tbuckley/cabot-search huggingface dataset:
Survival in advanced-stage ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations
Authors: R. A. Lacour, S. N. Westin, M. S. Daniels, M. R. Milam, C. C. Sun, D. L. Urbauer, P. T. Ramirez, D. C. Bodurka, D. M. Gershenson, K. H. Lu
Journal: Journal of Clinical Oncology (2007)

5514 Background: Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish BRCA founder mutations compared to sporadic ovarian cancer patients. The purpose of this study is to determine if this association exists in ovarian cancer patients with non- Ashkenazi Jewish (non-AJ) BRCA1 or BRCA2 mutations. Methods: Patients with stage III or IV ovarian, fallopian tube, or primary peritoneal cancer and a BRCA1 or BRCA2 mutation, seen for genetic testing between January 1996 and October 2006, were identified from the institutional and genetics databases. Medical records were reviewed for clinical factors including response to initial chemotherapy. Response is defined as no clinical evidence of disease with normalization of serum CA-125 and no radiographic evidence of disease or a negative second-look surgery. Patients with sporadic ovarian cancer, without a family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, and year of diagnosis. Progression-free and overall survival were calculated by the method of Kaplan-Meier. Chi-square tests and univariate logistic regression were also used in the data analysis. Results: Thirty-nine advanced-stage ovarian cancer patients with non-AJ BRCA mutations and 47 matched, advanced-stage sporadic ovarian cancer patients have been analyzed. Compared to patients with sporadic ovarian cancer, non-AJ BRCA mutation carriers had a longer progression-free survival (PFS, 32.4 mos. vs. 22.1 mos., p = 0.0303) and overall survival (OS, 101.4 mos. vs. 51.3 mos., p &lt; 0.001). Similarly, 72% of the non-AJ BRCA mutation carriers had a complete response to initial treatment, compared to 45% of the sporadic ovarian cancer patients (p = 0.01). The odds of complete response to initial treatment were 3.2 times greater in the non-AJ BRCA group than in the sporadic group (OR 3.2; 95% CI 1.27 - 8.15). Conclusions: This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations when compared to similar patients with sporadic ovarian cancer. Response to initial treatment appears to impact this improved survival. No significant financial relationships to disclose.
FOxTROT: Randomized phase II study of neoadjuvant chemotherapy with or without an anti-EGFR monoclonal antibody for locally advanced, operable colon cancer.
Authors: R. G. Gray, D. Morton, G. Brown, D. R. Ferry, L. Magill, P. Quirke, M. T. Seymour, B. Warren
Journal: Journal of Clinical Oncology (2010)

TPS192 Background: For many patients with high-risk, operable colon cancer, surgical excision followed by adjuvant CT fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Micrometastases may be more readily eradicated by neoadjuvant CT than CT given after the delay and immunological stress of surgery. Shrinking the tumor before surgery may also reduce the risk of incomplete surgical excision, and tumor cell shedding during surgery. Preoperative CT and radiotherapy are surprisingly more effective than postoperative treatment in several other cancers, notably rectal, and neoadjuvant CT has become feasible in colon cancer now that response rates exceed 50% and radiological staging is more accurate. Preoperative CT also provides a unique opportunity to identify tumor markers predictive of response to CT and anti-EGFR therapy. Methods: FOxTROT (Fluoropyrimidine, Oxaliplatin and Targeted Receptor Pre-Operative Therapy) has randomized 98 patients (target=150) with radiologically staged T4 or “T3 bad” (extramural depth of ≥ 5 mm), M0, resectable colon cancer 2:1 to receive the first 6 weeks of OxMdG (oxaliplatin 85 mg/m2, l-folinic acid 175 mg, 5-FU 400 mg/m2 bolus then 2,400 mg/m2 by 46h infusion) CT preoperatively or all 24 weeks postoperatively. KRAS wildtype patients are randomised 1:1 to receive an anti- EGFR monoclonal antibody, panitumumab (6 mg/kg; 2-weekly) with the first 6 weeks of CT, or control. Outcomes are feasibility of preoperative KRAS testing, radiological staging, randomization and CT, toxicity and perioperative morbidity with neoadjuvant CT, accuracy of radiological compared to pathological stage, accuracy of radiological eligibility criteria in selecting high-risk patients suitable for CT and excluding low-risk cancers. If neoadjuvant CT of colon cancer is feasible, FOxTROT will proceed to a phase III trial, with target 900 patients and integrated studies of potential molecular markers of response. Primary outcomes will be 2-year recurrence for pre-operative CT, pathological downstaging for panitumumab, and value of molecular markers in predicting response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen
Sequential methotrexate, 5-fluorouracil, and cisplatin in the treatment of recurrent squamous-cell carcinoma of the head and neck: failure of hypertonic saline to reduce the nephrotoxicity of cisplatin.
Authors: I W Dimery, S S Legha
Journal: Journal of Clinical Oncology (1986)

