tbuckley/cabot-search huggingface dataset:
Phase I trial of combination nab-paclitaxel and pemetrexed in advanced solid tumors
Authors: C. Ho, A. M. Davies, P. N. Lara, H. K. Chew, L. Beckett, R. S. Sangha, P. C. Mack, D. R. Gandara
Journal: Journal of Clinical Oncology (2008)

13530 Background: nab-paclitaxel (ABI 007) is a 130 nm nanoparticle composed of paclitaxel and non-modified human serum albumin designed to increase intra-tumoral delivery and concentration. Pemetrexed (P) is a multitargeted antifolate that inhibits several key enzymes in cell proliferation including thymidylate synthase (TS), dihydrofolate reductase and glycinamide ribonucleotide formyl transferase (GARFT). Pre-clinical investigations combining paclitaxel and pemetrexed resulted in additive to greater than additive tumor responses. We hypothesized that the combination of ABI-007 and pemetrexed will have at least an additive anti-tumor effect and will be well-tolerated with manageable side effects. Methods: Three dose levels were tested: P 500 mg/m2 day 1 in all cohorts and ABI 007 on day 1 at doses of 180, 220, 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) using the CTCAE V 3.0 was defined as: grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding, febrile neutropenia, neutropenia with documented infection, or any other grade ≥ 3 non hematologic toxicity. A grade 3 hypersensitivity infusion reaction was not considered a DLT. Results: Planned dose escalation has been completed without reaching the MTD. 9 patients were treated including 5 NSCLC, 2 H&N, 1 ovary and 1 prostate cancer. Patient characteristics: age range 51–76, median 71; gender M:F 6:3; KPS <80/≥80: 1/8; median cycles 3. There were no DLTs, and the final cohort is being expanded to include 6 patients. Grade ≥ 3 toxicities were syncope (1) and fatigue (1). In 7 patients assessable for response: 1 PR and 2 stable disease. Correlative science studies are ongoing evaluating the expression of markers of folate homeostasis including TS, GARFT, reduced folate carrier and alpha-folate receptor; taxane associated markers p27, bcl2, Tub III, Tau, SPARC, CAV1. Shed tumor DNA in plasma will be assessed for KRAS mutations, p16 and APC gene promoter methylation. Conclusions: Pemetrexed 500 mg/m2 day 1 with ABI 007 260 mg/m2 is feasible and well tolerated. Phase II trials are planned in NSCLC and breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Abraxis Oncology
Cognitive functioning in breast cancer patients during and following chemotherapy
Authors: M. C. Janelsins, J. A. Roscoe, P. Jean-Pierre, G. R. Morrow
Journal: Journal of Clinical Oncology (2009)

e20571 Background: The development of cognitive difficulties, including memory loss, confusion, and difficulty concentrating following cancer treatment is a significant concern in patients receiving chemotherapy. Methods: This secondary analysis of a study assessing the effects of a RCT of paroxetine on fatigue in cancer patients investigated changes in self-report cognitive functioning over four cycles of chemotherapy and then approximately two years later. Approximately half of the patients were chemotherapy naïve. Questions on 5 point scales anchored by 1 = “absence of” and 5 = “a great deal” evaluating whether patients experienced heavy headedness, muddled thoughts, difficulty thinking, trouble concentrating, and forgetfulness. Each was answered seven days after each treatment and scores from each cycle were summed. Results: Fifty-eight of 84 patients completed questionnaires for all four cycles and are included herein. Paired t-tests showed cognitive difficulties were highest following the 1st on-study chemotherapy cycle (mean=7.9) and were significantly improved at the 3rd (mean=6.9) and 4th (mean=6.6) on-study cycles (both, p&lt;0.005). Independent sample t-tests revealed that paroxetine had no effect on cognitive functioning when compared to placebo at all 4 cycles (all, p&gt;0.54). Fifteen participants were reassessed two years after completing treatement. There was an increase in reported cognitive difficulties from the last cycle (mean=5.9) to the follow-up time-point (mean=7.8) that was not significant (p=0.18). Patients with ≥2 point change in score from the last on-study cycle to follow-up were categorized as “better” or “worse”. Those with &lt;2 point change in score were classified as “no change”. Four (27 %) patients got worse (mean change=9.0), 2 (13 %) got better (mean change=-3.5), and 9 (60%) did not change. Conclusions: These data suggest that self-report cognitive difficulties related to cancer treatment are most pronounced following initial cycles of chemotherapy treatment and improve during the treatment course. Further studies need to include objective neuropsychological examinations and biological correlates of cognitive functioning to understand the extent of cognitive decline due to chemotherapy. Funding: DOD DA17–96-C-6106, NCI R25CA10618. No significant financial relationships to disclose.
