tbuckley/cabot-search huggingface dataset:
Concurrent split course hyperfractionated radiotherapy (Hfx RT), cisplatin (DDP) and paclitaxel (P) in patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck (SCCHN): Update of RTOG 9911
Authors: E. M. Horwitz, J. Harris, C. J. Langer, N. Nicolaou, M. Kies, W. Curran, S. J. Wong, K. Ang
Journal: Journal of Clinical Oncology (2005)

5577 Background: Chemotherapy (CTx) alone (eg. DDP, 5FU) remains the standard therapy for recurrent SCCHN, but yields median survival times (MST) of only 8–10 mos & 1 yr survival (OS) of ≤ 35% at best. For limited relapse or new unresectable SCCHN within previous RT portals, a potential role for re-irradiation combined with radiosensitizing CTx, exists. Based on a prior phase I trial of split course HFx RT/ DDP/ P, in which we observed a response rate of 55% & ≥ 2 yr progression-free survival (PFS) in 5 of 31 pts (ASCO 1999, A-1551), RTOG initiated a phase II trial. Methods: Eligibility stipulated recurrent SCCHN or second 1° tumors (SPT) in a previous RT field with ≥ 75% of tumor volume previously treated to 45 Gy-75 Gy; ≥ 6 mos elapsed from prior RT, ECOG PS 0–1; ANC ≥1500, plts ≥ 100K, bili ≤1.5 mg/dl, creat ≤ 1.5 mg/dl, & absence of distant mets. Pts received HFx RT (1.5 Gy/Fx BID x 5d every 2 wks x 4), in combination with DDP 15 mg/m2 IV QD x 5 & P 20 mg/m2 IV QD x 5 q 2 wks x 4. G-CSF was given days 6 through 13 of each 2 wk cycle. Results: 105 pts (median age 60; 77% male; 66% PS 1) were entered between 3/00 & 6/03; 99 proved eligible. 23% had SPTs. Oropharynx (40%) & oral cavity (27%) were the predominant 1° sites. Median prior RT dose was 65.4 Gy (range, 45–75 Gy), median time from prior RT 40 mos. 74% of pts received all 4 scheduled cycles of chemo; 69% received RT as planned (median dose 60 Gy). Gr ≥ 4 acute toxicity (tox) occurred in 28%, gr ≥ 3 leukopenia in 30%, gr ≥ 3 anemia in 21%, and gr ≥ 3 GI toxicity in 48%. Delayed osteoradionecrosis occurred in 4%. There were 8 fatal (Gr 5) toxicities: 5 in the acute period (dehydration, pneumonitis, neutropenic fever [2], CVA) & 3 late (carotid hemorrhage in 2). At a median follow-up of 23.6 mos, MST is 12.1 mos with est. 1- & 2-yr OS rates of 50.2% (95% CI: 40.0, 59.6) & 25.9% (17.3, 35.3). Median & 1-yr PFS are 7.8 mos & 35% (CI 25.7, 44.4) Conclusions: Despite a fairly high incidence of Gr 5 tox, the 1- & 2-yr OS rates for split course HFxRT/DDP/P exceed results generally seen with chemotherapy alone. A phase III trial directly comparing CTx alone to concurrent CTx & re-irradiation with survival as the 1° enpoint is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Aventis, Bristol-Myers Squibb, Genentech, ImClone, MedImmune, Sanofi AstraZeneca, Aventis, Bristol-Myers Squibb, Lilly Oncology, Pfizer
Results from a phase I dose escalation study of PEGylated glutaminase in combination with 6-diazo-5-oxo-L-norleucine (DON) in advanced malignant solid tumors
Authors: C. Unger, C. Müller, E. Jäger, M. Bausch, J. Roberts, S. Al-Batran, N. Sethuraman
Journal: Journal of Clinical Oncology (2006)

