tbuckley/cabot-search huggingface dataset:
A phase III prevention trial of low-dose tamoxifen in HRT users: The HOT trial.
Authors: Bernardo Bonanni, Patrick Maisonneuve, Davide Serrano, Clara Varricchio, Nicole Rotmensz, Massimiliano Cazzaniga, Matteo Lazzeroni, Barbara Santillo, Raffaella Di Pace, Antuono Latronico, Carlo Belloni, Marco Rosselli Del Turco, Nereo Segnan, Pietro Masullo, Claudio Andreoli, Nadia Monti, Alessandro Vella, Giuseppe D'Aiuto, Umberto Veronesi, Andrea De Censi
Journal: Journal of Clinical Oncology (2012)

1500 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer (BC) incidence, but adverse events are a barrier to its broad use. The Italian Tamoxifen Prevention Trial showed a positive risk/benefit ratio in the subgroup of hormone replacement therapy (HRT) users in the T arm, with fewer BC and no cardiovascular disease (CVD) excess. In a dose-ranging study, T 5 mg/day showed a favorable biomarker modulation in HRT users. We conducted a multicentre, phase III, BC prevention trial in current or de novo HRT users, randomized to either T 5 mg/day or placebo (P) for 5 yrs, with 5yrs follow-up. Methods: The study was powered to detect a 40% decrease of BC on T from an annual rate of 4/1000 on P with 20% dropout and 5y recruitment. All analyses were performed on ITT basis. The cumulative incidence of events was determined using Kaplan-Meier methods. The two treatment groups were compared by using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals were obtained using Cox proportional regression model. All P values were two-sided. Results: Due to the WHI-HRT trial results, recruitment was lower than anticipated, with a total of 1884 subjects being randomized (946 P and 938 T arm, respectively). 79% were &gt;50 years old at study entry. 66% were normal weight, 21% were hysterectomized; 80% were already on HRT at baseline, 53% were on trasdermal route and 28% had 5y-Gail risk&gt;1.5%. At 7.7y mean follow-up, 43 BC were diagnosed, 24 (annual rate 4.1/1000) on P and 19 (3.3/1000) on T (HR 0.80, 95%CI 0.44-1.46). The efficacy of T was greater in luminal-A type (HR=0.32, 95% CI, 012-086). CVD events were rare (including 1 DVT on T), with no statistical difference between arms. A HR of 4.74 (95% CI, 1.96-11.5) was observed for benign endometrial polyps, but no increase of uterine cancers (3 on P vs 1 on T). Menopausal symptoms were more frequent on T, whereas headache was less frequent on T. Conclusions: The combination of low-dose T and HRT is safe and provides a promising way to retain the benefits while reducing the risks of either agent. While the insufficient power of our study prevents firmer conclusions, it supports further studies of low-dose T in the prevention setting.
The Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059: Single-agent activity in patients with relapsed and refractory non-GCB-DLBCL.
Authors: Martin Dyer, Claire Hutchinson, Simon Rule, Nimish Shah, Gilles A. Salles, Lionel Karlin, Franck Morschhauser, Louis Terriou, Christopher Fegan, Andrew Davison, Guillaume Cartron, Andrew Saunders, Hideyuki Honda, John Sharpe, Toshio Yoshizawa, Tomoko Yasuhiro, Kazuhito Kawabata, Hiroshi Awata, Joseph Birkett
Journal: Journal of Clinical Oncology (2014)