Fifty patients with histologically proven squamous-cell carcinoma of the head and neck, recurrent after surgery and/or radiation therapy, were treated with a triple-drug combination of methotrexate (MTX), 250 mg/m2 intravenously (IV) on day 1, followed by 5-fluorouracil (5-FU), 600 mg/m2 IV on days 1 and 2, followed by cisplatin, 50 to 60 mg/m2 IV on days 3 and 4. Patients were randomly assigned to receive cisplatin either in 300 mL of 3% saline or with standard mannitol diuresis along with appropriate hydration. The courses of treatment were repeated every 3 to 4 weeks. Among 47 evaluable patients, there were four complete responses (CRs) and 17 partial responses (PRs) (9% and 36%, respectively). The median duration of response was 23 weeks and the overall survival was 7 months. The median survival of responders v nonresponders was 12 months and 6 months, respectively. Nausea and vomiting was experienced by all patients and diarrhea was experienced by 36% of patients. Neutropenia occurred in 37 patients (79%) and resulted in fever or infection in 11 patients (23%) and death in two patients. Mild renal failure (persistent serum creatinine greater than 1.5 mg/ dL) was observed in ten patients (21%), six treated with 3% saline and four treated with mannitol. The median cumulative dose of cisplatin that lead to the development of renal impairment was 485 mg/m2 in the hypertonic saline arm and 550 mg/m2 in the mannitol arm (P = .40). The antitumor activity of this regimen was not superior to that of sequential MTX and 5-FU. The use of hypertonic saline was not effective in reducing the renal toxicity of cisplatin.
Phase II study evaluating the effect of concomitant ramucirumab (RAM) on the pharmacokinetics (PK) of irinotecan (IRI) and its metabolite SN-38 when coadministered with folinic acid (FA) and 5-fluorouracil (5-FU) (FOLFIRI) in patients (pts) with advanced malignant solid tumors.
Authors: Ding Wang, Fadi S. Braiteh, James J. Lee, Crystal Shereen Denlinger, Dale Randall Shepard, Archana Chaudhary, Yong Lin, Ling Gao, Christopher John Asakiewicz, Federico Nasroulah, Patricia LoRusso
Journal: Journal of Clinical Oncology (2015)

691 Background: The primary objective was to assess the effect of concomitant RAM on the PK of IRI and its metabolite SN-38 when coadministered with FA and 5-FU. Methods: Key eligibility criteria included pts aged ≥18 years with metastatic or locally advanced malignant solid tumors resistant to standard therapy or for which no standard therapy was available, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Pts received intravenous infusions of FOLFIRI and RAM 8 mg/kg on day 1 of a 2-week cycle. FOLFIRI was administered alone in cycle 1; RAM was administered followed by FOLFIRI in all subsequent cycles. Blood for PK was collected at regular intervals after infusions in cycles 1 and 2 to determine IRI and SN-38 plasma concentrations. Pts who completed the first 2 cycles of study treatment were included in the drug-drug interaction (DDI) population. All pts who received at least 1 dose of RAM or FOLFIRI were included in the safety population. Results: The safety population comprised 29 pts, and the DDI population included 25 of these 29 pts. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC (0-∞) ] and the maximum observed drug concentration (C max ) of IRI and SN-38 were comparable between cycle 1 (FOLFIRI alone) and cycle 2 (RAM+FOLFIRI). The ratios of geometric least-squares (LS) means for IRI were 0.93 (90% CI; 0.83, 1.05) for AUC (0-∞) and 1.04 (90% CI; 0.97, 1.12) for C max . The ratios of geometric LS means for SN-38 were 0.95 (90% CI; 0.88, 1.04) for AUC (0-∞) and 0.97 (90% CI; 0.85, 1.12) for C max . The most prevalent treatment-emergent adverse events (TEAEs) were fatigue/asthenia (n=19, 65.5%), diarrhea (n=16, 55.2%), neutropenia (n=15, 51.7%), nausea (n=14, 48.3%), and decreased appetite and anemia (n=13 each, 44.8%). Grade ≥3 TEAEs were rare, except for neutropenia in 7 (24.1%) pts. Conclusions: The PKs of IRI and its metabolite, SN-38, were not affected when coadministered with RAM. RAM with FOLFIRI was well-tolerated in this study without new safety concerns. Clinical trial information: NCT01634555.
A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naïve patients with metastatic castrate-resistant prostate cancer (CRPC).
Authors: R. Pili, M. Haggman, W. M. Stadler, J. R. Gingrich, V. J. Assikis, A. Björk, G. Forsberg, M. A. Carducci, A. J. Armstrong
Journal: Journal of Clinical Oncology (2010)

