tbuckley/cabot-search huggingface dataset:
DYNAMO: A phase 2 trial of the PI3K-δ,γ inhibitor IPI-145 in patients with refractory indolent non-Hodgkin lymphoma.
Authors: Nina Wagner-Johnston, Donald K Strickland, David Donald Wright, Scott A. Tetreault, Scott D. Lunin, James H. Essell, Charles D. Webb, Robert M. Langdon, Charles M. Farber, Nadim F. Nimeh, Mike Marris, Teresa A. Coleman, Patrick Francis Kelly, Lori Steelman, Karen Dewar, Patricia Pimental, Ian Flinn
Journal: Journal of Clinical Oncology (2014)

TPS8619 Background: Phosphoinositide 3-kinase (PI3K)-δ,γ isoforms are preferentially expressed in leukocytes, have significant roles in normal B and T cell function, and are central to the growth and survival of certain B and T cell malignancies. Inhibition of these isoforms by IPI-145, an oral PI3K-δ,γ inhibitor, has unique therapeutic potential in hematologic malignancies. IPI-145 has shown clinical activity and a favorable safety profile across a broad range of hematologic malignancies in an ongoing phase 1 trial (IPI-145-02). Based on these results, the DYNAMO phase 2 trial (IPI-145-06) was initiated in May 2013 to evaluate the efficacy and safety of IPI-145 in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to rituximab and chemotherapy or radioimmunotherapy (RIT). Methods: This open-label, single-arm trial includes adult patients diagnosed with iNHL (defined as follicular lymphoma [FL], marginal zone lymphoma, or small lymphocytic lymphoma) whose disease has progressed within 6 months of their last dose of a chemotherapy regimen or RIT. Eligible patients must have been previously treated with rituximab, and had either no objective response or documented progression within 6 months of completing therapy. Approximately 120 patients will be enrolled, including at least 100 patients with FL, at sites in and outside the US. All patients will receive 25 mg IPI-145 orally, twice daily during 28-day treatment cycles, for up to 12 cycles. After 12 cycles, patients may receive additional cycles of IPI-145 if they have documented evidence of response according to the International Working Group (IWG) criteria. The primary efficacy endpoint is the objective response rate and secondary endpoints include safety and tolerability of IPI-145, duration of response, progression-free survival, overall survival, and pharmacokinetic parameters. Assessment of response, best overall response, and progression status will be evaluated according to the IWG response criteria for NHL. This trial is currently enrolling patients. Clinical trial information: NCT01882803.
Randomized, phase III trial of the efficacy and safety of lenalidomide plus R-CHOP vs R-CHOP in patients with untreated ABC-type diffuse large B-cell lymphoma.
Authors: Grzegorz S. Nowakowski, Annalisa Chiappella, Thomas E. Witzig, Michele Spina, Lei Zhang, Jocelyne Flament, Jacqueline Repici, Umberto Vitolo
Journal: Journal of Clinical Oncology (2015)

TPS8600 Background: The activated B-cell like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL) is associated with inferior PFS and OS with R-CHOP-based chemotherapy. Lenalidomide demonstrated significant single agent activity in relapsed/refractory DLBCL, predominantly in ABC-type DLBCL. In first line therapy, lenalidomide + R-CHOP (R2-CHOP) showed improved efficacy over R-CHOP historical controls in two independent single arm phase II trials from Mayo Clinic and Fondazione Italiana Linfomi groups. R2-CHOP appears primarily to improve outcomes in ABC-type DLBCL. The objective of this multicenter, international trial is to compare the efficacy and safety of lenalidomide–R-CHOP (R2-CHOP) vs placebo–R-CHOP in patients with previously untreated ABC-type DLBCL. Methods: In this phase III placebo-controlled, double-blinded trial (DLC002; NCT02285062), patients with ABC-type DLBCL are randomized 1:1 to oral lenalidomide (15 mg, days 1-14/21-day cycle) plus standard-dose R-CHOP or placebo–R-CHOP, every 21 days for 6 cycles ± 2 additional doses of rituximab until PD, intolerability, inadequate response, or withdrawal of consent. Key eligibility criteria include previously untreated, histologically confirmed ABC-type CD20+ DLBCL (WHO classification), age 18-80 years, IPI score ≥ 2, Ann Arbor stage II-IV, and adequate organ function. ABC type will be determined by central pathology lab within 3 days by real-time gene expression profiling (GEP) using the NanoString nCounter Analysis System (Scott et al. Blood. 2014;123:1214-1217) on FFPE biopsy samples. Primary endpoint is PFS; secondary endpoints are EFS, OS, ORR, CR, duration of CR, time to next lymphoma therapy, and health-related QOL. Additional biological analyses for MRD detection are planned. Responses will be measured by 2007 IWG criteria with PET. Approximately 560 patients will be randomized during the estimated 34 month-accrual period. Enrollment began in January 2015, with expected accrual completion in October, 2017. To our knowledge, this is the first phase III trial in DLBCL using real time GEP to assess patient eligibility, thus allowing precision therapy of patients with DLBCL. Clinical trial information: NCT02285062.
Bioactivation of titanium dioxide scaffolds by ALP-functionalization
Authors: A. Sengottuvelan, P. Balasubramanian, J. Will, A.R. Boccaccini
Journal: Bioactive Materials (2017)