8553 Background: Bruton’s tyrosine kinase (BTK) is a critical kinase involved in B-cell receptor signal transduction. ONO-4059, a highly potent and selective oral BTK inhibitor has demonstrated anti-tumour activity in pre-clinical models (Yasuhiro et al, AACR 2013) and in the clinic in both NHL and CLL patients (Salles et al, ASH 2013; Rule et al, ASH 2013). Here, we present data from non-GCB DLBCL patients enrolled in the ongoing Phase I study ONO-4059POE001. Methods: Thirteen patients with relapsed (n=8) or refractory (n=5) non-GCB-DLBCL were administered ONO-4059 as monotherapy, given once daily (QD) at doses ranging from 160-480mg, to determine safety, pharmacokinetics and pharmacodynamics, as well as any preliminary efficacy. Patients had a median age of 65yrs [range 30-72], median of 4 prior therapies [2-8], and a median baseline tumour burden of 2,504mm2 [619-15,750mm2]. All 13 patients had prior exposure to a rituximab-containing regimen and 5/13 patients (38%) had prior ASCT. Results: Thirteen patients were evaluable for safety - ONO-4059 was found to be well tolerated with a total of twenty seven (27) ONO-4059 related adverse events reported in 5/13 patients (CTCAE-V4.0 G1 [n=20 in 4 patients] and G2 [n=5 in 3 patients]). Two ONO-4059-related G3 events reported in two patients were: drug reaction and lymphopenia, with drug reaction reported as an SAE. The pharmacokinetics of ONO-4059 reflects a half-life of ~5-7 hours with sustained inhibition of BTK observed in PBMCs up to 24 hours from first dose. Eight patients are currently evaluable for efficacy - Six patients experienced reductions in lymphadenopathy within the first treatment cycle. Responses occurred at doses of 160mg (n=6) and 320mg (n=2), including 2 refractory patients, with a best overall response rate of 75% (6/8) with 6 PR (median reduction of lymph nodes was 81.5% [52.4-86.6%]) and 2 PD. Of note, no CD79b mutations were identified (n=7 evaluable). Conclusions: ONO-4059 showed a favorable safety profile along with promising preliminary efficacy in this difficult-to-treat non-GCB-DLBCL patient population. The study is ongoing with additional dose escalation cohorts underway. Clinical trial information: NCT01659255.
Tumor genomic analysis for 128 renal cell carcinoma (RCC) patients receiving first-line everolimus: Correlation between outcome and mutations status in MTOR, TSC1, and TSC2.
Authors: Martin Henner Voss, David Chen, Mahtab Marker, Jianing Xu, Parul Patel, Xia Han, James Hsieh, Robert J. Motzer
Journal: Journal of Clinical Oncology (2017)

484 Background: MTOR inhibitors are standard agents in the management of advanced RCC. Case series have suggested somatic mutations in MTOR, TSC1, and TSC2 may sensitize tumors to everolimus (EVE) [Voss et al., CCR 2014; Kwiatkowski et al., CCR 2016]. We sought to test this hypothesis through next generation sequencing (NGS) of tumors from a large cohort of patients (pts) treated with everolimus (EVE) on the randomized RECORD3 trial of first-line EVE vs. sunitinib. Methods: Somatic mutations were investigated using a custom exon-targeted NGS platform with deep sequence coverage. This analysis focused on mutations in TSC1, TSC2, PTEN, PIK3CA, and MTOR. Association between genotypes and progression free survival (PFS) was assessed by Cox PH models and log-rank tests. Mutations in other pathways and non-genetic covariates were investigated. Functional investigation of individual mutations in MTOR, TSC1, and TSC2 were undertaken. Results: 238 pts received 1 st line EVE with median PFS of 7.85 mo (95% CI 5.6-8.2). Tumor sampleswere analyzed for 128 pts. Median depth of coverage was ~540X. There was no correlation between PFS and mutation status of mTOR, TSC1, or TSC2 (15 pts [12%]; HR 0.99 [95% CI 0.47-2.07]; p=0.4697); the objective response rate (ORR) in this group was 0%. Individual PFS for all 15 pts clustered outside the 95% CI for the population of 128 everolimus-treated pts (8 pts PFS&lt;2.8mo; 7pts PFS&gt;8.3mo). 3 of 8 pts with PFS&lt;2.8mo had &gt;1 mutation in MTOR, TSC1, or TSC2, while none among the 7 pts with PFS &gt;8.3mo. When including pts with mutations in PTEN, PIK3Ca, MTOR, or TSC1 (30pts [23%]), we found no association between mutation status and PFS (HR 1.02 [95% CI 0.61-1.71]; p=0.3025). Functional investigations suggest varying biologic effects of individual mutations. Conclusions: "One-dimensional" mutation status for core components of the MTOR signaling pathway did not correlate with PFS in this dataset. Grouping based on more detailed characterization incorporating copy number status and functional annotation may provide better insights and should be considered for future biomarker development. Clinical trial information: NCT00903175.
Assessment of microvessel density in young (< 40 years) and old patients with colorectal cancer.
Authors: Dr Chetan Dilip Deshmukh, Dr Sujit Joshi, Dr Sachin Sharadchandra Hingmire, Dr Sheetal Patil, Dr Dhananjay Kelkar
Journal: Journal of Clinical Oncology (2014)