4510 Background: Tasquinimod (TASQ) is a quinoline-3-carboxamide derivative that binds to S100A9 and displays anti-angiogenic properties and anti-tumor activity in prostate cancer (PC) models. Phase I studies in PC indicated that TASQ is well tolerated and may delay PC progression. Methods: 206 patients (pts) with metastatic CRPC were assigned (2:1) to either receive oral TASQ once-daily at an initial dose level of 0.25 mg/day escalating to 1.0 mg/day over 4 weeks, or placebo (P). The primary endpoint was proportion of pts without disease progression (DP) at 6 months, defined by PCWG2 or pain criteria, but excluding PSA. Secondary endpoints comprised safety, progression free survival (PFS), and changes in biological markers, including PSA. Results: 200 (133 TASQ, 67 P) pts with a median age of 72.5 years were evaluable for efficacy and safety. Median baseline characteristics were (TASQ/P): Karnofsky (95/95), Gleason (7/7), LDH (201/206 U/L), Alk Phos (98/87 U/L), Hgb (12.9/13.2 g/dL), PSA (29/19 μ g/L) and PSADT (4.2/5.0 mo). 6-mo progression free proportion for TASQ and P groups was 57% and 33% respectively (p=0.0001) and median PFS was 24.7 vs. 12.9 weeks. In clinical subgroups defined by PCWG2, the PFSs were (weeks/N): nodal 24.3/9 vs. 12.6/12; bone 30.6/90 vs. 13.4/42; visceral 23.9/32 vs. 12.1/10 for pts on TASQ and P. Pts treated with TASQ had significantly decreased serum LDH levels and stabilized bone alkaline phosphatase (BAP) levels, with less pronounced effects on PSA response and progression. Serious vascular events were more common in the TASQ arm (myocardial infarction, heart failure or stroke (3 % vs 0 %), deep vein thrombosis (4 % vs 0 %)). Common (>10%) adverse events (AEs) occurring more frequently in pts receiving TASQ included gastrointestinal disorders, fatigue, and musculoskeletal pains. and asymptomatic elevation of pancreatic enzymes and proinflammatory markers. G3-4 AEs (including labs) were reported in 38% pts on TASQ vs. 10 % on P. Conclusions: TASQ significantly slowed the rate of DP and improved PFS in pts with metastatic CRPC and a phase III study is planned. Side effects were manageable. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Active Biotech Active Biotech Active Biotech Active Biotech
Bortezomib plus modified R-CHOP as initial therapy for indolent B-cell lymphomas: Phase I results
Authors: C. Flowers, R. Sinha, J. Kaufman, P. Shenoy, C. Lewis, K. Bumpers, A. Rogatko
Journal: Journal of Clinical Oncology (2009)

