tbuckley/cabot-search huggingface dataset:
Adjuvant (adj) bevacizumab (B) plus dose-dense (dd) doxorubicin/cyclophosphamide (AC) followed by nanoparticle albumin- bound paclitaxel (nab-p) in early stage breast cancer (BC) patients (pts): Cardiac safety
Authors: M. N. Dickler, T. Traina, K. Panageas, R. Steingart, C. Dang, M. Fornier, S. Sugarman, L. Norton, C. Hudis, H. Rugo
Journal: Journal of Clinical Oncology (2007)

567 Background: Dose dense, q2 wk AC-paclitaxel (T) is superior to q3 wk therapy (Rx) (Citron, JCO 2003). The risk of congestive heart failure (CHF) with ddAC-T is not increased at &lt;1%. In MBC, B improves PFS when added to T (Miller, SABCS 2005). It is unclear if doxorubicin plus B increases risk of CHF. Hence, we are testing the cardiac safety of ddAC-nab-p with concurrent B as adj therapy. Based upon the accepted cardiac event (CE) rate of ≤4% in trials with adj trastuzumab (an agent with known cardiac toxicity), we designed this study with similar monitoring &amp; tolerability thresholds. The primary endpoint is cardiac safety, defined as discontinuation of B due to cardiac death from LV dysfunction or symptomatic CHF (dyspnea and LVEF&lt;50%). Secondary endpoints: toxicity, disease-free &amp; overall survival. Methods: Eligible pts have resected HER2(-) BC and normal LVEF. Rx consists of q2wk AC (60/600 mg/m 2 ) ×4 then nab-p (260 mg/m 2 ) x4 with pegfilgrastim on Day 2 plus B for one year (10mg/kg IV q2wk ×8 with chemoRx then B 15mg/kg q3wk); radiation &amp; endocrine Rx per standard of care. MUGA obtained at baseline &amp; mos. 2, 6, 9, 18. Pts with significant asymptomatic ↓LVEF during Rx may have B held per protocol. These pts are not counted as CEs but will have long-term cardiac monitoring. Accrual goal is 75 pts. If ≥3 CE (∼4.7%) or &gt;1 cardiac death from LV dysfunction, B + ddAC-nab-p will not be considered safe. Results: 44 pts have enrolled, median (med) age 46.5 yrs (33–67). 28 pts have baseline &amp; month 2 LVEF data: med baseline LVEF 68% (61–82), med LVEF at mo. 2 after ddAC+B 68% (53–75); 1 pt had an 18 point asymptomatic drop to 53% - B held but reinitiated in 4 wks with repeat LVEF 63%. 12 pts completed nab-p+B but none have reached the 6 mo. MUGA. Rx-related Gr 3/4 toxicity: neutropenia gr4 (6.8%), diarrhea gr3 (2.3%), hypertension gr3 (2.3%), neuropathy gr 3 (2.3%), fatigue gr 3 (2.3%), mucositis gr 3 (2.3%). 4 pts have withdrawn from study Rx, but only 1 due to toxicity including gr3 fatigue, mucositis &amp; neuropathy. Conclusions: No LV dysfunction has been observed with B + ddAC-nab-p; this trial is on-going. Long-term follow-up and analysis of troponin, renin and circulating endothelial &amp; tumor cells are planned. No significant financial relationships to disclose.
Advancing clinical development pathways for new CFTR modulators in cystic fibrosis
Authors: Nicole Mayer-Hamblett, Michael Boyle, Donald VanDevanter
Journal: Thorax (2016)

Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70 000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant <i>CFTR</i> genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF.
Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: Analysis of response, survival, and outcome wi
Authors: S. V. Rajkumar, S. Jacobus, N. Callander, R. Fonseca, D. Vesole, M. V. Williams, R. Abonour, D. S. Siegel, M. Katz, P. R. Greipp
Journal: Journal of Clinical Oncology (2008)