Three dimensional TiO2 scaffolds are receiving renewed attention for bone tissue engineering (TE) due to their biocompatibility and attractive mechanical properties. However the bioactivity of these scaffolds is comparatively lower than that of bioactive glass or hydroxyapatite (HA) scaffolds. One strategy to improve bioactivity is to functionalize the surface of the scaffolds using biomolecules. Alkaline phosphatase (ALP) was chosen in this study due to its important role in the bone mineralization process. The current study investigated the ALP functionalization of 3D titanium dioxide scaffolds using self-polymerization of dopamine. Robust titanium scaffolds (compressive strength∼2.7 ± 0.3 MPa) were produced via foam replica method. Enzyme grafting was performed by dip-coating in polydopamine/ALP solution. The presence of ALP was indirectly confirmed by contact angle measurements and enzymatic activity study. The influence of the enzyme on the bioactivity, e.g. hydroxyapatite formation on the scaffold surface, was measured in simulated body fluid (SBF). After 28 days in SBF, 5 mg ALP coated titania scaffolds exhibited increased hydroxyapatite formation. It was thus confirmed that ALP enhances the bioactivity of titania scaffolds, converting an inert bioceramic in an attractive bioactive system for bone TE.
Tivozanib vs sorafenib targeted therapy for advanced renal cell carcinoma: Final results of a phase III trial (901) and efficacy results of a 2nd line tivozanib extension study (902).
Authors: Thomas Hutson, Dimitry Nosov, Piotr Tomczak, Igor Bondarenko, Oleg N. Lipatov, Cora N. Sternberg, Michael N. Needle, Tim Eisen
Journal: Journal of Clinical Oncology (2015)

4557 Background: An extension and open access study allowed follow up of patients (pts) from TIVO-1 (301), an open label, phase III multinational trial in which pts with metastatic renal cell carcinoma (mRCC) were randomized to either tivozanib or sorafenib (both VEGF TKIs). TIVO-1 met its primary endpoint of improved median progression free survival (PFS) over sorafenib, but overall survival (OS) was shorter (J Clin Oncol. 2013; 31:3791). Follow up analysis of all pts from that trial is presented. Methods: Pts were treated until documented progression or unacceptable tolerability on both treatments. These pts were followed for OS, investigator assessed PFS, and long term safety. The majority of pts who received first line tivozanib had no subsequent therapy; the majority of pts initially treated with sorafenib were crossed over to tivozanib per protocol. Results: Few second line therapy options were available to pts who discontinued initial tivozanib. Of the 259 tivozanib pts, 69.3% received no subsequent therapy, 11.7% VEGF therapy (not tivozanib), 9.7% mTOR inhibitor therapy, and 10.0% non-targeted therapy. All 257 pts discontinued initial sorafenib therapy and 168 (65.4%) went on to subsequent VEGF therapy (163 treated with tivozanib), 1.2% to mTOR, 2.0% to non targeted therapy, and 31.5% to no additional therapy. Follow up PFS and OS from initial randomization for the 260 pts originally receiving tivozanib was 14.6 and 29.0 mos, and for the 257 pts originally receiving sorafenib was 9.7 and 34.1 mos, respectively (PFS HR = 0.77, OS HR = 1.18). Long term safety assessment of pts who continued tivozanib indicated that incidence of the most common on target AEs (hypertension and dysphonia) decreased over time. For the 163 pts who crossed over from sorafenib to second line tivozanib, median PFS was 11 mos and median OS was 21.6 mos from the start of second line tivozanib. Conclusions: This long term analysis of PFS and OS underscores the positive impact of tivozanib treatment after sorafenib failure in mRCC. Lack of access to second line therapies in pts in the tivozanib arm due to geographical reasons most likely affected trial results. Clinical trial information: NCT01030783, NCT01076010, NCT01369433.
Hormonal treatment (HT) and late recurrence in early-stage breast cancer (BC) patients.
Authors: Carlos Hernando Barcenas, Arup Kumar Sinha, Gabriel N. Hortobagyi, Vicente Valero, Naoto T. Ueno, Sharon Hermes Giordano, Mariana Chavez-Mac Gregor, Abenaa M. Brewster, Anthony Lucci, Debu Tripathy
Journal: Journal of Clinical Oncology (2015)