13017 Background: To cope with the increased demand with concomitant down-regulation of glutamine synthesis, tumor cells in general have an upregulated glutamine uptake. The rationale is based on the premise that the therapeutic effectiveness of the glutamine anti-metabolite 6-diazo-5-oxo-L-norleucine (DON) is enhanced by strong depletion of the available pool of glutamine through PEGylated glutaminase (PEG-PGA). The optimal dose of PEG-PGA was found in step one of this study. Methods: Step two of this Phase I study was designed to determine the safety and tolerability of 120 I.U./m 2 PEG-PGA in combination with increasing dose levels of DON both administered i.v. twice weekly. DON was administered four hours after PEG-PGA at levels of 5–185 mg/m 2 with cohorts of three patients. Cohorts were expanded in case of possibly drug related AEs≥G3. All patients exhibited solid tumors of various indications refractory to standard treatment. Toxicity was measured according to NCI-CTC criteria. Response was evaluated according to RECIST criteria. Results: 61 patients have been enrolled in step two of this study wherein 58 received at least one treatment and 46 (57% male) were available for preliminary evaluation. Median age was 62.5 years (range 43–79) and 36% had a Karnofksy-index &lt;90%. At 25 mg/m 2 of DON three patients exhibited G3 nausea and vomiting which was managed effectively with antiemetic therapy. Possibly drug related AEs ≥ G3 like dyspnoea (n = 1), allergic reaction (n = 1), haematemesis (n = 1), 1 thrombosis (n = 1) and neurological diseases (n = 4) were reported in 19.6% of the patients. Haematological toxicities were neither frequent nor severe. No G4 toxicity in any dose level has been observed. DLT (two AEs ≥ G3 in one cohort) was reached in the 11 th escalation step resulting in an adequate MTD which will be used in the following studies. In 38 patients available for tumor response 1 confirmed PR (renal) and at least 12 SDs have been reported. Conclusions: PEG-PGA in combination with DON has shown promising efficacy in heavily pre-treated solid tumors with a favourable toxicity profile. A clinical proof of concept study with statistically sufficient number of patients is ongoing. [Table: see text]
Phase II Southwest Oncology Group study of docetaxel and vinorelbine plus filgrastim with weekly trastuzumab for HER2-positive, stage IV breast cancer
Authors: J. Kash, W. E. Barlow, K. S. Albain, J. R. Gralow, D. Lew, L. E. Flaherty, M. E. Royce, G. N. Hortobagyi, R. B. Livingston
Journal: Journal of Clinical Oncology (2008)

1033 Background: The taxane, docetaxel (DOC), and the vinca alkaloid, vinorelbine (VNR), have significant activity in combination as first line chemotherapy for HER2-negative, stage IV breast cancer (BC). Preclinical studies suggest potential synergy between these two classes of anti-tubulin drugs. Each agent has significant activity when combined with trastuzumab in HER2-positive BC. This study evaluates both agents together with trastuzumab as first-line chemotherapy for stage IV disease. Methods: Patients (pts) with HER2-positive, metastatic BC were eligible. Pts may have received prior adjuvant chemotherapy that did not include DOC or VNR. DOC (60 mg/m2) on day 1 and VNR (27.5 mg/m2) on days 8 and 15 were given intravenously each 21-day cycle. Trastuzumab was administered concurrently (standard weekly schedule), with filgrastim days 2–21. The primary endpoint was overall survival (OS) at 1-year, with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. The planned sample size was 90 pts, sufficient to estimate 1-year OS within 11% at α=0.05 (2-sided). Results: Due to slow accrual, the study was closed with a total of 76 pts registered between 2/03 and 12/06. The OS analysis includes 71 eligible pts with available data. One-year OS is 94% (95% CI 88%-100%) with a median OS of 39 months (95% CI 29–41). One-year PFS is 70% (95% CI 59%-80%) with median PFS of 19 months (95% CI 14–28). Of 63 pts with measurable disease, there were 45 (71%) CR+PRs (95% CI 59–82%). Six pts remain on treatment, with the most common reasons for discontinuation being progression (n=17) and adverse events (n=16). Of 67 pts evaluable for toxicity, 14 (21%) had a grade 4 event and 20 (30%) had a grade 3 event as the highest adverse event. Neutropenia was the predominant G 4 event. The most common G 3/4 non-hematologic toxicities were fatigue (10%) and hyperglycemia (7%). No G 5 toxicity was reported. Conclusions: The combination of docetaxel, vinorelbine, and trastuzumab is very active as first-line chemotherapy in HER2-positive, stage IV breast cancer and has the best survival rate published to date in this population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology, GlaxoSmithKline, sanofi-aventis Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Roche, sanofi-aventis
Predictive factors in advanced head and neck cancer treated by radio-chemotherapy and hypoxia modification
Authors: B. Clavo, F. Robaina, A. Ruiz, M. Lloret, D. Macias, J. Rivero, B. Pinar, S. Quintero, J. M. Cuyas, M. A. Hernandez
Journal: Journal of Clinical Oncology (2007)