8504 Background: We compared lenalidomide (Len) plus high (standard) dose Dex (RD) vs Len plus low dose Dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Len dose was 25 mg/day PO d 1–21 every 28 days. Pts in the RD arm received high-dose Dex 40 mg d 1–4, 9–12, and 17–20 PO q 28 d; pts in the Rd arm received low dose Dex 40 mg d 1, 8, 15, and 22 PO q 28 d. The primary null hypothesis was that response rates at 4 mos on the 2 arms are equivalent (difference >15% unacceptable), one-sided 0.10 Type I and 0.05 Type II error rate. All analysis were intent to treat. Results: 445 pts (median age, 65 yrs) were randomized: 223 (RD) and 222 (Rd). 383 were eligible as of Dec 2007. Arms were well balanced. Grade ≥3 toxicities occurred within 1st 4 cycles in 50% (RD) vs 30% (Rd) respectively, P<0.001. 149 pts reported stem cell harvest attempt; 97% were successful. PR or higher within the first 4 cycles was seen in 82% (RD) vs 70% (Rd), P=0.007 (excluding 14 pts with missing data). CR+VGPR rates were 52% vs 42%, P=0.06 (excluding 9 pts missing data). Overall survival (OS) was significantly superior with Rd, P=0.006; one yr survival 96% (Rd) vs 88% (RD); 2 year OS rates 87% (Rd) vs 75% (RD). We performed a landmark analysis after 4 mos of treatment. Of 421 pts alive at the landmark analysis, 210 went off-study and 211 continued primary therapy with RD/Rd. Of pts who went off study at 4 mos, 108 pts (51%) did not pursue SCT (median age 67); 1 yr OS and 2 yr OS rates were 85% and 70% respectively. The remaining 102 pts (49%) underwent SCT (median age 57); the 1 yr OS and 2 yr OS rates were 99% and 94% respectively. There was no difference in % pts who went to SCT between the 2 arms, 29% (RD) and 31% (Rd). Corresponding 1 yr and 2 yr OS rates among 211 pts (median age 67) who continued on primary therapy beyond 4 mos were: RD (n=91) 96% and 80% respectively, and Rd (n=120) 99% and 91% respectively. Conclusions: Rd results in superior OS compared to RD. In a landmark analysis, the two year OS rate was 91% among pts who received primary therapy with Rd, and 94% among pts who received RD/Rd followed by SCT. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene
A phase II NCCTG/CALGB trial of imatinib (STI571) in patients (pts) with c-kit-expressing relapsed small cell lung cancer (SCLC)
Authors: G. K. Dy, A. A. Miller, S. Mandrekar, M.-C. Aubry, R. M. Langdon, S. E. Schild, J. R. Jett, A. A. Adjei
Journal: Journal of Clinical Oncology (2005)

7048 Background c-Kit over-expression is found in multiple cancers including up to 70% of SCLC. STI571 can inhibit c-kit tyrosine kinase activity and has high efficacy in chemoresistant c-kit positive (c-kit+) gastrointestinal stromal tumors. A phase II study of STI571 in unselected SCLC pts by Johnson et al., was negative, but inconclusive for proof- of - principle purposes, since 80% of tumors did not express c-kit. We therefore sought to evaluate clinical activity of STI571 in the treatment of patients with recurrent and refractory c-kit+ SCLC. Methods Only c-kit+ SCLC cases were enrolled on this study (≥ 1+ by immunohistochemistry). Arm A included pts progressing < 3 months and Arm B included pts progressing ≥ 3 months after previous treatment. STI571 was administered at a dose of 400 mg bid continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16 week progression free rate in each arm. Results A total of 29 evaluable pts were entered into the study (7 arm A, median age 68; 22 arm B, median age 65). Median number of treatment cycles was 1 in both arms. All pts are now off active treatment. Grade3+ non-hematologic adverse events were seen in 15(52%) pts, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration occurring in at least 10% of pts. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 month for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to progression (29%), early deaths (29%), and refusal (42%). No objective responses and no confirmed stable disease ≥ 6 weeks were seen in either arm. Accrual was permanently terminated to both arms as no patient was progression-free at 16 weeks. Conclusion STI571 was inactive in spite of pt selection for c-kit+ SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example through activating mutations), may not be a valid paradigm for drug development. No significant financial relationships to disclose.
Posttransplant immunotherapy with a GM-CSF-based tumor vaccine following autologous stem cell transplant (ASCT) for acute myeloid leukemia (AML)
Authors: W. Stock, H. I. Levitsky, I. M. Borrello, D. Sher, D. J. Deangelo, E. P. Alyea, L. E. Damon, C. A. Linker, K. Hege
Journal: Journal of Clinical Oncology (2004)

