tbuckley/cabot-search huggingface dataset:
Time to symptomatic progression: An emerging clinical trial endpoint in oncology
Authors: N. Aronson, L. Melilli, D. Cella, K. Gondek
Journal: Journal of Clinical Oncology (2007)

19529 Background: One of the critical challenges in oncology today is assessment of clinical trial results to inform clinical decision making. Because trials typically focus on overall survival, it is often difficult to determine individual patient benefits early on treatment. Surrogate endpoints such as time to disease progression and progression-free survival may not correlate with survival. Based on a growing body of evidence, cancer symptom assessment has been shown to provide immediate treatment responses and to predict long-term outcomes_including tumor response, disease progression and survival. Methods: Results from a comprehensive literature review of oncology clinical trials and observational studies with symptom endpoints to date are provided. Analyses methods are described including potential biases. To illustrate the potential clinical value of time to symptomatic progression (TTSP) in longitudinal clinical trials, a retrospective analysis of data from a three-arm (cisplatin/etoposide versus two dosage regimens of cisplatin/paclitaxel arms) randomized cooperative-group clinical trial in non-small-cell lung cancer (NSCLC) was conducted. Results: In a three-arm randomized cooperative group clinical trial of NSCLC, TTSP was significantly associated with best clinical response (p&lt;0.01) and survival (p&lt;0.05). Conclusion: The utility of cancer symptom response for comparing cancer treatments has been well documented. This endpoint has been shown to act as an early signal of disease progression and death. Opportunities for refinement include methods for more accurate assessment, reduction in the number of symptoms evaluated, and refined statistical methods for reducing bias due to missing data. Given the success demonstrated in clinical trials, clinicians may consider ongoing cancer symptom evaluation in clinical practice. No significant financial relationships to disclose.
A phase II trial of temolozomide in patients with untreated high grade oligodengroglial brain tumours
Authors: H. K. Gan, L. Cher, A. Benson, A. Dowling, M. Rosenthal
Journal: Journal of Clinical Oncology (2008)

13005 Background: Whilst oligodendroglial tumours are chemosensitive, the data about Temozolomide in high grade oligodendrogliomas are almost exclusively in recurrent tumours. Methods: 40 untreated patients of a planned 50 with high grade oligodendrogliomas were enrolled in a Phase II trial of Temozolomide. Eligible patients had confirmed oligodendrogliomas/astrocytomas and adequate organ function. Patients were excluded for prior chemotherapy or radiotherapy. Once recovered from surgery, patients were treated with 6 monthly cycles of Temozolomide (200 mg/m2 for five days), with post-chemotherapy radiotherapy at investigator discretion. Patients were assessed for loss of heterozygosity (LOH) of 1p and 19q, which are markers of chemosensitivity. The primary endpoint was disease-free progression at six months. Results: Patients were accrued within 42 months with 17 women (42.5%) and 37 (92.5%) having a performance status (ECOG) 0–2. Eight patients did not complete the full 6 cycles (6 progressed during chemotherapy, 1 withdrew consent and 1 for other reasons). At 6 months, there were 11 patients (30%) who had responded (6 CR, 5 PR), 19 showed SD (47.5%) and 3 experienced PD (22.5%). Of patients showing a clinical benefit (CR/PR/SD), 9 also had adjuvant radiotherapy (55–60 Gy) and 1 had surgery followed by radiotherapy. All patients who progressed were treated with radiotherapy except for one who had surgery prior to post-operative radiotherapy. With a median follow-up of 34 months, patients who experienced a clinical benefit did significantly better than those who progressed [median survival not yet reached vs 13 months (range 10.5–15.5 months) respectively, p=0.003 Kaplan-Meier analysis]. The benefits of Temozolomide were durable, with only 4 of those who benefited initially (2 CR’s and 2 SD’s) subsequently relapsing. Early data shows no added survival benefit for giving radiotherapy to patients who benefit with temozolomide (p=0.317 by Kaplan-Meier analysis). The impact of LOH of 1p and 19q is still being assessed. Treatment was generally well tolerated. Conclusions: First-line temozolomide in patients with high-grade oligodendrogliomas is highly efficacious. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Schering-Plough Schering-Plough
E2205: A phase II study to measure response rate and toxicity of neoadjuvant chemoradiotherapy (CRT) with oxaliplatin (OX) and infusional 5-fluorouracil (5-FU) plus cetuximab (C) followed by postoperative docetaxel (DT) and C in patients with operable adenocarcinoma of the esophagus.
Authors: M. K. Gibson, P. J. Catalano, L. Kleinberg, C. A. Staley, E. Montgomery, W. Song, M. F. Mulcahy, L. P. Leichman, A. B. Benson
Journal: Journal of Clinical Oncology (2010)

