxicity. Results: By April 30, 2009, 1015 CP patients have been randomized (326 for IM 400, 338 for IM 800, 351 for IM+IFN). The median daily doses were 646 (209-800) mg in the IM 800 and 400 (184-720) mg in the IM 400 ± IFN arms. The cumulative incidences (cum. inc.) of CCR and MMR with IM 400, IM 800 and IM+IFN are shown in the Table. MMR at 12 months was reached in more patients with IM 800 than with IM 400 (p<0.01) or IM+IFN (p<0.01). Optimal molecular response was reached with IM 800 after a median of 31.3 months vs. 42.5 with IM 400 and 47.5 with IM + IFN. Also CCR was reached faster with IM 800 (p<0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients, but not in high risk patients. Patients receiving more than 600 mg/day reached remissions faster than those receiving less (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). OS (92%) and PFS (88%) at 5 years showed no difference between treatment arms. With individual dose adjustments IM 800 was well tolerated. Grade III/IV AEs were rare and did not differ between treatment arms. Conclusions: These data show a significantly faster achievement of MMR and CCR with IM 800 as compared to IM 400 ± IFN. The data indicate that the optimal imatinib dose in CP may be higher than 400 mg/day. Longer observation is required to determine whether this faster achievement of MMR and CCR will translate into better OS or PFS. Time after start of treatment Cum. inc. CCR (%) MMR (%) IM400 n=273 Δ IM800 n=268 Δ IM+IFN n=304 IM400 n=279 Δ IM800 n=283 Δ IM+IFN n=309 6 mo 21.5 12.0 33.5 15.1 18.4 6.1 11.3 17.4 11.2 6.2 12 mo 49.8 13.4 63.2 13.7 49.5 31.1 24.7 55.8 22.8 33.0 18 mo 66.6 7.2 73.8 3.8 70.0 51.5 18.7 70.2 15.5 54.7 24 mo 74.5 8.5 83.0 6.6 76.4 64.2 13.3 77.5 14.7 62.8 Δ: Difference between IM 800 and IM 400 or IM 800 and IM+IFN, respectively. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Deutsche José-Carreras Leukämiestiftung, Deutsche Krebshilfe, Deutsches Kompetenznetz für Akute and Chronische Leukämien, Essex Pharma, European LeukemiaNet, Novartis, Roche, Grenzach-Wyhlen, Germany
Mutant P53 vaccination of patients with advanced cancers generates specific immunological responses
Authors: R. A. Ibrahim, M. S. Achtar, V. E. Herrin, B. Gause, S. A. Bernstein, T. B. Brent-Steel, C. M. Maruffi, J. A. Berzofsky, S. N. Khleif
Journal: Journal of Clinical Oncology (2004)

2521 Background: Mutations of the p53 tumor suppressor gene are the most common genetic abnormality implicated in development and progression of various tumors. These mutations produce unique proteins that are processed and displayed as short peptides through HLA molecules on the tumor cell surface. Previously, we have demonstrated that animal vaccination with the mutated P53 peptide can generate specific cytotoxic T lymphocytes that lyse tumor cells expressing mutant p53. Therefore, mutant p53 peptides can be a widely applicable cancer therapy. Methods: Twenty-four patients with advanced malignancies (10 colorectal, 9 ovarian, 2 SCLC, and 3 other) expressing mutant p53 were vaccinated with the specific mutant P53. Autologous Peripheral blood mononuclear cells (PBMCs) were cultured for 48hours in the presence of the peptide and granulocyte-macrophage colony-stimulating factor and then administered to the patients IV. During the second and subsequent cycles, autologous PBMCs were cultures with the mutant peptide and IL-2 for 1 week and then administered IV on day 15 and six mIU/m2/day of subcutaneous interleukin-2 (IL-2) on days 15–19 and 22–26. Phenotype analysis of the vaccine product was done using a flow cytometer (FACS). Results: The overall progression-free survival (PFS) and post-vaccination survival (PVS) were longer than expected at 12.5 and 27.2 months, respectively. Twenty patients out of the twenty four were immunologically evaluated. Elispot assay was the main test used to monitor the immunological response in those patients. Nine patients (45%) showed a statistically significant increase in the level of IFN-γ producing specific T-cells after vaccination with the mutant P53. The difference in the level of IFN-γ producing cells between pre and post vaccination was only significant when the cells were challenged with the mutant P53 and not with the irrelevant peptide. Conclusions: Despite the advanced disease and the poor immunological status of the patients, favorable clinical and immunological responses were detected. We believe that this approach may form a promising treatment modality for a wide variety of cancers in the future. No significant financial relationships to disclose.