6545 Background: Preclinical models have demonstrated the efficacy of GM-CSF secreting cancer vaccines accompanied by vaccine-primed lymphocyte infusion following ASCT. Methods: Patients ≤ 60 years old with de novo AML (excluding M3) were enrolled. Leukemia cells were harvested at diagnosis followed by induction and consolidation chemotherapy and ASCT. A pretransplant vaccine composed of irradiated autologous leukemia cells mixed with GM-CSF gene-modified K562 cells (K562/GM) was given followed by collection of vaccine-primed lymphocytes that were reinfused with the stem cell graft. Posttransplant vaccinations were initiated at week 6 (or upon platelet engraftment) and given every 3 weeks (10x107 tumor cells + 4x107 K562/GM cells) x 8 vaccinations. Results: Leukemia cell harvest was successful in 44/45 patients (blood draw 17, leukapheresis 24, bone marrow aspirate 4). To date, 34/41 patients (83%) have obtained a complete remission (CR) with induction chemotherapy, 17 have received the pretransplant vaccination, and 8 have initiated posttransplant vaccinations. Vaccines have been well tolerated with evidence of local injection site reactions in 16/17 patients. Delayed-type hypersensitivity (DTH) reactions to irradiated autologous tumor were negative pre-vaccination in 14/16 and converted to positive in 3/5 to date following 4 posttransplant vaccinations. Minimal residual disease (MRD) is being monitored by quantitative analysis of peripheral blood (PB) and bone marrow (BM) for WT1, a leukemia-associated gene, by RT-PCR. All patients had persistently detectable WT1 transcripts in PB and BM at enrollment. Most patients in CR analyzed to date had detectable WT1 transcripts in BM following induction (27/27), consolidation (14/15), and ASCT (4/6). A decrease in WT1 levels in BM was noted in 8/12 following the pretransplant vaccination. Conclusions: Collection of large quantities of autologous leukemia cells for vaccine production is feasible. Analysis of MRD by WT1 RT-PCR, in addition to immune response, may serve as a useful surrogate marker of efficacy in patients vaccinated in remission. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Gensys Cell Genesys Cell Genesys
The prognostic significance of IL-1-B and GST T1/M1 polymorphisms in non-metastatic gastric cancer
Authors: M. S. Al-Moundhri, B. Al-Bahrani, M. Al-Nabhani, I. Burney, M. Al-Kindy, S. S. Ganguly, M. Tanira
Journal: Journal of Clinical Oncology (2006)

4084 Background: Gastric cancer is the most common malignancy in Oman. The proinflammatory cytokine IL-1-B polymorphisms have been associated with increased gastric cancer risk and shown to be of a prognostic value in advanced gastric cancer. Our aim is to study the prognostic significance of IL-1B- 31, -3954, IL-1RN- and GST T1/M1 polymorphisms in non-metastatic gastric cancer and correlate it with clinicopthological features. Methods: Genomic DNA was extracted from peripheral blood of 40 gastric cancer patients treated with adjuvant chemotherapy or chemoradiotherapy. The DNA samples were analyzed using TaqMan real-time polymerase chain reaction and 5’ nuclease assay. The deletion of GST T1/M1 genes was assessed by PCR. Results: The pathological stages were stage I = 1, stage II = 13, stage III = 22, stage IV = 3. The median follow up was 17 months. There was no prognostic significance for all the above polymorphisms in isolation. However, IL-1RN 2/2 IL-31 C/C genotypes (n = 13) were associated with worst outcome compared with IL-1RN L/L or 2/L and IL-31 T/T and T/C genotypes (n = 27). The median survival of IL-1RN 2/2 IL-31 C/C genotype was 16 months versus 63 months for IL-1RN L/L or 2/L and IL-31 T/T and T/C genotypes (p = 0.035). The IL-1RN 2/2 IL-31 C/C genotype correlated with signet ring pathology (p = 0.01) and non-distal gastric cancer location (p = 0.01). There was no significant association with T, N, or overall stage. Conclusion: These preliminary results suggest a prognostic value for IL-1-B polymorphisms in non-metastatic gastric cancer. No significant financial relationships to disclose.
Structural organization of the beta-globin locus of B-haplotype sheep.
Authors: K J Garner, J B Lingrel
Journal: Molecular Biology and Evolution (1988)