4064 Background: One approach to treating resectable esophageal adenocarcinoma is CRT followed by surgery; however, recurrence is common. To improve on this, we designed a single-arm, phase II trial that added an EGF-R inhibitor, C, to CRT. Methods: We aimed to increase the pathologic complete response (pCR) rate from 25% to 45%. A Simon two-stage design (α and β of 0.10) required pCR/enrolled of 5/18 for stage I and 14/40 total. 22 pts enrolled. CRT: OX 85 mg/m2 D1, 15, 29; infusional 5-FU 180 mg/m2/24 hr × 35 days; C 400 mg/m2 D1 then 250 mg/m2 D8, 15, 22, 29 and radiation (IMRT allowed) 180 cGy/day × 25 fractions (M-F). Following esophagectomy, adjuvant chemotherapy (CT): weekly DT 35 mg/m2 and C 250 mg/m2 5/6 weeks × 2 cycles. Endpoints: efficacy by pCR rate and toxicity. Results: Of 22 patients enrolled, 18 had surgery (C reaction off study, died PE 4 days after CRT, G3 diarrhea during CRT died disease progression, died sepsis/hypoxia during CRT). pCR = 7 patients. 13/18 started adjuvant CT. 12/13 completed adjuvant CT. Four post-op deaths, all from ARDS, for a total of 7 deaths on study. 2/7 pts with pCR died, both of ARDS. With small numbers, the use of IMRT did not correlate with ARDS, but analysis of dosimetry is ongoing. Data updated 010610. Conclusions: This regimen demonstrated promising activity based on pCR rate. Toxicity was significant, leading to closure after stage I. All post-op deaths were due to ARDS. Investigation of ARDS cause is ongoing. Correlative studies underway. This regimen is not recommended. No significant financial relationships to disclose.
Bexxar Protocol CP98–020 : Preliminary results with I-131 labeled antibody in patients with non-Hodgkin’s lymphoma refractory to chemotherapy and rituxan
Authors: M. Nair, R. Mark, P. Anderson, T. Neumann, D. Quick
Journal: Journal of Clinical Oncology (2005)

6716 Background: Non-Hodgkin’s Lymphoma (NHL) B-Cell subtype, is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present preliminary results in 11 patients treated according to the Bexxar CP98–020 Protocol. Methods: Candidates for Bexxar CP98–020 Protocol, were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Eligibility criteria included Platelet count > 100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2004, 10 patients received I-131 labeled Antibody. The total body dose was 75 cGy for Platelet counts > 150,000 and 65 cGy for Plt 100–150,000. Activity ranged from 60 mCi to 120 mCi. Results: Median follow-up was 26 months (range 6–38 months). The response rate was 72% (8/11), with complete response achieved in 27% (3/11) of the patients. At last follow-up, 7/11 patients were alive. Toxicity was moderate, with 18% (2/11) of patients experiencing profound (Platelets < 10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. For the remaining 9 patients, Plt counts decreased mildly for 4–6 weeks following RIT, and then returned to normal values by 10–20 weeks. Conclusions: RIT yielded promising preliminary results in NHL patients refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. Longer follow-up is needed. No significant financial relationships to disclose.
Phase II trial of the mTOR inhibitor everolimus (RAD-001) in metastatic melanoma
Authors: R. D. Rao, H. E. Windschitl, J. B. Allred, V. J. Lowe, W. J. Maples, M. K. Gornet, V. J. Suman, E. T. Creagan, H. C. Pitot, S. N. Markovic
Journal: Journal of Clinical Oncology (2006)