The effect of alcohol and smoking on testosterone function and aggression in chronic alcoholics
Authors: H Persky, C P O'Brien, E Fine, W J Howard, M A Khan, R W Beck
Journal: American Journal of Psychiatry (1977)

Forty alcoholics without other significant medical or psychiatric problems were studied on a research ward for two weeks. All subjects abstained from alcohol and cigarettes during the first week; 30 randomly selected subjects were permitted unlimited alcohol and/or cigarettes during the second week. Plasma testosterone levels were normal during the first week but decreased rapidly and significantly in those subjects allowed alcohol. A variety of measures of affect failed to show a significant correlation between hostility/aggression and plasma testosterone levels or alcohol ingestion.
Effective treatment of refractory and relapsed AML with the triple combination of mitoxantrone, topotecan and cytosin-arabinoside (MTC)
Authors: L. Bergmann, G. Heil, A. Ganser, H. Martin, A. Rhagavachar, H. Einsele, D. Hoelzer, B. Hoechsmann
Journal: Journal of Clinical Oncology (2005)

6613 Background: About 60% - 70% of AML patients in 1st CR achieve a relapse. Here, effective new treatment options are required to achieve second CRs without major toxicities and to open the possibilities of a potential curative alloSCT.We designed a study in relapsed or refractory pts. with the triple combination of mitoxantrone, the topoisemerase-I inhibitor topotecan and cytarabine (MTC). Methods: 114 pts with 1st relapse or refractory AML were entered, 111 pts are eligible and 107 pts are evaluble. The median age was 55 years (18 - 78). 72.5% of the pts received the IVA regimen as induction therapy in 1st line, 39.3% of the pts had had a consolidation with high-dose AraC. Cytogenetics were routinely done.The patients received the MTC regimen with mitoxantrone (12 mg/m2 i.v., day 1+2), topotecan (1.5 mg/m2 i.v., day 3–7) and AraC (1g/m2 2h infusion, day 3–7). MTC I and MTC II were administerd as induction therapy and a 3rd cycle as consolidation therapy. Results: 45/81 (56%)pts with 1st relapse of AML achieved a CR and 4/10 (40%)pts with refracroty AML. The chance to induce a second CR was dependent on the 1st remission duration (RD). Those with a 1st RD of 12 mths had a CR-rate of 71%, those a 1st RD < 6mths of only 22%. There were 5 early deaths. 40 pts received an allo SCT, 25 pts. in 2nd CR, 4 in MR/PR and 11 in PD. 17/25 pts and 2/4 pts., who have been transplanted in CR or MR/PR, respectively, are still alive, but only 1/11 pts, who have been transplanted in PD. The 2-year OS probability was 41% for those with allo SCT and 11% for those without allo SCT. The MTC regimen was well tolerated even for elderly pts. The median duration of cytopenia was 19 d, the non-hematological toxicities were low with about 10% grade III diarhea and an elevation of transaminases. Mucositis was generally mild. Conclusions: MTC is an effective regimen in relapsed or refractory AML with tolerable toxicities.AlloSCT following MTC regimen was feasible and, if possible, should be preferred afterwards as a curative option. However, the rate of CR at least in refractory pts. or those with short 1st RD need to be improved. Here, a study is now ongoing with combination of MTC and signal transduction inhibitors. No significant financial relationships to disclose.