Combined chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 for malignant ascites due to advanced gastric cancer with peritoneal dissemination
Authors: J. Kitayama, H. Ishigami, S. Kaisaki, A. Hidemura, M. Kato, H. Nagawa
Journal: Journal of Clinical Oncology (2009)

e15524 Background: Malignant ascites caused by peritoneal metastasis the most life-threatening mode of metastasis and recurrence and seriously impair the quality of life in patients with gastric cancer. However, none of the treatment protocols have proved satisfactory clinical outcome. Methods: Twenty one patients with malignant ascites due to the peritoneal dissemination of gastric cancer were enrolled. Intraperitoneal catheter with infusing port was placed subcutaneously in all patients, and Paclitaxel was administered intraperitoneally at 20 mg/m 2 , together with intravenously at 50 mg/m 2 , on days 1 and 8. S-1 was administered at 80 mg/m 2 /day for 14 consecutive days, followed by 7 days rest. The change of the ascetic volume was prospectively investigated as the primary endopoint of the response rate. The volume of malignant ascites was objectively measured with the calculation of the consecutive computed tomography (CT) images using NIH image J software. Peritoneal cytology and mRNA of CEA in acitic fluid were also evaluated in 17 and 16 cases, respectively. Results: The volume of malignant ascites before the treatment was more than 500ml in 8 patients and less than 300ml in 13 patients. The average course of the treatment was 9 (2–19). The ascetic volume was markedly (more than 33%) reduced in 8 patients and totally disappeared in 5 cases with CT image, and thus the response rate was 62%. Malignant cells in peritoneal cytology disappeared in 13 cases while CEA mRNA became negative only in 2 cases. The one year overall survival was 71% in all patients and 85% in patients with reduced ascites. Conclusions: Combined chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 was a useful protocol for malignant ascites caused by peritoneal dissemination of gastric cancer. No significant financial relationships to disclose.
Activity of new agents (NAs) as third-line treatment in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) showing a primary resistance (PRes) to NAs-based second line therapy after docetaxel (DOC): Preliminary results from a multicenter Italian study.
Authors: Orazio Caffo, Ugo De Giorgi, Gaetano Facchini, Lucia Fratino, Donatello Gasparro, Umberto Basso, Daniele Alesini, Marcello Tucci, Cinzia Ortega, Francesco Verderame, Giuseppe Procopio, Giovanni Lo Re, Enrico Campadelli, Claudia Omarini, Maddalena Donini, Franco Morelli, Paolo A. Zucali, Donata Sartori, Vincenza Conteduca, Enzo Galligioni
Journal: Journal of Clinical Oncology (2015)

216 Background: The androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, abiraterone acetate (AA), cabazitaxel (CAB), and enzalutamide (ENZ). It is postulated that some mechanisms of resistance may be common to all NAs. This may be crucial in planning their sequential use, mainly when a PRes to one of them is observed. The present study assessed the activity of NAs in pts who previously experienced a PRes to another NA administered after DOC. Methods: We collected data of pts who received sequentially two NAs after DOC in 32 Italian hospital. For each pt we recorded the clinical outcomes of all treatments received after DOC. For the study purpose, we consider with PRes all pts progressing within 3 months after second line NA start. All other pts were considered as without PRes. Results: A consecutive series of 271 mCRPC pts, median age 71 yrs (46-91), with bone (89%), nodal (56%) or visceral (19%) mets, was collected. All pts received NAs as second line after DOC (AA 54% – CAB 34%– ENZ 12%) and 54 (20%) showed a PRes. Among these, third line treatment [AA (31%), CAB (42%), and ENZ (27%)], produced a biochemical and an objective response rate of 11% in both cases, with a median progression free survival (PFS) and a median overall survival (OS) of 4 mos and 8 mos, respectively. No statistically significant differences were observed in terms of clinical outcomes on the basis of NA sequences (see Table). Conclusions: It appears from this preliminary data, that the activity of NAs in pts showing a PRes to second line NAs is very limited, regardless the NA is administered. [Table: see text]
Prevalence of BRCA2 mutations and other clinical characteristics in women with triple-negative breast cancer.