6085 Background: Anemia and tumor hypoxia are known factors for resistance to radio-chemotherapy (RT-CT). In a previous report we have suggested that spinal cord stimulation (SCS) can modify tumor oxygenation and regional blood flow in head and neck cancer (HNC). The aim of the present prospective study was to test the predictive value of pO2 measurement in HNC treated by RT-CT and hypoxia modification using SCS. Methods: Twelve male patients with advanced HNC were analyzed. Stage IVb-IVa: 8–4; mean age 58 + 7.6 years (46–70). Scheduled therapy was hyperfractionated RT (120 cGy/fraction, two fractions/day, total dose 81.6 Gy) from a Co- 60 source, and tegafur 800 mg/day. SCS devices were placed before RT-CT under local anesthesia. During treatment, SCS was connected from 20–30 min before to 20–30 min after each radiotherapy session. Before treatment, they were assessed: Hemoglobin levels and tumor oxygenation pre-SCS and pos-SCS (measured by a polarographic probe system ‘pO2 Histograph‘), expressed as median-pO2, and the fraction of pO2 values less than 5 mmHg (HF5) and less than 2.5 mmHg (HF2.5). Correlations were assessed using Pearson and Spearman tests, and actuarial survival using Kaplan-Meier estimates and Log-rank test. Results: Hemoglobin levels were correlated with oxygenation pre-SCS and pos-SCS: median-pO2 (p=0.005 and p=0.011), HF5 (p=0.048 and p=0.005) respectively. Anemia was associated with more advanced stage (IVb vs IVa, p=0.022), higher HF5 pos-SCS (p=0.028) and lower disease-free survival (p=0.019). The HF2.5 pos-SCS was adversely correlated with the 2 years actuarial: disease-free survival (p=0.027), cause-specific survival (p=0.008) and overall survival (p=0.008). HF2.5 was also correlated with hematocrit (p=0.044). Conclusions: Low hemoglobin levels and anemia are associated with more hypoxic and more advanced tumors. Pre-treatment tumor hypoxia (assessed by the fraction of pO2 values less than 2.5 mmHg during-SCS) is a strong predictive factor for survival in advanced HNC. Patients with highly hypoxic tumors should be selected for more aggressive treatments. Partially supported by: Grant ‘FUNCIS: PI 31–98‘. Scientific supervision was carried out by GICOR. No significant financial relationships to disclose.
Significance of responses reported in single agent phase I studies of investigational anticancer agents
Authors: J. Manela, R. Haynes, G. Gallant
Journal: Journal of Clinical Oncology (2005)