Phase II evaluation of cetuximab (C225) combined with induction paclitaxel and carboplatin followed by C225, paclitaxel, carboplatin, and radiation for stage III/IV operable squamous cancer of the head and neck (ECOG, E2303)
Authors: H. J. Wanebo, M. Ghebremichael, B. Burtness, S. Spencer, J. Ridge, A. Forastiere, M. Ghebremichael
Journal: Journal of Clinical Oncology (2007)

6015 Introduction: Neoadjuvant C225 with induction chemotherapy and chemo-radiation was studied in stage III/IV head and neck squamous cancer with primary and secondary objectives of 1year event- free survival, pathologic complete response rate at the primary site (PS) (determined by mandatory biopsy week 8) and toxicity. Protocol Design: Operable patients (pts) staged by triple endoscopy, CT/MRI, had gastrostomy, signed IRB approved consent and received induction chemotherapy with weekly C225 250 mg/m 2 , P 90 mg/m 2 , C (AUC=2). Restaging PS biopsy was done at week 8, if there was a clinical response. Pts with positive biopsy (or persistent tumor) at PS had restaging biopsy at week 14 after chemo radiation (C225 250 mg/m 2 , P 30 mg/m 2 , C(AUC=1) and 50 Gy). If PS Bx was negative patients had completion RT (68–72 Gy, plus continued C225, P,C). If PS Bx was positive at 14 weeks salvage surgery was required. Results: 74 patients were enrolled (67 are evaluable). T and N stage were T1/2 (11%/27%), T ¾ (47%/14%); N O/N1 (11%/23 %), N 2/3 (50%/16%). Site: tonsil 30%, oral cavity/tongue 24%, Post pharynx (BOT) 42%, Larynx 34%; performance status 0/1 (61% / 39%). PS re biopsy was done at week 8 in 40 patients; no residual tumor was detected in 26 (65%). Restaging biopsy after induction and chemo radiation was done at week 14 in 28 pts (14 with persistent tumor and 14 with previous positive biopsy) and was negative in all 28 patients. All 54 patients with negative PS biopsy had completion RT. Data on disease status are incomplete. Post treatment toxicity (Gr 3/4) included acneiform rash (12%), leukopenia/neutropenia 32%/24%, dysphagia (29%), and stomatitis (82%). One grade 5 AE occurred (death from encephalopathy). Conclusion: Neoadjuvant induction C225, plus chemotherapy followed by C225 plus chemo-radiation elicited a complete pathologic response at the primary site, by restaging biopsy (65%) with induction alone, and 100% among sampled patients after chemo RT 50Gy. These preliminary results suggest a high pathologic complete response rate to induction chemotherapy plus cetuximab followed by chemo radiation plus cetuximab. Progression and survival data are not yet mature. No significant financial relationships to disclose.
Dose-escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) plus low-dose dexamethasone (Dex) (CRd) in relapsed/refractory multiple myeloma (R/R MM).