8043 Background: Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that regulates the production vascular endothelial growth factor (VEGF) and cell growth and proliferation. Inhibitors of mTOR have anti-mitotic and anti-angiogenic effects in various cancers (including melanoma). Everolimus (RAD-001), an orally administered inhibitor of mTOR, is well tolerated at a dose of 30 mg/week. We conducted a phase II study to evaluate the role of RAD-001 in treating patients with metastatic melanoma (MM). Methods: A 2 stage, phase II multi-institutional trial was conducted in patients with MM to assess progression free survival (PFS) rate at 16 weeks was at least 50% against the alternative it was at most 30%. Data about expected baseline PFS were derived from historical controls. Each cycle was 8 weeks in duration. Inclusion criteria: measurable disease, ECOG performance score (PS) of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal hepatic, renal or bone marrow function. Correlative studies included changes pharmacodynamic endpoints to evaluate effect of therapy on signaling pathways. Results: 24 patients with MM were enrolled. Median age was 56 years (33–79), 21 (88%) had at 2 or more sites of metastatic disease. Most (75%) had stage M1c, with 13% each having 1a and 1b disease. PS was 0, 1 and 2 in 58, 38% and 4%, resp. All but 9 had received previous therapy for MM. Planned interim analysis was done after 20 patients were enrolled. Of these, 7 (i.e., 35%) were PF at 16 weeks, which exceeded the decision rule for restarting accrual. No patient had an objective response; all 7 had stable disease. There were no grade 3 toxicities. Grade 2 toxic events (at least possibly related to therapy) were: fatigue (17%), diarrhea (8%) and anemia (8%). Patients had a clinically relevant benefit, with the median PFS for all 24 patients of 3 months. Median overall survival was not reached. Three patients continue on therapy. RAD-001 treatment resulted in changes in serum VEGF levels. Conclusion: Interim analysis after enrollment of 20 patients suggests that RAD-001 is well tolerated and has sufficient anti-tumor activity in MM to warrant the opening of enrollment to the second stage of this trial. Further accrual is planned. No significant financial relationships to disclose.
Ex vivo chemoresponse assay of ovarian cancers predicts clinical outcome
Authors: H. Gallion, W. Christopherson, R. Coleman, T. Herzog, B.-U. Sevin, A. Wells, L. Fiori
Journal: Journal of Clinical Oncology (2004)

5074 Background: Advanced ovarian cancer remains without chemotherapeutic cure. Numerous regimens can achieve clinical responses, but each only in a subset of women. The challenge is to predict which regimen an individual will respond to prior to its administration. Methods: We examined the clinical outcome of 317 women from 9 practices from whom ovarian cancer specimens were tested with an ex vivo chemoresponse assay between 4/30/97 and 4/30/02. The assay results were scored for sensitivity or resistance based on live cell number after exposure to varied concentrations of each chemotherapeutic regimen, and reported to the referring physician. Clinical data was compiled by an independent clinical research organization. Cox Proportional Hazard Model analysis identified independent prognostic factors. Results: Classification into two groups (sensitive and resistant) failed to yield statistically significant differences in progression free interval (PFI). Reclassification into three groups (sensitive, intermediate, and resistant) and the application of quality filters developed since 1997 was highly predictive of outcome. Of the 317 cases, 135 were treated with the same regimen that had been tested: the hazard ratio (HR) for PFI of ex vivo resistant tumors was 2.9 times (95% CI: 1.4 to 6.3; P<0.01) that of ex vivo sensitive tumors. The PFI of women whose tumors scored as intermediate fell between those scored as sensitive and those scored as resistant. When analyses were expanded to include all women who received at least one of the drugs tested, the relationship remained robust (HR=2.1; CI: 1.2 to 3.1; P=0.01; N=256). In the most challenging cohort, recurrent cancer, the HR was 2.6 (CI: 1.1 to 6.5; P<0.05; N=77). Conclusions: These data strongly suggest that incorporating an ex vivo chemoresponse assay can improve the clinical outcome of individual patients receiving either single or combination chemotherapy regimens. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Precision Therapeutics, Inc. Precision Therapeutics, Inc. Precision Therapeutics, Inc.
Prognostic Relevance of CD200/Btla Deletions in Pediatric Precursor-B Cell Acute Lymphoblastic Leukemia Treated According to the EORTC-CLG 58951 Protocol
Authors: Farzaneh Ghazavi, Tim Lammens, Emmanuelle Clappier, Stefan Suciu, Aurélie Caye, Samira Zegrari, Marleen Bakkus, Nathalie Grardel, Yves Benoit, Yves Bertrand, Odile Minckes, Vitor Costa, Alina Ferster, Françoise Mazingue, Geneviève Plat, Emmanuel Plouvier, Marilyne Poirée, Anne Uyttebroeck, Jutte Van der Werff Ten Bosch, Hetty Helsmoortel, Magali Meul, Nadine Van Roy, Jan Philippé, Frank Speleman, Hélène Cavé, Pieter Van Vlierberghe, Barbara De Moerloose
Journal: Blood (2014)
Locally advanced prostate cancer: A population-based study of treatment patterns and predictors
Authors: W. Lowrance, J. Eastham, L. Jacks, D. Yee, P. Scardino, E. Elkin
Journal: Journal of Clinical Oncology (2009)