8577 Background: Adding rituximab (R) to chemotherapy improves survival for patients (pts) with follicular lymphoma (FL) and other indolent non-Hodgkin lymphomas (NHL), but not all pts respond. Bortezomib (B) + RCHOP has a high complete response (CR) rate, but higher doses of B with standard vincristine produced severe neuropathy. We developed a phase I/II trial to test if adding B to RCHOP with modified vincristine dosing can be well-tolerated and yield a high CR rate. Methods: Untreated pts with indolent NHL and indications for treatment based on GELF criteria or FLIPI ≥3 received R 375mg/m 2 , cyclophosphamide 750mg/m 2 , doxorubicin 50mg/m 2 , vincristine 1.4mg/m 2 (capped at 1.5mg) on day 1, B 1.0- 1.6mg/m 2 days 1 and 8, and prednisone 100mg days 1–5 for 6–8 cycles. The maximum tolerated dose (MTD) was defined as the regimen at which &lt;30% grade ≥3 non-hematological or grade ≥4 hematological toxicity (&gt;14 days) occurs. Dose escalation used the Escalation with Overdose Control Bayesian method with upper bound (θ=0.3). This facilitated MTD finding with fewer pts given prior data on B+RCHOP. Functional Assessment of Cancer Therapy (FACT) Neurotoxicity (11-item; 4 point scale), EMG, nerve conduction velocity and epidermal nerve fiber density measures were taken at baseline and after cycle 4. Results: 11 pts with FL (n=6) or other indolent NHL enrolled in phase I. Median age was 59 years (range 29–69). 6 pts (55%) had stage IV disease; 8 (64%) had FLIPI ≥2. Pts received RCHOP + B at 1.0 mg/m 2 (n=1), 1.3 mg/m 2 (n= 6) or 1.6 mg/m 2 (n= 4) and together completed 67 cycles. Treatment was well tolerated. Neuropathy occurred in 4 pts (36%), with 2 grade 1, 1 grade 2 and 1 grade 3 toxicity ( Table ). Grade 4 neutropenia occurred in 4 pts (36%), but none &gt;14 days. Overall response rate was 100% with 5/8 finished pts (63%) achieving CR. 3 continue on treatment. Mean FACT Neurotoxicity after cycle 4 remained &lt; 1 for all items. Conclusions: Adding bortezomib to RCHOP produces limited toxicity when vincristine is capped at 1.5 mg. Phase II will explore the efficacy of this regimen. [Table: see text] [Table: see text]
Analysis of prostate-specific antigen decline as a surrogate for overall survival in metastatic hormone-refractory prostate cancer (HRPC)
Authors: A. J. Armstrong, M. A. Eisenberger, E. S. Garrett-Mayer, Y. Ou Yang, M. A. Carducci, R. de Wit, I. Tannock
Journal: Journal of Clinical Oncology (2007)

5009 Background: A 30% PSA decline following initiation of cytotoxic chemotherapy has been identified as a potential surrogate for overall survival in metastatic HRPC. We sought to examine whether various levels of PSA decline were surrogates for overall survival in TAX327, a randomized trial of q3w docetaxel and prednisone (DP), q1w DP, and q3w mitoxantrone and prednisone (MP). Methods: In this trial of 1006 men with HRPC, 943 men had sufficient data on 3-month post-treatment PSA decline for analysis, and 646 had sufficient data for analysis for a change in PSA kinetics with therapy. Surrogacy was examined for a range of PSA decline from 0% to 90% and PSA normalization, and for post-treatment changes in PSA kinetics. We investigated the Prentice Criteria for surrogacy using Cox proportional hazards models and calculated the proportion of treatment effect explained (PTE) by each surrogate marker. Results: In this analysis, a 30% or greater PSA decline with therapy was identified as the optimal cutoff that correlated with overall survival, based on the highest PTE point estimate (0.66, 95% CI 0.23–1.0), with 1.0 being a perfect surrogate. A 30% decline in PSA in the first 3 months after treatment occurred in 65% of subjects receiving q3w DP, 67% q1w DP, and 44% q3w MP, despite the significant survival benefits seen only with q3w DP. A 30% PSA decline was associated with a hazard ratio (HR) of 0.43 (95% CI 0.36–0.51) for overall survival after adjusting for treatment effect, while treatment effect itself lost significance, indicating surrogacy. Additionally, PSA normalization, changes in PSA kinetics, and pain response were significant prognostic variables, yet were only modest surrogates for the survival benefit seen with q3w DP therapy. Conclusions: In this trial of two schedules of DP as compared to MP for HRPC, a PSA decline of 30% in the first three months following initiation of cytotoxic chemotherapy was found to have the highest degree of surrogacy for overall survival, thus confirming data from the SWOG 9916 trial. However, given that the confidence interval for the estimate of this surrogate effect is wide, overall survival should remain the preferred endpoint for phase III trials of cytotoxic agents in HRPC. No significant financial relationships to disclose.
Aglycone Protopanaxadiol, a ginseng saponin inhibits P-glycoprotein and sensitizes chemotherapy drugs on multidrug resistant cancer cells
Authors: W. Jia, H. Yan, X. Bu, G. Liu, Y. Zhao
Journal: Journal of Clinical Oncology (2004)