Authors: W. Bensinger, M. Wang, R. Z. Orlowski, M. Alsina, T. Martin, S. Singhal, N. Y. Gabrail, M. Vallone, M. Kauffman, R. Niesvizky
Journal: Journal of Clinical Oncology (2010)

8029 Background: CFZ, a specific, irreversible proteasome inhibitor, is highly active with a favorable side effect profile in R/R MM. This open-label, phase Ib dose-escalation study evaluated the safety and maximum recommended dose of CFZ + LEN+ low-dose Dex, (CRd). Methods: Eligible patients (pts) included those with relapsed or progressive MM after 1–3 prior therapies. CRd was given on 28 day cycles (C) in 6 cohorts as shown in the Table. Primary endpoints included safety and establishment of the maximum recommended dose. Other endpoints included overall response rate (ORR) and clinical benefit response (CBR). Results: To date, 40 pts were enrolled in cohorts 1–6 and 27 in a cohort 6 expansion. 27/32 pts in cohorts 1–5 were evaluable for safety and 29/32 for response. Pts were heavily pretreated; 72% received prior BTZ and 87.5% received prior IMiD. 47% of pts were refractory to their last therapy; 84% had a history of neuropathy (67% related to prior BTZ or thalidomide). No treatment emergent fatigue, neuropathy, or thrombotic events ≥ Grade (G) 3 were observed. Hematological AEs ≥G3 (thrombocytopenia [n=6], anemia [n=4], and neutropenia [n=6]) were reversible. 4 pts had drug-related SAEs (transient G3 sinus bradycardia, G3 upper respiratory tract infection, febrile neutropenia, and G3 diarrhea + G3 urinary infection). ORR and CBR for 29 evaluable pts are 59% and 72%, respectively which included 21% CR/nCR, 17% VGPR, and 21% PR. Initial responses improved with continued therapy, up to 18 C. 43/67 pts remain on study. No dose- limiting toxicities or deaths have been reported. Conclusions: CRd is well-tolerated in pts with R/R MM, even in those with a history of neuropathy. Nonoverlapping toxicity profiles of CFZ and LEN allow their combination at full doses for extended durations up to 18 C. Prior therapy with either BTZ or an IMiD, or disease refractory to the immediately preceding regimen does not preclude achieving MR, PR, VGPR or CR to CRd. Authors wish to acknowledge support from Celgene Corp. Cohort Administration day 1 2 3 4 5 6/E C1-4 C5-8 C9-16 CFZ IV bolus (mg/m2) 15 20 20→27* 1, 2, 8, 9, 15, 16 1, 2, 15, 16 LEN po (mg) 10 15 20 25 1-21 Dex po (mg) 40 1, 8, 15, 22 1 * 20 mg/m2 on C1 days 1 and 2; 27 mg/m2 thereafter. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Pharmaceuticals Celgene, Millennium, Onyx Onyx, Onyx Pharmaceuticals Celgene, Millennium, Onyx Pharmaceuticals Celgene, Millennium, Novartis, Onyx, Seattle Genetics
Efficacy of S-1 for advanced gastric cancer (AGC) in clinical practice: Results from a nation-wide post-marketing survey in 3801 patients (pts)
Authors: A. Ohtsu, M. Fukushima
Journal: Journal of Clinical Oncology (2004)

4225 Background: It is likely that there are some discrepancies in safety and efficacy results of anti-cancer agents between those in registration studies for approval and in clinical practice after commercially available. S-1, a new oral fluoropyrimidine, has been commercially available and widely used for AGC in Japan. The aim of this analysis was to compare efficacy results of this agent between the above two setting. Methods: After approval of S-1 in 1999, all pts had to be registered into and be monitored by the company as a post-marketing survey according to the government recommendation. The safety profile was previously reported (Nagashima et al. ASCO '02), which revealed similar profile to the registration studies. Survival data of all pts registered were updated at one year after each registration and these data were compared with those in the previous phase II studies before approval that showed a median survival time (MST) of 8.0 months and one-year survival rate (1ysr) of 36.6%. Results: Between March 1999 and March 2000, a total of 3801 pts with AGC (inoperable: 1303, recurrent: 1578, non-curative resection: 920 pts) were registered in the nation-wide post-marketing survey. There were 282 (7.4%) pts lost to follow-up. MST and 1ysr of all pts were 8.3 (95% CI: 8.0–8.6) months and 33.4% (95%CI: 31.8–34.9%), respectively. Multivariate analysis for survival showed that PS, liver metastasis, and passage disturbance were independent prognostic factors. Of the 3801, 1540 pts had had no prior chemotherapy and 483 pts had met the eligibility criteria of the prior registration study according to their baseline data. MST and 1ysr of the 483 pts were 9.3 (95%CI: 8.4–10.3) months and 36.3% (95%CI: 31.8–40.8%), respectively. Conclusions: This agent provided at least similar efficacy to those seen in the prior phase II studies even when used in real world clinical practice. This post-marketing totally registered outcome research was useful to find out reproducibility of efficacy results obtained from prior clinical trials. (This work was based on MHLW mandatory post-marketing surveillance by Taiho pharmaceutical company.) No significant financial relationships to disclose.