563 Background: BC patients who are disease free after 5 years (Y) of diagnosis still remain at risk of developing a late recurrence. We assessed the effect of HT on the risk of late recurrence in early-stage BC patients with hormone-receptor-positive, HER2-negative disease from a large institutional database. Methods: We retrospectively identified a cohort of female early-stage (I to III) BC patients who had hormone-receptor-positive, HER2-negative (or not tested) disease, diagnosed between January 1997 and August 2008, who had received initial treatment at MD Anderson, and had remained disease free for ≥ 5 Y. We excluded patients who had incomplete HT data and those who received > 10 Y of HT. The primary endpoint was recurrence-free survival measured from the initial BC diagnosis to the first local-regional or distant recurrence. HT agents were categorized as aromatase inhibitors (AI), tamoxifen (T), sequential T and AI (T→AI), and other. The length of HT was categorized as “ < 5 Y”, “5 Y”, “ > 5- < 10 Y” and “10 Y”. We used a multivariable Cox proportional hazard model to calculate hazard ratios (HR) and 95% confidence intervals (CI) for recurrence-free survival adjusted for patient demographics, tumor characteristics and treatments received. Results: We identified 2,839 patients; 155 (5.5%) developed late recurrence (median follow-up of 8.8 Y, range 5-16 Y). Compared to patients who received 5 Y of HT (72%), those who received 10 Y (4.4%) had a 79% reduced risk of late recurrence (HR = 0.21, 95% CI = 0.05, 0.88), while patients who received < 5 Y (14%) had an increased risk (HR = 1.88, 95% CI = 1.23, 2.89), with no difference in the HT length category “ > 5- < 10 Y”. Compared to patients who received T alone (32%), those who received T→AI (26%) had a significantly lower risk of late recurrence (HR = 0.52, 95% CI = 0.32, 0.85), with no difference for patients who received AI alone or other. Conclusions: In this retrospective cohort, HT duration of 10 Y, and the sequential use of T→AI were both factors independently associated with a significantly lower risk of late recurrence, after adjusting for several other known prognostic factors.
The impact of pretreatment MRI on genitourinary and gastrointestinal toxicity after radiation therapy in patients with localized prostate cancer.
Authors: Kyle Kilinski, Arash Naghavi, Yazan Asad Abuodeh, Michelle Echevarria, Kosj Yamoah
Journal: Journal of Clinical Oncology (2017)