6606 Background: Treatment of locally advanced prostate cancer (LA PCa) is controversial, but recent trial results demonstrate superior outcomes for combination therapy compared to monotherapy. We aimed to identify treatment patterns, predictors, and trends in a population-based cohort of men with LA PCa. Methods: From Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims, we identified men age 65 and older diagnosed with clinical stage T3 and T4 nonmetastatic PCa from1995 through 2002. Using Medicare claims, we classified treatments (radical prostatectomy (RP), radiation therapy (RT), or androgen deprivation (AD)) received within 6 and 24 months of PCa diagnosis. We assessed trends over time and used multivariable logistic regression to assess sociodemographic and clinical predictors of treatment. Results: The Table shows the distribution of treatments given within 6 months following diagnosis among 3,412 men with LA PCa. Approximately one third of patients were treated with a combination of RT and AD (31%), 46% received monotherapy, and 17% received no active treatment. Between 1995 and 2002, the most notable change was an increase in use of the combination of RT and AD as primary therapy. The percent of patients who received RT and AD rose from 16% in 1995 to 39% in 2002. Significant predictors of receiving combination therapy over the study period were age, race, urban residence, marital status, clinical stage, year of diagnosis, and Charlson comorbidity score. All results were similar when we examined treatments received within 24 months of diagnosis. Conclusions: Patterns of treatment for locally advanced prostate cancer shifted during the study period, with the combination of RT and AD becoming the most common treatment modality. This movement toward combination therapy for LA PCA is encouraging, given recent evidence of the superiority of such therapy in these patients. Future efforts should focus on further increasing the use of multimodality therapy in LA PCa. [Table: see text] No significant financial relationships to disclose.
Pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) given alone and with bevacizumab (B) in patients with recurrent epithelial ovarian cancer (rEOC).
Authors: F. Muggia, T. Safra, L. Borgato, A. Gandhi, G. Mancinc, A. Gabizon, L. Liebes
Journal: Journal of Clinical Oncology (2010)

5064 Background: Increased vascular permeability greatly enhances liposome deposition in tumors. Normalization of vasculature by B may interfere with liposomal tumor entry but a concomitant reduction in tumor interstitial pressure could improve PLD delivery. NYU patients on a rEOC trial of PLD + B (Muggia et al, abstract 5548, ASCO 2009) had PLD PK determinations providing comparison of cycle 1 (PLD) and cycle 2 (PLD + B) parameters. Methods: Plasma for PLD PK at 1 hour, day (d) 7 and d21 was obtained on cycles 1 and 2 after PLD 30 mg/m2. B 15 mg/kg was added in cycle 2 after 1h PK (Cmax) sampling. Upon centrifugation, liposomes were lysed with acidified detergent and released doxorubicin measured by HPLC with fluorescence to a sensitivity of 65 ng/ml. C max (1h), half life (t¾), clearance (CL), volume of distribution (Vss) and area under the curve (AUC) were estimated from the 3 points obtained, and cycles 1 vs. 2 were compared. Results: PK analysis (n=6) shows (Table) longer elimination t¾ on cycle 2 (p= 0.043, paired t-test). C7d/Cmax in 6 of 7 patients decreased after B (p = 0.038, N=7). PLD d21 blood levels was also increased in cycle 2 relative to cycle 1 (p=0.012, N=7). So far, skin toxicity and antitumor effects appear similar to PLD alone. Conclusions: PK show an increase in PLD t¾ and increases in the C7d/Cmax and PLD d21 levels after B is introduced. This may reflect B effects, but ↓clearance with repeated PLD cycles cannot be excluded (Cancer Chemother Pharm 61:695-702, 2008). These changes may result in greater delivery of PLD to tumors in spite of antiangiogenic effects of B. Unaltered toxicity spectrum and retained activity support this interpretation. AUC(μ g/ml*hr) t¾ (hr) Cmax(μ g/ml) CL(ml/hr) Vss(ml) C7d/Cmax(%), (N=7) D21 (ng/ml), (N=7) Mean cycle1 2,385.0 95.4 18.1 21.5 2,990.2 28.2 322.0 SEM 199.0 7.4 2.6 2.35 437.73 3.3 77.0.4 Mean cycle2 2,561.7 108.9 16.4 20.5 3,303.4 33.9 475.3 SEM 252.6 7.9 1.5 2.9 223.9 2.2 86.1 PK results (N = 6) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Yissum-Hadasit Doxil Royalties
A phase 2 study (2-stage, 2-cohort) of the oral PARP inhibitor talazoparib (BMN 673) in patients with germline BRCA mutation and locally advanced and/or metastatic breast cancer (ABRAZO).
Authors: Nicholas C. Turner, Judith Balmaña, Peter A. Fasching, Sara A. Hurvitz, Melinda L. Telli, Fran Visco, Andrew M. Wardley, Charlie Zhang, Nathalie Andrienne Lokker, Debra L. Lounsbury, Mark E. Robson
Journal: Journal of Clinical Oncology (2015)