9663 Background:Aglycone Protopanaxadiol (aPPD) is an aglycone derivative of ginseng saponins. Our previous work showed that a natural ginseng product CARESENG™ containing mainly aPPD induced cell apoptosis through various signal pathways including caspases. CARESENG™ also enhances the sensitivity of multidrug resistant cancer cells to various chemotherapy drugs. P-glycoprotein (P-gp, MDR1) is one of the major causes of multidrug resistance of many tumor cells. Blocking the function of P-gp may enhance efficacy of chemotherapy. In the present study, we investigated the possible mechanism of chemosensitizing effect of purified aPPD compound as well as CARESENG™. Methods:Breast cancer cell MCF-7adr and leukemia cell line P388adr, both overexpressing P-gp, were used to test the interaction between the compound and P-gp. Calcein-AM, a P-gp substrate, efflux assay was used to measure function of P-gp. Membrane preparation was also used to measure the ATPase activity of P-gp in the presence of aPPD or verapamil. Results:Our results demonstrated that 70uM aPPD could significantly block P-gp function on both MCF-7adr and P388adr cells showing increased intracellular concentrations of calcein-AM. Furthermore, the maximum effects of aPPD and verapamil on P-gp inhibition was additive when treated together on P388adr cells. On the other hand, aPPD had no effect on ATPase activity of P-gp while verapamil increased it by more than 2-fold. 20uM of aPPD completely reversed P-gp induced drug resistant to Taxol or Doxorubicin on MCF-7adr cells. CARESENG™ gave rise to similar results in all the above experiments. Conclusions: These results suggest that aPPD is an effective P-gp blocker with a mechanism different from that of verapamil. Given extremely low toxicity of the compound, aPPD is a potential candidate of chemosensitizer for treatment of multidrug resistant tumors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PanaGin Pharmaceuticals PanaGin Pharmaceuticals PanaGin Pharmaceuticals
Optimizing the dose and schedule of KW-2449, FLT3/Aurora inhibitor, through analysis of in vivo target inhibition
Authors: K. W. Pratz, A. Stine, J. Karp, D. Small, J. Cortez, G. Roboz, N. Rao, S. Akinaga, Y. Shiotsu, M. Levis
Journal: Journal of Clinical Oncology (2008)

7069 Background: FLT3 inhibitors have shown promising activity in AML patients with FLT3 activating mutations. FLT3 mutant AML cells are killed when FLT3 is inhibited in sustained fashion to less than 10% of its baseline activity. This degree of inhibition has been difficult to achieve in the majority of patients treated with FLT3 inhibitors thus far. KW-2449 is a novel multi-targeted kinase inhibitor with activity against FLT3, KIT, ABL and Aurora kinase. We conducted correlative pharmacodynamic and pharmacokinetic studies in the context of a phase I trial in order to determine if adequate FLT3 inhibition could be achieved using a twice daily dosing schedule of KW-2449. Methods: Leukemia patients enrolled on a phase I trial received KW-2449 orally twice daily, with doses escalating from 12.5 mg to 250 mg. Whole blood samples were obtained prior to treatment as well as at pre-determined intervals after dosing. Leukemia cells were isolated and analyzed for FLT3 and STAT5 inhibition as well as for susceptibility to killing by KW-2449 in vitro. Plasma was used for determination of FLT3 plasma inhibitory activity (PIA) as well as conventional pharmacokinetic analysis of KW-2449 and its principle metabolite (M1). Results: FLT3 inhibition measured by the surrogate PIA assay correlated with the inhibition observed by direct analysis of circulating leukemia cells. FLT3 inhibition was observed in some cases at peak time points at the first dose level, and complete inhibition was achieved at doses as low as 50 mg. However, inhibition was not sustained, and in most cases, FLT3 phosphorylation returned to baseline levels by 12 hours after dosing. The M1 metabolite accounted for a significant fraction of FLT3 inhibition at all dose levels. Clinical activity, manifesting as a reduction in peripheral blasts, could be predicted based on the results of cytotoxicity assays using pre-treatment leukemia blasts. Conclusions: KW-2449 displayed consistent pharmacokinetics and effective FLT3 inhibition, but FLT3 inhibition was not sustained on the current 12 hour schedule. A new trial using a dose schedule of every 6–8 hours is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Kyowa Pharmaceutical Inc Kyowa Pharmaceutical Inc