119 Background: MRI has several advantages relative to other imaging modalities in evaluating, diagnosing, and planning treatment for prostate cancer yet it is rarely ordered for localized disease. While the diagnostic abilities have been studied, little has been done to associate clinical outcomes with prostate cancer patients who received MRI. We evaluated the effect of pre-treatment MRI on genitourinary (GU) and gastrointestinal (GI) toxicity in prostate cancer patients who received definitive radiation treatment. Methods: We retrospectively analyzed prostate cancer patients who underwent definitive radiation treatment at our facility between January 01, 1999 and July 31, 2014. All patients who underwent MRI of the pelvis or prostate within 5 years prior to treatment were included in the MRI cohort. The American Urological Symptom Score (AUA) and Rectal Assessment Scale (RAS) were used to measure GU and GI toxicity, respectively. We compared the toxicity profile of patients in our MRI cohort to a comparable cohort of patients who did not receive pre-treatment MRI. Results: 1085 patients (211 with MRI) were analyzed. Median follow-up was 30 months. Mean increase from baseline in AUA scores at 6 months was 3.58 for the MRI cohort and 5.04 for the comparison cohort (p = 0.017). RAS scores were not significantly different between the MRI and comparison cohorts at 6 months (mean increase: 0.62 vs. 0.77, p = 0.662). AUA scores returned to baseline after 6 months in the MRI cohort and after 12 months in the comparison cohort. RAS scores returned to baseline after 12 months in the MRI cohort but never returned to baseline in the comparison cohort. Biochemical failure rates were not significantly different between the MRI cohort and comparison cohort (86.3% vs. 91.1%, p = 0.083). Conclusions: Pre-treatment MRI was associated with significantly less GU and GI toxicity. These results may be influenced by more advanced disease and higher use of hormonal therapy in the MRI cohort. Future prospective studies in a risk-matched cohort are required to validate these findings.
NCCTG N0872 (Alliance): A randomized placebo-controlled phase II trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma (GBM).
Authors: Evanthia Galanis, S. Keith Anderson, Panagiotis Anastasiadis, David Dinh Tran, Suriya A. Jeyapalan, Daniel M. Anderson, Timothy J. Kaufmann, Caterina Giannini, Jan C. Buckner, David Schiff
Journal: Journal of Clinical Oncology (2015)

2004 Background: Preclinical data indicate that Src kinase signaling is markedly upregulated at the invasive GBM front following administration of the anti-VEGF antibody bevacizumab (Bev). The broad spectrum Src kinase inhibitor dasatinib can effectively block Bev-induced glioma invasion (Huveldt et al, 2013). We therefore hypothesized that combining dasatinib with Bev could increase Bev efficacy in the recurrent GBM setting. Methods: Eligible patients (pts) had progressive GBM; up to 1 chemotherapy regimen was allowed for recurrent disease. Following a 16 pt phase I dose escalation trial that established Bev 10 mg/kg every 2 weeks in combination with dasatinib 100 mg PO bid as the phase II dose of the combination, the randomized placebo-controlled phase II portion of the trial was initiated. The study followed a 2:1 randomization procedure with 85% power to detect a 20% difference in progression-free survival at 6 months (mo) (primary endpoint) between the two arms, and a type I error rate of 0.15 Results: This analysis includes 121 evaluable patients. Median follow-up was 6.8 mo for Arm A (Bev/Dasatinib, N = 83 pts), and 7.8 mo for Arm B (Bev/placebo, N = 38 pts). Although a higher percentage of Arm A patients were progression free at 6 mo, (27.16% vs 18.42%), this difference did not reach statistical significance (p = 0.30). There was no significant difference in OS (7.2 mo vs 7.9 mo; HR 0.86, 95% CI 0.56-1.31, p = 0.48). Response rate was 18.3% in Arm A and 26.5% in Arm B (p = 0.48). The overall incidence of grade 3+ hematologic and non-hematologic toxicity was comparable in Arms A and B (19.3% vs 16.7% for hematologic toxicity and 45% vs 43.4% for non-hematologic toxicity). Grade 2+ treatment-related hypophosphatemia and diarrhea were more common in the dasatinib arm than in the placebo arm (21.7 vs 5.3% and 19.3 vs 2.6%, respectively). Conclusions: The combination of the Src kinase inhibitor dasatinib with Bev did not improve the outcome of recurrent GBM pts as compared to single agent Bev. Ongoing correlative analysis in baseline tumor samples is exploring associations between sarc family kinase expression (c-Sarc, Lyn, c-Yes) and activation of downstream signaling pathways and outcome. Clinical trial information: NCT00892177.
Surgical outcomes of advanced NSCLC (stage IIIB and IV).
Authors: Jae Hyun Kim, Jong Ho Park, Hae Won Lee, Jin Wook Hwang, Moon Chul Kang, HeeJong Baek
Journal: Journal of Clinical Oncology (2012)