e22003 Background: The incidence of colorectal cancer (CRC) in India is approximately 3-5 per 1,00,000 men and is on the rise. The median age at presentation is 50 years but an increasing number of young patients (< 40 years) are being diagnosed with CRC. Patients with CRC < 40 years of age were likely to have a worse outcome. However the reasons for this are unknown and may be due to an aggressive biology of these tumors. Angiogenesis plays a major role in local invasion and tumor metastasis. Microvessel density in the cancer tissue is one of the surrogate markers of angiogenesis. The present study aims to assess the median microvessel density in tissue specimens of young and old patients with CRC. Methods: Formalin fixed paraffin-embedded pretreatment specimens of tumors from patients young and old patients with CRC were studied. Microvessel density (MVD) assessment, a technique used to quantify intratumoral angiogenesis in carcinomas was studied using pan-endothelial immunohistochemical staining of blood microvessels by a monoclonal antibody anti-CD34. Light microscopy and computerized image analysis systems were used for blinded optical reading of slides. Microvessel density of the specimen was estimated as a mean of MVD in three histological fields. Results: Tumor specimens from 25 young(< 40 years)and 25 patients (age > 40 years) were studied for microvessel density. The median age of young patients was 32 (range 25-38). There were 17 males and 8 females. The median age of older patients was 61 years (range 43-84). The median microvessel density in both groups was as follows (see Table). Conclusions: Young patients had a significantly higher microvessel density which may account for their presentation in an advanced stage, aggressive behavior and poor overall outcomes. Population Median age Median microvessel density P value Young CRC 32 years 51 p = 0.02 Old CRC 61 years 33
Trans Tasman Radiation Oncology Group (TROG) 02.03 phase III trial: Concurrent weekly cisplatin and radiation therapy in localized muscle- invasive bladder cancer—Compliance, toxicity, QOL, and overall results.
Authors: Nirdosh Kumar Gogna, Peter O'Brien, Nigel Spry, Sandra Turner, John Matthews, Martin Borg, Gillian M. Duchesne, Kathryn Baumann, Madeleine King, Elizabeth Burmeister
Journal: Journal of Clinical Oncology (2014)

4543 Background: This phase III trial investigated the benefits and toxicities of a combination of weekly cisplatin and radiation therapy (Arm A) compared with radiation therapy (RT) alone (Arm B)in the definitive treatment of muscle-invasive bladder cancer (MIBC). Methods: Adult patients with localized Stage T2-T4a, bladder cancer of predominant transitional cell carcinoma histology with no contraindications to the use of pelvic radiation therapy or cisplatin chemotherapy were eligible. Othet exclusion criteria included extensive or multifocal carcinoma in situ and a contracted bladder. An initial maximal transurethral resection of the bladder tumour (TURBT) preceded randomisation. The primary outcome was local failure at 3 years. The secondary endpoints included complete response rate at3 months, overall and disease free survival, acute and late toxicity and QoL. The QoL of patients receiving organ preserving treatments for MIBC had not been previously investigated in a randomised Phase III setting. Intitial accrual target was set at 150 patients over 4 years. Slow accrual lead to early closure with Thirty eight patients were being randomised to arm A and 30 patients to arm B. Results: Compliance with RT in both arms was excellent. About 15% of patients in the chemoradiation arm required a significant reduction in cisplatin dose delivery mainly because of declining renal function. Acute and late toxicity was similar in the two arms, but in the short to medium term chemoradiation did affect QoL. Trends towards better local control, distant disease free and overall survival were noted in the chemoradiation arm. Conclusions: Overall weekly cisplatin and radiation therapy in MIBC are reasonably well tolerated. Treatment however in the short to medium term does affect Qol. Notwithstanding this negative impact, recovery does follow in the longer term. This is yet another study which suggests that chemoradiation does offer the prospect of improving local control and overall survival compared to radiation therapy alone. Clinical trial information: No NCT00330499.
Phase II trial of nemorubicin hydrochloride (N) in combination with cisplatin (cDDP) administered by intra-hepatic artery (IHA) in patients (pts) with hepatocellular carcinoma (HCC): Final results.
Authors: Francesco Izzo, Thomas J. Vogl, Gennaro Gadaleta-Caldarola, Mark R. Middleton, Juan W. Valle, Renate Hammerstingl, Cosmo D. Gadaleta, Marcella Martignoni, Anna Petroccione, Mariangela Mariani, Cristina Davite, Francesco Fiore
Journal: Journal of Clinical Oncology (2013)