Goats and some sheep synthesize a juvenile hemoglobin, Hb C (alpha 2 beta C2), at birth and produce this hemoglobin exclusively during severe anemia. Sheep that synthesize this juvenile hemoglobin are of the A haplotype. Other sheep, belonging to a separate group, the B haplotype, do not synthesize hemoglobin C and during anemia continue to produce their adult hemoglobin. To understand the basis for this difference we have determined the structural organization of the beta-globin locus of B-type sheep by constructing and isolating overlapping genomic clones. These clones have allowed us to establish the linkage map 5' epsilon I-epsilon II-psi beta I-beta B-epsilon III-epsilon IV-psi beta II-beta F3' in this haplotype. Thus, B sheep lack four genes, including the BC gene, and have only eight genes, compared with the 12 found in the goat globin locus. The goat beta-globin locus is as follows: 5' epsilon I-epsilon II-psi beta X-beta C-epsilon III-epsilon IV-psi beta Z-beta A-epsilon V-epsilon VI-psi beta Y-beta F3'. Southern blot analysis of A-type sheep reveals that these animals have a beta-globin locus similar to that of goat, i.e., 12 globin genes. Thus, the beta-globin locus of B-haplotype sheep resembles that of cows and may have retained the duplicated locus of the ancestor of cows and sheep. Alternatively, the B-sheep locus arrangement may be the result of a deletion of a four-gene set from the triplicated locus.
Hypogonadism in patients with advanced cancer: Impact on fatigue, anxiety and depression, hemoglobin, and sexual desire
Authors: F. Strasser, B. Degracia, J. L. Palmer, J. Willey, H.-M. Chang, E. Bruera
Journal: Journal of Clinical Oncology (2004)

8112 Background: Low testosterone (T) levels in men are associated with diminished muscle strength, sexual dysfunction, cognitive deficits, and anemia. To investigate in patients (pts) with advanced cancer the impact of hypogonadism on fatigue, anxiety, depression, anemia, sexual dysfunction and anorexia/cachexia. Methods: Forty-eight consecutive male pts with advanced, metastatic cancer (not prostate) and no antineoplastic treatment for two weeks were evaluated for hypogonadism (serum total and free T, LH, FSH), fatigue (FACIT-Fatigue), anxiety/depression (HADS), anemia (Hb), sexual dysfunction (Sexual Desire Inventory [SDI-2], CARES), anorexia/cachexia related symptoms (FAACT), weight loss, symptoms (ESAS), and Karnofsky Performance Status (KPS). Results: Pts had solid tumors (24 lung, 4 pancreatic, 4 renal cell, 4 sarcoma, 12 other). 39/48 (81%) lived with a partner, 30/47 (64%) had college education. Median survival was 27 weeks (range 4–330 days). 7/48 (15%) pts had normal (241–827) total T (median 101 pg/ml; SD 170), 16/45 (36%) normal (34–194) free T (median 22 pg/ml; SD 26). Correlation (Spearman) of total and free T: 0.94 (p<.001), of free T with FSH (median 7.7 [SD 8]) 0.47 (p=.001), with LH (median 4.1 [SD 4]) 0.5 (p<.001), with duration of opioid treatment (median 2 months, SD 17, range 0–72) −.34 (p=0.025). The FACIT-F score was correlated (Spearman) with hb (.38, p=.007), HADS-A (−.46, p=.001), HADS-D (−.62, p<.001), FAACT (.65, p<.001), and KPS (.41, p=.003). Conclusion: Hypogonadism is 1) frequent in pts with advanced cancer, 2) may be a contributing - but not dominant - factor to cancer-related fatigue, seems to be associated with 3) anxiety and depression, and 4) anorexia/cachexia related symptoms, and 5) does not correlate with sexual dysfunction as measured. Further research might investigate the multidimensional impact of androgen replacement therapy. No significant financial relationships to disclose.
α‐Galactosidase‐A Loaded‐Nanoliposomes with Enhanced Enzymatic Activity and Intracellular Penetration
Authors: Ingrid Cabrera, Ibane Abasolo, José L. Corchero, Elisa Elizondo, Pilar Rivera Gil, Evelyn Moreno, Jordi Faraudo, Santi Sala, Dolores Bueno, Elisabet González‐Mira, Merche Rivas, Marta Melgarejo, Daniel Pulido, Fernando Albericio, Miriam Royo, Antonio Villaverde, Maria F. García‐Parajo, Simó Schwartz, Nora Ventosa, Jaume Veciana
Journal: Advanced Healthcare Materials (2016)

