tbuckley/cabot-search huggingface dataset:
Cohort compassionate-use program (CUP) and early access program (EAP) with cabazitaxel (Cbz) plus prednisone (P; Cbz + P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D): Analysis by age group.
Authors: Zafar Malik, Giuseppe di Lorenzo, Sergio Bracarda, Alexandros Ardavanis, Mert Basaran, Phillip Parente, Wito de Schultz, Fred Saad, Inge van Oort, Winald R. Gerritsen, Luis M. Antón Aparicio, Geoffrey Matus, Simon Hitier, Axel Heidenreich, Amit Bahl
Journal: Journal of Clinical Oncology (2014)

109 Background: Cbz + P demonstrated an overall survival benefit vs mitoxantrone + P in pts with mCRPC in the Phase III TROPIC trial. The CUP (CABAZ_C_05005) and EAP (NCT01254279) (both funded by Sanofi) were established to allow access to Cbz ahead of commercial availability. The programs are also evaluating Cbz safety in a real-world population. Data analyzed by age group (≤75 and &gt;75 years) are presented here. Methods: Expected enrolment across both programs is 1,450 pts from 236 centres worldwide. Pts received Cbz 25 mg/m 2 IV Q3W + P 10 mg QD until disease progression, death, unacceptable toxicity or physician/pt decision. G-CSF is administered as per ASCO guidelines. Results: As of May 30, 2012, 1,301 pts have enrolled (≤75 years: 1,061 pts [81.6%]; &gt;75 years: 240 pts [18.4%]). Eastern Cooperative Oncology Group performance status and incidence of visceral metastases were generally balanced between treatment groups. The most frequent reasons for discontinuation were disease progression (46.8%) followed by adverse events (AEs; 24.4%) in pts ≤75 years, and AEs (36.4%) followed by disease progression (31.1%) in pts &gt;75 years. Time from initial diagnosis to inclusion was greater in pts &gt;75 years (median 79.66 months) than in pts ≤75 years (median 53.94 months), but time from mCRPC diagnosis to inclusion was approximately equivalent (&gt;75 years: median 22.6 months; ≤75 years: median 20.94 months). G-CSF use was more frequent in pts &gt;75 years (cycle 1: 62.9% of pts) compared with pts ≤75 years (cycle 1: 52.2% of pts). AEs of clinical concern were more frequent in the older age group (Grade ≥3 AEs: &gt;75 years 64.2%; ≤75 years 54.8%). Grade ≥3 neutropenia was observed in 25.8% of pts &gt;75 years and in 17.0% of pts ≤75 years. Conclusions: We observed several differences between age groups in baseline and on-treatment parameters, suggesting differences in the natural history of mCRPC (faster disease progression in pts ≤75 years than in pts &gt;75 years) and secondary to treatment (AEs more frequent in pts &gt;75 years compared with pts ≤75 years). Clinical trial information: NCT01254279.