Characterization of AZD8931, a potent reversible small molecule inhibitor against epidermal growth factor receptor (EGFR), erythroblastic leukemia viral oncogene homolog 2 (HER2) and 3 (HER3) with a unique and balanced pharmacological profile
Authors: G. Speake, T. Klinowska, M. Hickinson, G. Marshall, P. Smith, J. Vincent, J. Anderton, N. Gray, I. Smith, D. Ogilvie
Journal: Journal of Clinical Oncology (2009)

11072 Background: Successful combined pharmacological inhibition of EGFR, HER2, and HER3 signaling is currently under investigation in the clinic. HERs (erbB receptors including EGFR, erbB2, erbB3, erbB4) undergo various types of alteration and in many cancers HER ligands are produced either by the tumor cells themselves or surrounding stromal cells. These mechanisms of receptor activation all lead to constitutive proliferative and/or survival signaling driven by homo- and/or heterodimerization of the HER family. Characterization of a novel tyrosine kinase inhibitor with a potent and balanced profile against EGFR, HER2 (erbB2), and HER3 (erbB3) has been carried out. Methods: A range of assays has been developed to assess the detailed pharmacology of AZD8931 and understand how the profile of AZD8931 compares with other HER family inhibitors, such as gefitinib and lapatinib. These assays have provided unique insights into the pharmacology of these drugs that result from the varying levels of HER and their associated ligands. Results: Across a number of cell systems, AZD8931 has been shown to be a potent inhibitor of tumor cell growth. This effect is through the ability of AZD8931 to inhibit potently the phosphorylation of EGFR (0.004 μM; 95% CIR: 1.377), HER2 (0.003 μM; 95% CIR: 1.817) and HER3 (0.004 μM; 95% CIR: 1.890) in a balanced manner. Furthermore, when compared to control AZD8931 has significant and dramatic effects on the downstream signaling pathways (pAKT [p=0.002] &amp; pMAK [NS]), apoptotic (M30 [p=0.004]), and proliferative (Ki67 [p&lt;0.0005]) endpoints. The novel agent AZD8931 displays a distinct pharmacological profile compared to both gefitinib and lapatinib. Conclusions: Based on our data as well as published literature, the combined pharmacological inhibition of EGFR, HER2, and HER3 signaling has not yet been tested in the clinic. AZD8931 offers an agent to test the hypothesis that combined inhibition of HER signaling could provide additional clinical benefit in cancer, particularly in the majority of solid tumors that do not overexpress HER2. [Table: see text]
Decreased T cell infiltration and lymphocyte/dendritic cell/monocyte gene expression as well as increased Cyp3A5 mRNA predicts early recurrence of non-small cell lung cancer (NSCLC) following surgical resection
Authors: D. A. Potter, L. Li, S. Badve, K. Kesler, K. Rieger, N. Hanna, C. McDonald, H. Edenberg, L. H. Einhorn, R. Mitra
Journal: Journal of Clinical Oncology (2004)

7141 BackgroundRecent phase III data (T. Le Chevalier et al., Proc Am Soc Clin Oncol, 2003) indicate a potential benefit of adjuvant chemotherapy in NSCLC, following surgical resection. Thus, we examined whether cDNA microarray analysis could be used to identify markers that correlate with early recurrence of NSCLC in patients treated with surgery alone. Methods An observational protocol to assay NSCLC tissue banked at resection from patients with stage Ia-IIIb tumors was implemented, using a longitudinal database. The patients were stratified into two groups: Group A (n=15) exhibited no recurrence at two years following surgery and Group B (n=11) exhibited recurrence, documented by tissue diagnosis. Group A was 73% stage I, 20% stage II and 7% stage III. Group B was 36% stage I, 9% stage II and 55% stage III. All evaluable patients were included in the analysis. RNA was