TPS1108 Background: Poly-ADP-ribose polymerase (PARP) represents a family of enzymes of which at least two (PARP1 and PARP2) play important roles in DNA repair. PARP inhibition induces synthetic lethality in tumor cells bearing deleterious mutations in the genes BRCA1/2. Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that potently inhibits the PARP enzyme and effectively traps PARP on DNA [1]. In preclinical models, trapping PARP on DNA was more likely to induce cancer cell death than inhibition of PARP alone [1,2]. Talazoparib is the most potent preclinical PARP inhibitor described to date with the highest efficiency at trapping PARP-DNA complexes [1]. Talazoparib has shown promising single-agent anti-tumor efficacy in several solid tumor types and was generally well tolerated in a Phase 1/2 clinical study [3]. Methods: This Phase 2 trial (ABRAZO) evaluates the safety and efficacy of talazoparib in patients with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Eligible subjects will be assigned to one of two cohorts: 1) Subjects (n = 70) previously responding to a platinum-containing regimen for metastatic disease (PR or CR) or 2) Subjects (n = 70) with > 2 prior chemotherapy regimens in metastatic setting, no prior platinum therapy. The primary objective is objective response rate (ORR). Secondary objectives include clinical benefit rate (CBR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). Health-related quality of life assessments are an exploratory objective. Patient eligibility includes ≥ 18 years, locally advanced and/or metastatic disease, deleterious BRCA1/2 mutation, and ECOG performance status ≤ 1. Eligible patients will receive oral talazoparib (1.0 mg/day, 21-day cycles) until disease progression or unacceptable toxicity. This trial is enrolling patients in the United States, France, Germany, Spain, and the United Kingdom. (NCT02034916). [1] Murai J et al. Cancer Res. 2012;72(21):5588-5599. [2] Murai J et al. Mol Cancer Ther. 2014;13:433-443. [3] Wainberg ZA et al. J Clin Oncol. 2014;32(suppl):5; abstr 7522 Clinical trial information: NCT02034916.
Why do women get mastectomy? Results from a population-based study
Authors: M. Morrow, A. S. Hamilton, S. J. Katz
Journal: Journal of Clinical Oncology (2007)

605 Background: Persistently high rates of mastectomy (M) use for breast cancer have motivated lingering concerns about over-treatment. Yet, little information exists about the etiology of current rates of M. Methods: 2,030 women with non- metastatic breast cancer diagnosed from August 2005 to May 2006 and reported to the LA County SEER registry were identified and mailed a survey shortly after receipt of surgical treatment. Latina and African American women were over-sampled. Survey data were merged to SEER data. We report results on a 50% respondent sample (n=736) which will be updated based on a final respondent sample of 1400 patients (projected response rate, 72%). Results: M was ultimately performed in 279 women (37.9%): 47.3% (n=132) received initial M based on surgeon recommendation and most (80.8%) reported a clinical contraindication to breast conserving surgery (BCS); 69 patients (24.7%) chose M despite a surgeon recommendation for BCS or no recommendation favoring either procedure; and 28.0% (n=78) received M after initial attempts at BCS. This latter group included 16 of 22 patients who attempted BCS in spite of a surgeon recommendation for M. The failure rate of BCS in patients thought to be candidates for the procedure was 12.6%. One quarter of patients who received an initial recommendation for M sought a second opinion, and 80.6% reported concordance in recommendation for M between their first and second surgeons. Conclusions: Receipt of M in this large population sample was the result of clinical contraindications to BCS and, to a lesser extent, patient preference. The infrequent discordance in surgical opinions about the need for M and infrequent conversion to M in patients selected for BCS suggest that surgeons have accepted BCS and recognize standard contraindications to the procedure. Initiatives to improve surgical treatment decision-making should focus on patient perspectives about risk and benefits of surgical options and clinicopathologic features predictive of the success of re-excision after initial attempt at BCS. [Table: see text] No significant financial relationships to disclose.