Authors: Jennifer Chun, Freya Ruth Schnabel, Shira Schwartz, Jessica Billig, Karen Hiotis, Amber Guth, Deborah M. Axelrod
Journal: Journal of Clinical Oncology (2014)

160 Background: Triple-negative breast cancers (TNBC) represent 10%–20% of invasive breast cancers. Current guidelines recommend genetic testing for women who are diagnosed with TNBC. Studies have shown that BRCA1 mutations are associated with TNBC, but there is little information on the relationship of BRCA2 mutations and TNBC. The purpose of this study was to look at the clinical characteristics of TNBC compared to non-TNBC in a cohort of women with newly diagnosed breast cancer. Methods: The Breast Cancer Database at our institution was queried for patients with invasive breast cancer. We included the following variables: age, race, BRCA1,2, tumor characteristics, and personal history of breast cancer (PHBC). Statistical analyses included Pearson’s Chi-Square and Fisher’s Exact Tests. Results: Out of a total of 1,332 women, 125 (9%) had TNBC. The median age for both TNBC and non-TNBC was 59 years. Majority of women had early stage breast cancer (92%) with ductal carcinoma (80%). There was a significantly higher proportion of Blacks and Asians with TNBC (p &lt; 0.0001). Women with TNBC had higher Ki-67 (p &lt; 0.0001). Within the TNBC group, there were 12 (29%) patients who tested positive for BRCA1,2 mutation and 23 (8%) who tested positive for BRCA 1,2 mutations in the non-TNBC group. Interestingly, BRCA1 was not associated with TNBC (p = 0.40) and BRCA2 was significantly associated with TNBC (p &lt; 0.0001). We also found a higher proportion of TNBC in women who had a PHBC (p = 0.01). Conclusions: In our study, women with TNBC were similar in age to women who did not have TNBC. We found that the women with TNBC in our cohort had elevated rates of BRCA2 mutations. We also found that women with a personal history of breast cancer were at risk for developing TNBC. This may be related to the use of hormonal therapy that reduces the risk of ER/PR-positive tumors. Women of all ages are at risk for developing TNBC and older age at TNBC should not deter from genetic testing.