Lysosomal storage disorders (LSD) are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of macromolecules, such as lipids, glycoproteins, and mucopolysaccharides. For instance, the lack of α‐galactosidase A (GLA) activity in Fabry disease patients causes the accumulation of glycosphingolipids in the vasculature leading to multiple organ pathology. Enzyme replacement therapy, which is the most common treatment of LSD, exhibits several drawbacks mainly related to the instability and low efficacy of the exogenously administered therapeutic enzyme. In this work, the unprecedented increased enzymatic activity and intracellular penetration achieved by the association of a human recombinant GLA to nanoliposomes functionalized with Arginine‐Glycine‐Aspartic acid (RGD) peptides is reported. Moreover, these new GLA loaded nanoliposomes lead to a higher efficacy in the reduction of the GLA substrate named globotriasylceramide in a cellular model of Fabry disease, than that achieved by the same concentration of the free enzyme. The preparation of these new liposomal formulations by DELOS‐SUSP, based on the depressurization of a CO 2 ‐expanded liquid organic solution, shows the great potential of this CO 2 ‐based methodology for the one‐step production of protein‐nanoliposome conjugates as bioactive nanomaterials with therapeutic interest.
Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies
Authors: M. M. Mita, E. K. Rowinsky, M. L. Goldston, A. C. Mita, Q. Chu, S. Syed, H. L. Knowles, V. M. Rivera, C. L. Bedrosian, A. W. Tolcher
Journal: Journal of Clinical Oncology (2004)

3076 Background: AP23573, a non-prodrug rapamycin analog, potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient signaling pathways. AP23573 demonstrated potent inhibition of proliferation in vitroin several human tumor cell lines and elicited antitumor activity in vivo in multiple xenograft animal models. Methods: This dose escalation trial utilizes an accelerated titration scheme to determine safety, tolerability and maximum tolerated dose of AP23573 administered without premedication as 30-minute IV infusion daily x 5 days every 2 weeks for 4-week cycles. It also is designed to characterize the PK profile, evaluate potential PD markers using western blot analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of skin biopsies, and ascertain preliminary data on antitumor activity. Results: As of 01 Dec 03: 11 pts (6M/5F), median age 57 yrs (range 23–65 yrs), were treated with AP23573 doses ranging from 3 to 28 mg in 5 dose level cohorts (total cycles, 32; median cycles, 2/pt). No dose-limiting toxicity or AP23573-related serious adverse events have been observed. Side effects for first cycle included grade (gr) 2 anemia (2 pts); gr 3 transient transaminase elevation (1 pt with hepatocellular cancer); gr 2 mucositis (2 pts); gr 1 skin rash (2 pts). PK analyses (doses 3 to 12.5 mg) suggest a mean AP23573 half-life of 44–54 hours. PD analyses (doses 3 and 6.25 mg) indicate rapid (within 1 hr) and prolonged (up to 10 days between doses) inhibition of mTOR activity as demonstrated by >80% decrease in phosphorylated 4EBP1 levels in PBMCs. Of 8 evaluable pts, one partial response has been observed in a pt with metastatic renal cell cancer; (6.25 mg) and 1 pt with metastatic sarcoma (3 mg) has had stable disease > 6 months. Conclusions:AP23573 can be administered safely using this schedule, and has exhibited antitumor activity as well as evidence of a substantial PD effect. Patient dosing and enrollment are ongoing. Further dose escalation as well as exploration of the relationship between PD (PBMC and skin) and PK are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.