A phase 1 study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer
Authors: I. Rabinowitz, C. F. Verschraegen, F. C. Lee, H. O. Smith, M. Royce
Journal: Journal of Clinical Oncology (2006)

13099 Background: Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor. The major toxicities are secretory diarrhea and neutropenia for the 72- and 1-hour infusion schedules, respectively, fatigue, and thrombosis. Gemcitabine or irinotecan (SN-38) followed by flavopiridol at concentrations that correlate with CDK inhibition, produce sequence-dependent cytotoxic synergy with increase in apoptosis by 10–15-fold in all the cell lines tested. Both gemcitabine and irinotecan have broad activity in a number of solid tumors and may be synergistic with flavopiridol. Methods: Eligibility criteria included: patients (pts) with any advanced solid tumors; &gt;18 years old; PS ≤ 2; life expectancy &gt; 3 months; and normal kidney, liver, and marrow functions. Treatment consisted in gemcitabine 800 mg/m 2 and irinotecan 80 mg/m 2 on day 1 and flavopiridol, starting dose of 30 mg/m 2 on day 2 with increment of 15 mg/m 2 per dose level, repeated on days 8 and 9 for the first 6 patients, then on days 15 and 16 for the other patients (protocol was amended for inability to redose after one week). Results: Fifteen pts (12 women and 3 men) were enrolled. Characteristics were: Median age, 49 (33–77) years; Median PS 1; ethnicities, 6 whites, 3 native americans, 3 hispanics, and 3 others; Median number of prior chemotherapies, 2 (0–9). Six pts were treated on the first schedule at the first dose level, which caused 1 neutropenic sepsis and death, 1 grade 3 diarrhea, and 5 neutropenia preventing retreatment. On the q 2 week schedule, we have reached the second dose level. Side effects at flavopiridol 30 mg/m 2 were all grade 1: nausea (3/3), fatigue (2/3), anorexia (1/3), and neuropathy (1/3). At 45 mg/m 2 one heavily pretreated pt had DLT of diarrhea and fatigue. The other 5 pts had grade 2 fatigue (2/5), nausea (2/5), diarrhea (1/5), anorexia (1/5). Additional grade 1 side effects include thrombocytopenia, pitting edema, and pain. Response were seen a small cell tumor of the ovary, and a leiomyosarcoma of the uterus. Conclusions: The every two week dosing is well tolerated and the MTD has not yet been reached. Main side effects are consistent with known toxicity profile for irinotecan and gemcitabine. Mild pitting edema and sensory neuropathy have been noted in 2 patients each. No significant financial relationships to disclose.
Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial
Authors: A. Ravaud, C. de la Fouchardière, F. Courbon, J. Asselineau, M. Klein, P. Nicoli-Sire, C. Bournaud, J. Delord, G. Weryha, B. Catargi
Journal: Journal of Clinical Oncology (2008)

6058 Background: There is no standard treatment for advanced thyroid cancer refractory to radioactive iodine (RTC). There are arguments for implication of angiogenesis in TC. Methods: In this phase II study, sunitinib (Su) was given at 50 mg/d for 4 weeks every 6 weeks. Patients (pts) had anaplastic, medullar or differentiated RTC being progressive during the last 6 months. Primary endpoint was objective response and secondary endpoints were safety, overall survival and time to progression. A 20% response rate is expected. A two-stage design was proposed to include 21 (+20) and 11 (+4–7) assessable pts in the non medullar and medullar RTC group during the 1st period, respectively. Results: Seventeen pts were included in 3 months. Eight pts had papillary, 4 medullar, 1 anaplastic and 4 miscellaneous. Median age was 64.3 years old. Median time from primary tumor to inclusion was 7.3 months (range: 2–240). Metastatic sites were lung (15pts), lymph nodes (8pts) and bone (5pts). Three pts had an increased thyroglobulin levels. Median number of Su cycles was 2.1 (range 1–4). Four pts needed a decrease of Su to 37.5mg/d. Toxicities were mainly hypertension, asthenia (7pts each), mucositis (5pts), hand foot syndrome (2pts), and thrombopenia (2pts). Grade 3/4 events were hypertension, asthenia, mucositis and hand foot syndrome. Fifteen pts were evaluable for response: 1 pt had a PR, 12 pts had a stable disease with 1 pt with > 90% decrease of thyroglobulin and 1 pt with a dramatic decrease of symptoms. Conclusion: Sunitinib appeared feasible in pts with RTC and efficacy evaluation has to be confirmed in the entire population of the study. Results from the 1st period will be presented at the ASCO meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Pfizer Bayer, Pfizer Bayer, Pfizer
An evaluation of clusterin antisense inhibitor OGX-011 in combination with the second-generation antiandrogen MDV3100 in a castrate-resistant prostate cancer model.