e15061 Background: N is a novel DNA-intercalator, mainly metabolized in liver by CYP3A4 enzyme and showing synergic antitumor activity with cDDP. The objective of this study was to evaluate the efficacy and toxicity of N administered by IHA in combination with cDDP to unresectable HCC pts. Methods: The study was in two HCC pt populations: advanced risk (ARP) (CLIP 2, bilirubin ≤ 2.5 mg/dL, portal vein thrombosis [PVT] admitted) and intermediate risk (IRP) (CLIP 0-1, bilirubin ≤ 1.5 x ULN, no PVT). Treatment was repeated every 4-6 wks for a maximum of 6 courses, if acceptable toxicity and no disease progression occurred. A single-arm, Simon’s Minimax two-stage design was adopted to evaluate the primary endpoint of tumour response (WHO criteria, critical numbers of responses to reject H 0 were ≥ 6/29 evaluable pts and ≥ 11/33 evaluable pts in ARP and IRP, respectively). Results: Thirty-seven ARP pts (27 evaluable) and 42 IRP pts (33 evaluable) were enrolled. The median number of cycles was 3 in both ARP (range 1-13; dose 400 mcg/m 2 nemorubicin and 60 mg/m 2 cDDP) and in IRP (range 1-6; dose 600 mcg/m 2 nemorubicin and 60 mg/m 2 cDDP). The trial was successful in ARP with 8 successes/27 evaluable pts (RR 30%): 7 partial responses (PR), 1 downstaging and 8 minor responses (MR)/ disease stabilization (SD) &gt; 3 months. The IRP did not meet the efficacy criteria:2 CR, 5 PR and 13 MR/SD &gt; 3 months (7 responses/33 evaluable pts; RR 21%). Overall, the main Grade 3-4 hematological and biochemical toxicities in ARP/IRP were thrombocytopenia (28/58%), neutropenia (26/60%), aspartate aminotransferase (25/31%), alanine aminotransferase (14/23%) and bilirubin increase (17/21%). The most frequent adverse events (any Grade ≥ 20%) were fatigue (38%), nausea (35/29%), and vomiting (24/26%). Conclusions: The trial was successful in ARP but not in IRP; IHA infusion of N with cDDP showed promising activity in both IRP and ARP with a well tolerated regimen. These encouraging results warrant further investigation in HCC, specially in multinodular type. Clinical trial information: 2005-000731-26.
First in-human phase 1 trial of a novel amino-peptidase inhibitor, CHR-2797
Authors: A. Protheroe, A. Reid, G. Attard, A. Davies, J. Spicer, L. Vidal, E. Bone, L. Hooftman, A. Harris, J. De-Bono
Journal: Journal of Clinical Oncology (2007)