Results of the ESOPE (European Standard Operating Procedures on Electrochemotherapy) study: Efficient, highly tolerable and simple palliative treatment of cutaneous and subcutaneous metastases from cancers of any histology
Authors: J. Gehl, G. Sersa, J. Garbay, D. Soden, Z. Rudolf, M. Marty, G. O’Sullivan, P. F. Geertsen, L. M. Mir
Journal: Journal of Clinical Oncology (2006)

8047 Background: By applying brief, electric pulses, cell membranes can be transiently permeabilised (electroporation). This can be applied focally to tumors, enhancing the uptake of certain chemotherapeutic agents dramatically (electrochemotherapy). Methods: From 2003 to 2005, patients with cancer of any histological diagnosis and symptomatic metastases to skin or subcutis were accrued in four cancer centers. Patients had been offered standard treatment options previously. Primary endpoint was response. One treatment was performed in either general anesthesia or local anesthesia, depending on anatomical site, size and number of tumors. The Cliniporator (IGEA, Italy) was used to deliver electric pulses, with 3 different electrode types: 1) Plate electrodes, 2) Linear array needle electrodes 3) Hexagonal needle electrodes. Eight pulses of 100 μs were applied using 1) 1300 V/cm, 2 and 3) 1000 V/cm. Either intravenous bleomycin 15000 IU/M-2, or intratumoral injections of either bleomycin or cisplatinum, were administered prior to application of electric pulses to the tumors. Responses were documented through direct tumor measurement and digital photography. Results: 41 patients, with altogether 171 cutaneous metastases of malignant melanoma (98 nodules, 57 %), carcinoma or sarcoma were treated. Overall, 145 (84.8%) of the treated nodules responded (CR or PR), with CR in 126 of the nodules (73.7%). Negative response was observed in very low percentage of the treated nodules being either NC (10.5%) or PD (4.7%). Treatment of melanoma and non-melanoma nodules was equally successful. Treatment time per session (one or more nodules) was median 25 min (range 6–60). Intravenous and intratumoral administration of bleomycin, or cisplatinum yielded similar results. No significant toxicity was found, and 96% of patients reported they would agree to another treatment if indicated. Conclusions: Electrochemotherapy is an efficient, safe and simple palliative treatment of cutaneous and subcutaneous metastases of cancers of various histologies. Patient acceptance of treatment was excellent and 73.7% of nodules were in CR after one single treatment. No significant financial relationships to disclose.
Abstract 14419: Natural History of Atherothrombotic Events According to the Primary Diseased Vascular Bed - Insights from the TRA2P-TIMI 50 Trial
Authors: Benjamin M Scirica, Marc P Bonaca, Eugene Braunwald, Curt H Diehm, Graeme J Hankey, David J Moliterno, Sabina A Murphy, David A Morrow
Journal: Circulation (2012)

Background: In clinical practice and research, patients with coronary, cerebral, or peripheral vascular disease are commonly grouped together with respect to their overall CV risk and potential tre...
Phase IIb double-blind, randomized, placebo-controlled trials for the efficacy and safety of sorafenib in patients (pts) with metastatic or locally advanced breast cancer (BC): Review of the Trials to Investigate the Effects of Sorafenib in BC (TIES) program
Authors: J. Baselga, L. Gianni, W. J. Gradishar, C. Hudis, E. A. Perez, M. Piccart-Gebhart, L. S. Schwartzberg, G. Sledge, T. R. Fleming
Journal: Journal of Clinical Oncology (2009)

e12000 Sorafenib is a potent multikinase inhibitor approved by the FDA and EMEA for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. As a single agent, sorafenib has been shown to have activity in pts with BC. Here, we review the TIES program, a compilation of currently ongoing investigator-sponsored phase IIb multinational, randomized, double-blind, placebo-controlled studies that aim to determine the optimal sequencing of pharmacologic agents for the treatment of BC. All studies will combine sorafenib with first- and/or second-line chemotherapy and/or hormonal therapy in pts with HER2-negative metastatic or locally advanced BC, enroll 220 pts, stratify pts by visceral vs nonvisceral disease, allow pts with evaluable and measurable disease, and include pts with treated brain metastases. The primary endpoint of all trials will be progression-free survival. Secondary endpoints will be safety, overall survival, objective response rate, duration of response, and time to progression. Some studies will also assess quality of life, pharmacokinetic sampling, and biomarkers. Additional information on four of the trials is shown below (Table). Patient characteristics and accruals will be reported. [Table: see text] No significant financial relationships to disclose.