Authors: H. Matsumoto, H. Kuruma, A. Zoubeidi, L. Fazli, M. E. Gleave
Journal: Journal of Clinical Oncology (2011)

4502 Background: Experimental evidence strongly implicate the AR and intra-tumoral androgen synthesis in promoting tumor cell survival and development of castrate resistant prostate cancer (CRPC). The new second generation AR antagonist, MDV3100, has shown activity in preclinical and clinical studies. Our previous studies link androgen ablation therapy with clusterin upregulation and castrate resistance, and we developed the antisense inhibitor, OGX-011, that synergistically enhances both castration and chemotherapies in prostate cancer (CaP) models. In this study, we tested whether OGX-011 sensitized MDV3100 and delayed progression in castrate-resistant LNCaP model. Methods: Effects of single vs combination MDV3100 and OGX-011 regimens on AR-positive LNCaP cell growth rates, protein, and gene expression were analyzed using crystal violet assay, flow cytometry, western blotting and RT-PCR, respectively. AR transcriptional activity was measured by PSA-luciferase reporter assay, while AR degradation was assessed by cycloheximide chase assay. The effects combination treatment on castrate-resistant LNCaP tumor growth was assessed in castrated male athymic mice. Results: Combination OGX-011 + MDV3100 showed synergistic effect and more potently suppressed LNCaP cell growth rates in a dose and time dependent manner compared to OGX-011 or MDV3100 monotherapy. As negative controls, no synergism was seen in AR negative PC3 cells. PARP cleavage, sub G0/G1 apoptotic fraction and repressed AKT phosphorylation was most enhanced with combined therapy. Interestingly, OGX-011 accelerated AR degradation and repressed AR transcriptional activity in combination with MDV3100. In vivo, combined OGX-011 + MDV3100 significantly delayed castration-resistant LNCaP tumor progression and PSA progression compared to scramble oligonucleotide + MDV3100 (p<0.05 and p<0.05 at 12weeks, respectively). Conclusions: OGX-011 combined with MDV3100 down-regulated AR levels and activity and suppressed castrate resistant LNCaP cell growth in vitro and in vivo, providing pre-clinical proof-of-principle as a promising approach for AR targeting therapy in CRPC.
Phase I study of epirubicin plus docetaxel (ET) in patients (pts) with hormone refractory prostate cancer (HRPC)
Authors: H. Henary, R. J. Amato
Journal: Journal of Clinical Oncology (2005)

4784 Background: Doxorubicin formulation with improved tolerance would increase the drug’s therapeutic ratio and enhance the efficacy. Anthracyclines demonstrates similar toxicity. Epirubicin has an advantage that a patient who is responding to therapy would receive a greater cumulative dose before one must discontinue the agent secondary to the potential of cardiac toxicity. Single agent activity was reported in HRPC. Docetaxel (Taxotere) represents an effective and well-tolerated agent, needing further development for HRPC. Data suggests in other solid tumors that epirubicin and taxotere is synergistic. First stage is to determine the maximum tolerated dose (MTD) of the combination ET in pts with HRPC. Methods: Eligibility included: progressive HRPC affecting bone, worsening cancer-related symptoms, increasing prostate-specific antigen (PSA) values on 2 occasions at least 2 weeks apart, castrate serum testosterone concentration of <50ng/L, disease progression after antiandrogen withdrawal, life expectancy >3 three months, Zubrod performance status of ≤2, and normal organ/marrow function. ET will be given by intravenous infusion over 1 hour weekly for 3 weeks on days 1, 8, and 15 over a 35-day cycle. To determine the MTD of the combination of ET, the “3+3” rule will be utilized. RECIST criteria is utilized to determine response rate. Results: Twelve men enrolled, median age of 69 (range 53–90) years. All pts had rising PSAs as per protocol design with evidence of metastatic involvement. Baseline PSA for this group ranged from 2.6 to 408. A median of 15 weeks of therapy has been completed. Three pts have been enrolled in dose level 0, 6 pts at dose level +1, 3 pts at dose level +2. Hematologic toxicity: 5 pts grade 2 neutropenia, 1 pt grade 2 thrombocytopenia. One pt had a >50% reduction in PSA to date. Conclusion: Enrollment is ongoing. Further data regarding determination of the MTD, in addition to PSA response will be presented. No significant financial relationships to disclose.