3537 Background: CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn ++ -dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, Noxa. CHR-79888 is an active metabolite of CHR-2797. Patients and Methods: This study was conducted according to an accelerated titration design to define the MTD, DLT, toxicity profile and PK of CHR-2797 when administered orally for 28 days or longer. Patients (ECOG PS = 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. Results: 37 pts (median age 61.5 years [range 22.4–80.1]; 30M/7F; median ECOG PS 1; median prior regimens 2, range 0–6) enrolled in 12 cohorts (doses between 10 and 320mg). The first four patients received a 10 mg dose for 7, 14, 21 or 28 days respectively. Subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity = Grade 2. Thereafter the study followed a 3+3 design with = 40% dose increments. Common (gr 1–2) toxicity included fatigue (47%), diarrhea (47%), dizziness (24%), constipation, vomiting, abdominal pain (all 21%), and thrombocytopenia (18%). Toxicities show dose dependency for thrombocytopenia and fatigue. MTD was declared at 320 mg after 2 DLT’s were reported: 2 patients were unable to complete 28 days of daily dosing due to syncope/anemia, and dizziness/visual disturbances/thrombocytopenia, respectively. Patients recovered fully after cessation of the drug. The dose level below (240 mg) was expanded to 13 patients. Plasma PK was determined for both CHR-2797 and -79888, on days 1 and 28, which showed dose proportional increases in AUC and Cmax. Intracellular and intratumoral levels of both the parent and metabolite were also measured. So far 4 patients continued therapy for 7–9 months: one patient (RCC [130 mg]) achieved a PR, and 3 patients (ovarian ca [40 mg], NSCLC [130 mg], and breast ca [180 mg] had confirmed SD (&gt; 3 months). Conclusion: Once daily oral CHR-2797 can be administered safely for 28 days in doses up to 240 mg and exhibits favorable PK. No significant financial relationships to disclose.
A phase I trial of doxorubicin and flavopiridol in soft tissue sarcoma
Authors: D. R. D’Adamo, K. Scheu, S. Singer, G. K. Schwartz, R. G. Maki
Journal: Journal of Clinical Oncology (2006)

9523 Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m 2 ), followed 1 hour later by escalating doses of F (40–70 mg/m 2 ) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m 2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m 2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m 2 . Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing. No significant financial relationships to disclose.
Survival improvement associated with access to biological agents: Updated results from the South Australian (SA) metastatic colorectal cancer (mCRC) registry.
Authors: Yoko Tomita, Christos Stelios Karapetis, Shahid Ullah, Amanda Rose Townsend, Rob Padbury, Timothy Jay Price
Journal: Journal of Clinical Oncology (2015)

e14576 Background: Survival from mCRC has improved over the last decade, in part due to access to biological agents. In Australia, the first VEGF and EGFR inhibitors were approved for subsidisation through Pharmaceutical Benefit Scheme (PBS) in July 2009 and September 2011, respectively. By comparing two time cohorts based on the change in accessibility, their impact on mCRC outcomes can be assessed. Methods: The SA mCRC registry data were analysed for differences in patient characteristics, treatment received and outcomes based on diagnosis in two time periods; 1/2/06-31/5/09 (A) vs 1/6/09-30/06/14 (B). Results: 3308 patients were analysed; 1464 (44.3%) (A) and 1844 (55.7%) (B). 60.7% and 58.8% respectively received systemic therapy (p = 0.26). Major differences in clinical characteristics were; median age 73.4 vs 71.5yrs (p < 0.001), biological agent use 17.8 vs 33.1% (p < 0.001), and clinical trial enrollment 12.3 v 6.5% (p < 0.001). Uptake of bevacizumab was; first-line 9.4 vs 41.6%, second-line 5.5 vs 16.4% and third/fourth-line 4.2 vs 3.2%. EGFR inhibitors were used; first-line 1.5 vs 2.2%, second-line 3.5 vs 4.6% and third/fourth-line 12.0 vs 10.1%. mOS for the entire group was 13.1 vs 17.1mths (p < 0.001). For those receiving systemic therapy, mOS was 15.9 vs 19.9mths (p ≤ 0.001). On multivariate analysis adjusting for age, sex, histological grade, right vs left primary, synchronous vs metachronous disease, chemotherapy and liver surgery, biological agent use and Cohort B were associated with improved mOS (HR = 0.37; p < 0.001 and HR = 0.82; p < 0.001, respectively). Conclusions: The expected rise in administration was observed in Cohort B for bevacizumab. Its use in first-line remained relatively low at 41.6% even after the reimbursement, potentially reflecting real world practice where co-morbidities, primary in-situ and age may contraindicate its use. Lack of increase in EGFR inhibitor use may be explained by the later reimbursement and the delay to third-line therapy in Cohort B. mOS improvement over time is attributed to increased access to biological agents, especially, bevacizumab and possibly advance in perioperative and supportive care.