e17523 Background: The role of surgery in the stage IIIB or IV NSCLC (AJCC 6th edition) patients is has been controversial. Now in AJCC 7th edition, the operable T4 and M1 stages were regrouped to IIIA. We analyzed the clinical outcome of the surgical resection for the patients with operable NSCLC of stage IIIB or IV in AJCC 6th edition to evaluate the role of surgery in this group. Methods: From January 1990 to Desember 2009, the 102 patients with stage IIIB(T4) NSCLC and the 36 patients with stage IV (separate tumor in ipsilateral different lobe) NSCLC had been operated in Korean cancer center. We analyzed the long term survival and the risk factors for long term survival of the 138 patient retrospectively. Results: 59 (42.7%) patients had the invasion of major mediastinal organ, and 43 (31.1%) had separate tumor nodules in ipsilateral different lobe, and 36 (26%) had satellite nodules in same lobe. N0 stage was identified in 42 (30.4%) patients, N1 stage in 29 (21%), and N2 stage in 67 (48.6%). Lobectomy was performed in 56 (40.5%) patients, bilobctomy in 14 (10.1%) and pneumonectomy in 68 (49.2%). Complete resection was achieved in 123 (89.1%) and operation mortality rate was 6.5% (9/138 patients). Median survival was 34 months and 5-year and 10-year survival rate was 34.6% and 21.9% respectively. Recurrence, surgery alone, N2 stage, incomplete resection were risk factors of long term survival in multivariate analysis. Conclusions: Although the role of a surgery in the stage IIIB, IV NSCLC patients is very limited, the long term outcomes of surgical resection of them are tolerable in Korean cancer center. So we thought the shifting of stage of the group with operable stage IIIB or IV NSCLC to IIIA is appropriate.
Identification of Bone Marrow Involvement of FL: Comparison of PET-CT and Bone Marrow Biopsy.
Authors: Yuki Nakajima, Shin Fujisawa, Chika Nigauri, Teshigawara Haruka, Ayako Matsumura, Taiki Ando, Taisei Suzuki, Eri Yamamoto, Eriko Ogusa, Yoshimi Ishii, Hiroyuki Takahashi, Kazuho Miyashita, Reina Watanabe, Takuya Miyazaki, Kenji Motohashi, Atsuko Fujita, Maki Hagihara, Kenji Matsumoto, Hideaki Nakajima
Journal: Blood (2016)
The ALK-2 Inhibitor, TP-0184, Demonstrates High Distribution to the Liver Contributing to Significant Preclinical Efficacy in Mouse Models of Anemia of Chronic Disease
Authors: Peter Peterson, Wontak Kim, Hillary Haws, Clifford J. Whatcott, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner
Journal: Blood (2016)
Rational molecularly targeted combinations: A parallel-arm phase I trial of the humanized anti-IGF-1R antibody dalotuzumab (D) in combination with the allosteric AKT inhibitor MK-2206 or the gamma secretase inhibitor MK-0752, in patients with advanced solid tumors.
Authors: Irene Brana, Jhanelle Elaine Gray, Paul Haluska, Raanan Berger, Talia Golan, Mary Elizabeth Jones, Alexandra Gunchenko, Jonathan D. Cheng, Lillian L. Siu
Journal: Journal of Clinical Oncology (2012)

3027 Background: Two rational strategies to interrogate the IGF-1R pathway were investigated in this parallel-arm phase I trial: 1) vertical inhibition with D and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk inhibition with D and MK-0752 to exert effects against cellular proliferation, angiogenesis and stem cell propagation. Methods: Patients (pts) with advanced solid tumors and no prior exposure to agents of the same targets were eligible. Dose escalation was based on a modified toxicity probability interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10 mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle = 4 weeks in both arms. Primary objectives were to determine DLT and RP2D of these combinations. Results: 30 patients were enrolled in the dose escalation phase (18 in Arm A and 12 in Arm B) with: median age = 56 (range 36-74); M:F = 13:17; ECOG 0:1 = 12:18; primary diagnosis = colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens = 3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg (G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events (AEs) were observed. RP2D of Arm A = D 10mg/m2 IV weekly and MK-2206 150 mg PO weekly. Other common AEs in Arm A included: fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10 mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B = D 10mg/m2 IV weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other common AEs in Arm B included: anorexia, nausea and fatigue. No PR was observed and SD &gt; 4 months occurred in 4 pts (all in Arm A). PK analyses are ongoing. Conclusions: Targeted combinations of D with MK-2206 or with MK-0752 were both tolerable. Expansion cohorts based on biomarker selection are underway, specifically ovarian cancer with high IGF1 expression/low RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low IGF2 expression for Arm B.