Histopathological features of breast cancers in women with germline TP53 mutations
Authors: S. Masciari, M. Kandel, L. Digianni, D. Dillon, F. Li, J. Garber
Journal: Journal of Clinical Oncology (2006)

10031 Background: Breast cancers (BR) in women with germline BRCA1 mutations are usually high-grade ductal carcinomas; 90% are negative for estrogen receptor (ER), progesterone receptor (PR) and HER2. No characteristic phenotype has been found for BRCA2-associated tumors. For women with germline TP53 mutations (Li Fraumeni Syndrome), breast cancer is the most common tumor; the risk of BR is 49% by age 60, with significant risk before age 40. The histopathological profile of BR in women with germline TP53 mutations has not been characterized. Methods: We identified BR from 17 female TP53 mutation carriers from the LFS family registry at Dana Farber Cancer Institute on which at least ER and PR data were available. Information on histology, hormone receptor and HER2 status by immunohistochemistry (IHC) was collected from medical records. Histology was not centrally reviewed. Results: 14 invasive ductal carcinoma (IDC) and 4 DCIS were identified in 17 women (1 woman had both) (see Table). The median age at diagnosis of invasive BR was 30 years (range 24–48), for DCIS it was 37 years (range 22–40). Of the 14 IDC, 11 (79%) were high grade (G3), 10 (71%) were ER positive, 7 (50%) PR positive, 6 PR negative and 1 PR unknown. Among 9 tumors with available HER2 status, 6 (67%) were positive. Both ER+/PR+ and ER-/PR- DCIS were observed. Conclusions: In young women with TP53 germline mutations, BR are more likely to be high grade and ER positive with no other distinct pattern in contrast to BRCA1-associated tumors. Findings of DCIS alone suggest potential value for mammographic screening. Confirmation of these results in a larger series will be important. [Table: see text] No significant financial relationships to disclose.
Thalidomide-dexamethasone versus melphalan-prednisolone as first line treatment in elderly patients with multiple myeloma: An interim analysis
Authors: H. Ludwig, J. Drach, E. Tóthová, H. Gisslinger, B. Jaksic, W. Linkesch, R. Hajek, R. Greil, M. Fridrik, B. Labar, N. Zojer
Journal: Journal of Clinical Oncology (2005)

6537 Background: Thalidomide-Dexamethasone (TD) has shown activity in pts with relapsing or refractory multiple myeloma (MM). In the present trial we compare TD with standard Melphalan-Prednisone (MP) in previously untreated elderly pts with MM. Methods: 137 of 350 pts planned have been enrolled (median age: 72 yrs, stage I: 6 (4%), stage II: 52 (38%), stage III: 79 (58%). Pts are randomised to either T 200mg/d and D 40mg, d1–4 and 15–18 on odd cycles and d1–4 on even cycles or M 2.5mg/kg d1–4 and P 2mg/kg d1–4, q 4–6 weeks. The dose of T is increased to 400mg/d if feasible. Pts achieving response or stabilisation are randomised to maintenance treatment either with T (maximal dose 200mg/d)-Interferon alpha-2b (3Mega U, TIW) or Interferon alpha-2b (3Mega U/TIW). All pts are scheduled for monthly zolendronate (4mg). Results: 93 pts are evaluable for response. Best response to TD was: CR 6 (13%), NCR 4 (8%), VGPR 5 (10%) PR 8 (17%), MR 7 (15%) yielding an ORR of 63%. 3 pts had SD (6%) and 15 PD or failure (31%). Results in the MP arm were: CR 2 (4%), NCR 5 (11%), VGPR 5 (11%), PR 8 (18%), MR 8 (18%), ORR 62% (ns) Analysis per protocol: ORR 88% in the TD and 68% in the MP group (p<0.05). Time to response and to best response were significantly shorter in the TD (8, 11 weeks, respectively) compared to the MP group (10, 39 weeks, respectively; p<0.01, p<0.0047, respectively). Data on progression-free and overall survival will be presented only for both groups combined. Toxicity: Grade III-IV leukopenia (38 vs 2%) and thrombocytopenia (18 vs 2%) was significantly more frequent in pts on MP (p<0.00001, p<0.028 respectively). Patients on TD had more grade II-III neuropathy (22%), psychological toxicity (19%) and skin toxicity (10%) compared to those on MP (0, 8, 2%, respectively). Thromboembolic complications were seen in 8% pts on TD and 4% of pts on MP. Conclusions: Time to response (and to best response) was significantly shorter in pts on TD. Per protocol analysis showed a higher RR in TD treated pts (88 vs 68%, p<0.05) but similar RR (63 vs 62%) were obtained in the intent to treat analysis. Toxicity profile is different in the 2 treatment arms. No significant financial relationships to disclose.