Long-Term Risk of Second Malignancy in Survivors of Hodgkin’s Disease Treated During Adolescence or Young Adulthood
Authors: Flora E. van Leeuwen, Willem J. Klokman, Mars B. van’t Veer, Anton Hagenbeek, Augustinus D. G. Krol, Ursula A. O. Vetter, Michael Schaapveld, Peter van Heerde, J. Marion V. Burgers, Reinier Somers, Berthe M. P. Aleman
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To quantify the long-term risk of second primary cancers (SCs) in patients diagnosed with Hodgkin’s disease (HD) during adolescence or young adulthood. PATIENTS AND METHODS: The risk of SCs was assessed in 1,253 patients diagnosed with HD before the age of 40 years and treated in two Dutch cancer centers between 1966 and 1986. The median follow-up duration was 14.1 years. RESULTS: In all, 137 patients developed SCs, compared with 19.4 cases expected on the basis of incidence rates in the general population (relative risk [RR] = 7.0; 95% confidence interval, 5.9 to 8.3). The 25-year actuarial risk of SC overall was 27.7%. The RR of solid tumors increased greatly with younger age at the first treatment of HD, not only for breast cancer but also for all other solid tumors, with RRs of 4.9, 6.9, and 12.7 for patients first treated at ages 31 to 39 years, 21 to 30 years, and ≤ 20 years, respectively. Among patients first treated at the age of 20 years or younger, the RR of developing a solid tumor before the age of 40 years was significantly greater than the RR of solid tumor development at ages 40 to 49 years (RR = 27.9 v RR = 4.2; P = .0001). Patients who received salvage chemotherapy had significantly greater risk of solid cancers other than breast cancer than did patients whose treatment was restricted to initial radiotherapy or initial combined-modality treatment (RR = 9.4 and 4.7, respectively; P = .004). CONCLUSION: After more than 20 years of follow-up, the risk of solid tumors is still much greater in survivors of HD than in the population at large. Reassuringly, the greatly increased risk of solid tumors in patients who were young (≤ 20 years of age) at the first treatment seems to decrease as these patients grow older. Our data suggest that chemotherapy may increase the risk of solid tumors from radiotherapy.
Methylenetetrahydrofolate reductase gene polymorphisms in Korean gastric cancer patients: Relationship with in vitro chemosensitivity assay and clinical response to 5-fluorouracil containing regimen
Authors: J. H. Kim, H. G. Lee, B. J. Suh, H. J. Yu, J. P. Kim
Journal: Journal of Clinical Oncology (2005)

4186 Background: Fluorouracil(5-FU) is widely used in the treatment of gastric cancer. The folate pool in cancer tissue is essential for the effect of 5-FU-based chemotherapy. Many enzymes including thymidilate synthase(TS), dihydropyrimidine dehydrogenase(DPD) and methylenetetrahydrofolate reductase(MTHFR) play a role in the metabolism of folate. We evaluated whether single nucleotide polymorphisms(SNPs) in MTHFR associated with in vitro chemosensitivity and clinical response to 5-FU-based chemotherapy in Korean gastric cancer patients. Methods: One hundred and thirteen patients with gastric adenocarcinoma were analyzed. Eighty-five out of 113 patients were operable and the other inoperable 28 patients were treated with 5-FU, cisplatin and docetaxel in combination. Chemosensitivity tests were done with ATP-CRA(chemosensitivity response assay) and HDRA(histoculture drug response assay) by endoscopic biopsy and surgical specimens respectively. Genomic DNA was extracted from blood or paraffin-fixed tumor tissues and genotypes (677 C->T; A222V) were determined by direct sequencing. Clinical responses were evaluated in inoperable 28 patients by RECIST. Computer-assisted analyses were carried out using SPSS for Windows (Version 10.05). The Fisher’s exact test was used to assess the association between MTHFR 677 genotype and clinical response. Results: In 82 patients at least one copy of valline allele(56 heterozygotes and 26 homozygotes) was noted. The other 31 patients carried the homozygotes alanine allele. In chemosensitivity test 5-FU was sensitive in 75.0%, 51.2% and 34.7% of patients with MTHFR VV, AV and AA genotype respectively(p=0.099). Overall clinical response rate was 53.8% in inoperable patients. Response rate was 66.6% for 8 patients with MTHFR VV genotype, 52.0% for 13 patients with AV, and 46.6% for 7 patients with AA(p=0.56). Conclusions: Our results show a relationship between MTHFR polymorphism and 5-FU chemosensitivity. But in advanced cases the predictability of clinical response was low. No significant financial relationships to disclose.