6049 Background: It has become common to place increased scrutiny on phase I trials of investigational agents in search of early glimpses of anticancer activity. The hope has been that such data will prevent from subjecting patients to and spending resources on inactive agents. However, it is unclear whether such a decision should be made based exclusively on the data collected in a phase I trial. The objective of this study was to review and identify if there have been approved and/or effective agents that showed little to no activity in the phase I setting. Methods: An analysis of publicly available literature was conducted on a mix of 14 currently marketed and investigational agents. For each phase I single agent trial, the number of patients (N), complete responses (CR), partial responses (PR), and minor responses or stable disease (MR/SD) as reported by the investigators (based on RECIST or WHO criteria) were calculated and compared. Results: For all agents analyzed, 36% achieved a CR, 50% achieved a PR, and 14% achieved SD as best response in at least 1 patient. Of the 7 approved agents with complete dataset available, 4 achieved a response (CR or PR), 1 achieved MR/SD, and 2 had no activity as best response for the use later approved. Of the 6 approved drugs with phase I single agent programs in advanced solid tumors, 3 achieved a response in several tumor types, 1 achieved a response as a single agent in only the tumor type which was later approved, and 2 agents, bevacizumab and cetuximab, which are approved and active in the treatment of colorectal cancer, achieved no response in any tumor type as a single agent. Conclusions: Complete responses are uncommon in phase I single agent studies of investigational anticancer agents. For those agents where responses are seen, continued development usually proceeds in the indications where the responses were reported. However, a lack of response should not necessarily deter the continued development of what may prove to be a promising anticancer agent in future trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences
Phase II dosing study of cytarabine chemotherapy in combination with cenersen (EL625) and idarubicin in refractory and relapsed acute myelogenous leukemia (AML)
Authors: Y. Alvarado, H. Kantarjian, E. J. Freireich, G. Garcia-Manero, A. Ferrajoli, C. Koller, Z. Estrov, S. Kornblau, N. Laddie, L. Smith, J. Cortes
Journal: Journal of Clinical Oncology (2007)

7070 Background: Cenersen is an antisense oligonucleotide that blocks production of p53. It sensitizes acute myeloid leukemia (AML) stem cells in vitro to DNA damage. Methods: Thirty-seven patients (13 refractory, 24 relapsed) with AML have been enrolled in the ongoing trial. All patients received cenersen (0.1 mg/kg/hr continuous intravenous infusion over 4 days [d]) plus Idarubicin (12mg/m 2 /dx3). Cytarabine was administered as follows: group (1) no cytarabine; (2) 100mg/m 2 /dx7; (3) 1g/m 2 /dx4 (3d &gt; 60y). Chemotherapy started day 2. Results: Eighteen patients were treated per protocol and 19 were inevaluable to include 16 who received prohibited substances that block the action of cenersen (acetaminophen and/or high dose antioxidants). Six (33%) of those treated per protocol achieved CR compared to none of the 16 who received prohibited substances (p=0.02). This rate compares favorably to a literature report of a similar patient population (14%; Estey 1996). There were 2 patients who achieved a CRp, one of whom received acetaminophen on day 7. No significant differences in response occurred between the three treatment arms. The remission duration for 7 of the 8 responding patients was longer than the prior remission duration for the same patients. Several adverse events (AEs) (infection, bleeding, mucositis and hair loss) were significantly (p&lt;0.001) less common for patients in this trial compared to the AE frequency described in the package insert for Idarubicin for its use in combination with standard dose Cytarabine. No adverse events attributable to cenersen were identified. Conclusions: We conclude that cenersen in combination with chemotherapy may improve the response rate compared to that expected with chemotherapy alone. No significant financial relationships to disclose.
Pharmacokinetic evaluation of the auto-inductive effect of a single dose of ifosfamide administered each 15 days
Authors: B. Gourmel, J. Alexandre, F. Rabillon, F. Goldwasser
Journal: Journal of Clinical Oncology (2005)