Esophageal cancer at the VA: Does histology matter?
Authors: A. K. Gupta, M. S. Beg, R. Komrokji, M. Atiq, S. Mekan, M. Safa
Journal: Journal of Clinical Oncology (2007)

15069 Introduction: In recent years esophageal cancer has shown a shift from largely squamous cell carcinoma (SCC) histology to adenocarcinoma (AC). This is felt to be due to changing risk factor profiles among the American population. Methods: The VA Central Cancer Registry is a function of the Chief, Program Office for Oncology at VA Headquarters in Washington DC. We queried the VACCR database for all diagnosed esophageal cancer cases between 1995 and 2005 using ICD codes 150–159. The data was transformed, entered and analyzed using SPSS v.13.0. Results: There were a total of 6874 cases diagnosed between 1995 and 2005. Out of those, 2968 (43.2%) were diagnosed with AC and 2894 (42.1%) with SCC. Black patients were more likely to have SCC than AC. Baseline characteristics are summarized in table 1 . Staging information was available in 2823 (48.1%) patients. Patients with AC were more likely to present with metastatic disease than those with SCC (52.7% vs. 44.3%). Median survival in AC was better than SCC for non-metastatic disease (12.3 mo vs. 8.6 mo, p=0.0009). No difference in survival was seen in metastatic disease between the two histologies (AC 4.2 mo vs. SCC 3.97 mo p=0.537). In Cox- regression analysis using variables including race, histology, stage, grade and treatment, only histology, stage, grade and treatment were significant predictors of survival. Conclusions: In non-metastatic esophageal cancer at the VA, SCC has worse outcome compared to AC. However, in metastatic disease, SCC and AC have similar outcome. We recommend further studies to determine if the differences in histology are determined by biological or lifestyle differences. [Table: see text] No significant financial relationships to disclose.
Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma (NPC)
Authors: D. Poon, B. Chowbay, S. S. Leong, Y. B. Cheung, C. K. Toh, M. H. Tay, W. T. Lim, E. H. Tan
Journal: Journal of Clinical Oncology (2004)

5576 Background: Advanced NPC is chemosensitive and responsive even to third-line salvage regimen, therefore the continued search for active agents to enhance salvage potential. Topoisomerase I targeters have been shown to induce apoptosis in NPC cell lines in in-vitro experiments. This phase II study was designed to evaluate efficacy and safety of irinotecan in patients with advanced NPC. The pharmacokinetic and pharmacogenetic study component is reported separately. Methods: Eligibility criteria included AJCC stage IVC nasopharyngeal undifferentiated carcinoma, ECOG performance status (PS) 0–2, progressive disease during or less than 3 months after platinum-based and/or taxane-based regimen, and bidimensionally measurable disease. Irinotecan at 100 mg/m2 was administered on days 1, 8, 15, every 28 days up to maximum of 6 cycles, or until disease progression or appearance of non-tolerable toxicity. Tumor response was evaluated after every 2 cycles based on WHO criteria. Results: Between September 2001 and November 2003, 30 patients were enrolled. Currently data is available for 25 patients. Patient characteristics included mean age 50.9 (standard deviation - SD 7.5), 21 males; 4 females, 23 (92%) are Chinese, 22 (88%) had ECOG PS 0–1, and a mean 2.0 (SD 1.8) prior lines of chemotherapy. To date, all 25 patients are evaluable for toxicity with a mean 3.0 (SD 1.6) cycles of irinotecan administered. Severe toxicities of greater than grade 3 (WHO) included: grade 3 neutropenia –3 (12%), grade 3 anemia –5 (20%), grade 3 and 4 diarrhea –2 (8%) and 1 (4%) respectively, grade 3 alkaline phosphatase elevation –2 (8%). With a median follow up of 183 days (range 8 –476 days), outcome data is currently available for 23 patients. Best responses included 4 (17%) partial responses, 1 (4%) stable disease and 18 (78%) progressive disease. By Kaplan-Meier method, median progression free survival was 111 days and median overall survival was 303 days. Conclusions: Preliminary results from this trial suggest that irinotecan is an active agent as salvage treatment with modest toxicity in patients with advanced NPC refractory to platinum/taxane-based chemotherapy. No significant financial relationships to disclose.
The cell cycle regulation of anti-cancer bioactive peptide (ACBP) on gastric cancer cell lines
Authors: X. Su, X. Ouyang, G. Xu, J. Shen, M. Yan
Journal: Journal of Clinical Oncology (2007)

15087 Background: Anti-cancer bioactive peptide (ACBP) was extracted from the spleen of the goat suffered immune inducement by immunoreaction, supercentrifuge and ultra-filtration. Our previous studies have identified ACBP had significantly inhibited the growth of the human gastric cancer cell lines BGC-823 and MGC-803, the human rhinopharyngocele cell line CNE and the leukemic cell line. The in vivo experiments showed ACBP could dramatically repress the growth of tumor, and had few side-effects in the long-term toxic experiments. In clinical trials, ACBP could enhance the survival and life quality of the patients with advanced gastric cancer. In this study, we will explore the influence and mechanism of the effect of ACBP on cell cycle using human gastric cancer cell lines BGC-823 and MGC-803. Methods: Human gastric cancer cell lines BGC-823 and MGC-803 were cultured with different concentrations (10–25 ug/ml) of ACBP. The MTT method was employed to measure the growth inhibition rates of the cells with different concentrations of ACBP; the morphological changes were observed under the light microscope; the semi-quantitative RT-PCR was used to assay the changes of mRNA for p16,p21,p27,c-myc,cyclin D1,bax,bcl-2 gene. Results: Different concentrations of ACBP in the range of 10.0–25.0 μg/ml could inhibit the growth of BGC-823 and MGC-803 cell and such effect was both concentration and time dependent. 25.0 μg/ml ACBP had an inhibition rate (IR) of 84.4%, 72.3% and a median concentration (IC 50 ) of 17.86 μg/ml, 13.16 ug/ml. After ACBP treatment, the cells showed typical apoptotic changes under the light microscope. On RT-PCR, the expressions of p16,p21,p27,bax mRNA in the two cell lines were markedly increased after ACBP treatment. On the contrary, the expression of c-myc,cyclin D1,bcl-2 mRNA in the two cell lines were obviously decreased after ACBP treatment. Conclusion: ACBP had markedly repressed the growth of BGC-823 and MGC-803 cell lines through inducing the cellular apoptosis. The possible mechanism is ACBP affects the cell cycle molecules expression including p16,p21,p27,cyclin D1 and regulate c-myc,bcl-2 and bax to induce apoptosis. No significant financial relationships to disclose.