isolated from whole tumor tissue and individual tumors were compared using U133 Affymetrix chips. Results A set of 35 T and B cell, dendritic cell and monocyte mRNA species was significantly increased in Group A compared to Group B (F test P<0.0043). Group A tumors exhibited intraepithelial tumor infiltrating T cells (TIL) in 80% (12/15) of cases, by CD2 IHC, compared to 27% (3/11) of Group B (P=0.022). Cyp3A5 mRNA was increased 18.7-fold in Group B (P=0.0001), Notch3 1.7-fold (P=0.002) and collagen 18A1 2.2-fold (P=0.005). Conclusions A set of 35 gene expression markers from lymphocytes/dendritic cells/monocytes negatively associated with early relapse of NSCLC has been identified. Intraepithelial T cell tumor infiltration is confirmed to be negatively associated with relapse. These results suggest that infiltration by specific lymphocyte, dendritic, and monocyte cell types inhibits NSCLC recurrence. Increased Cyp3A5, Notch3 and collagen 18A1 mRNA also correlates with recurrence. These markers may help determine which NSCLC patients may benefit from adjuvant chemotherapy. This work was supported by NIH Grant P20-GM66402–02 and the Thoracic Oncology Program at Indiana University. No significant financial relationships to disclose.
Impact of gene promoter polymorphism of the UGT1A1-gene on the occurrance of irinotecan-induced side effects and drug effiacy
Authors: C. Schulz, A. Schalhorn, W. Schwabe, P. Haeusler, T. Zwingers, V. Heinemann
Journal: Journal of Clinical Oncology (2005)

3570 Background: Irinotecan is an effective agent in the treatment of advanced colorectal cancer (CRC). The most common side effects of irinotecan are myelotoxicity, nausea and delayed diarrhea. The active metabolite of irinotecan (SN 38) is inactivated by uridine diphosphate glucuronosyl transferase (UGT1A1), the enzyme by wich also bilirubin is conjugated. In this study, we investigated the correlation between the gene promoter polymorphism of the UGT1A1 gene and the occurrence of irinotecan-induced side effects as well as the parameters of drug efficacy. Methods: Genotypes were identified by gene scan analysis on the ABI 310 sequencer of the TATA box in the promoter region of the UGT1A1-gene in blood samples from 81 patients (pts) with advanced CRC receiving 1st-line therapy with irinotecan-based chemotherapy. Results: The wildtype allele (6/6) had a frequency of 40.7%, whereas the heterozygous allele (6/7) was observed in 49.4%, and the homozygous allele (7/7) in 9.9% of the pts. The most frequent adverse events were nausea (69.1%), anemia (69.1%), and delayed diarrhea (58.0%). There was no significant difference in nausea (69.7% vs. 68.9%) and anemia (67.1% vs. 71.2%) between pts with wildtype and mutant homozygous or heterozygous genotypes. However, the incidence of delayed diarrhea CTC-NCI grades II, III and IV was higher among pts with the mutant genotype 6/7 (17.0%, 5.4%, 2.7%) and the genotype 7/7 (20.0%, 20.0%, 0%) as compared to the wildtype genotype (6/6) (13.2%, 3.9%, 1.3%). Toxicity-related treatment stop was observed at a rate of 18.6% in mutant genotype pts, but not in wildtype pts (p=0.019). The overall response rate was lower in the 6/7 (45.5%) and 7/7 genotypes (33.3%) as compared to the wildtype genotype (57.1%) (p=0.316). Moreover, no sign. differences were observed between patient groups with regard to TTP (p=0.652) and OS (p=0.626). Conclusions: This study demonstrates that the incidence of delayed diarrhea was higher in pts with a homozygous or heterozygous mutant genotype as compared to the wild-type genotype. Toxicity related treatment stop only occurred in mutant genotype pts. The genetic polymorphism did not appear to have a significant impact on treatment efficacy. No significant financial relationships to disclose.