2111 Background: Ifosfamide (Ifos) is an alkylating agent active in various malignancies. Its auto-inductive effect is well documented. We have previously reported that this induction seems to have a positive effect on the relative ratio of active metabolite 4 hydroxy Ifosfamide (4 OH)/inactive dechlorinated metabolites (2d Ifos, 3d Ifos). Nevertheless, the duration of this phenomenon, its as well as the dose needed to induce it, remain to be determined. We investigated pharmacokinetic parameters during 2 consecutive courses of one infusion of ifos (2.5 g/m2, 2 hours infusion) given as a single agent every two weeks. Methods: Blood samples were collected at the end of the infusion and 2 and 5 hours later. Ifos and metabolites were determinated by a gaz chromatographic method as previously described. Pharmacokinetic parameters were calculated following two consecutive administrations (C1, C2) for 8 adult patients. Results: Ifosfamide levels, and pharmacokinetic parameters (mean values +/- SD) were respectively for C1 and C2: T G \(\frac{1}{2}\) 449 and 418 min, Cmax 55.9 and 55.5 μg/ml, Clearance 71.2 and 84.5 ml/min. The areas under the curve (AUC) decreased by 2% between the 2 infusions. Nevertheless, we noticed inter-individual variations. The Cmax could be decreased by 30% (1), 20% (1) 0–10% (5), or slightly increased (1). Similar variations in the patients metabolites levels were observed. Of note, a higher production of all metabolites was observed at C2. The average increase in the AUC is 12.5 and 24.2% for the dechlorinated (2d, 3d Ifos) metabolites and 12.1% for the active metabolite 4 OH. The positive effect of the induction is not cleary established in this conditions. Conclusions: A single 2.5g/m2, during a 2 hour infusion of Ifos seems a limit dose for reaching an induction effect 15 days later. This phenomenon is detectable for half of the patients. We are presently studying the auto-induction following a dose of 3 g/m2 of ifos. No significant financial relationships to disclose.
Heparanase and Survivin—potential markers of aggressiveness of colon cancers
Authors: A. C. Hoffmann, C. Hoffmann, K. D. Danenberg, H. J. Lenz, P. V. Danenberg
Journal: Journal of Clinical Oncology (2007)

14524 Background: Survivin is an inhibitor of apoptosis and specifically expressed in several human cancers. Heparanase seems to play an important role in cancer metastasis, angiogenesis and regulation of COX-2 expression. The purpose of this pilot study was to evaluate whether there is a difference in the level of survivin and heparanase expression in paraffin-embedded tissue from patients with colon cancer with and without metastasis. Methods: Paraffin-embedded tissue samples were obtained from 32 patients with primary colon tumors with (n = 15) and without liver metastases (n = 17) at the time of diagnosis. After laser capture microdissection direct quantitative real-time reverse transcriptase PCR (RT-PCR, TaqMan™) assays were performed in triplicates to determine survivin and heparanase gene expression levels. Gene expression was normalized with beta-Actin. Decision tree analysis was used to assess whether higher levels of these genes are associated with the existence of metastasis. Results: Neither survivin nor heparanase gene expression alone showed a significant relationship with the pM-Stage, although the detection levels of heparanase showed a tendency towards significant correlation with the existence of liver metastasis (p = 0.06). Decision tree analysis was used to split patients into two groups based on cut-off values of gene expression most closely associated with the pM-stage. The groupings determined by this analysis were significantly differently correlated with metastasis by Spearman’s test (p=0.03). Conclusions: Our results show that high expression levels of both survivin and heparanase in paraffin- embedded tissue are significantly correlated with the pM-Stage in this patient cohort. In conclusion, using intratumoral survivin and heparanase gene expression levels might be useful to identify patients at risk for liver metastasis. Prospective and larger clinical studies are warranted to validate our preliminary findings. No significant financial relationships to disclose.
Preliminary evidence of efficacy and tolerance for weekly intravenous bortezomib plus mitoxantrone in patients with advanced androgen-independent prostate cancer (AIPCa)
Authors: A. O. Siefker-Radtke, V. Poulter, P. Mathew, S.-M. Tu, C. J. Logothetis, C. N. Papandreou
Journal: Journal of Clinical Oncology (2005)

4567 Background: Bortezomib, a dipeptidyl boronic acid inhibitor of the 20S proteasome, has evidence of activity when given on a weekly schedule in patients with AIPCa. Of the cytotoxic agents approved for treatment of AIPCa, experimental models suggest anthracyclines exhibit consistently enhanced activity when given in combination with bortezomib. In an effort to build on these potential additive or synergistic effects, we developed a phase I study of weekly bortezomib (B) with weekly mitoxantrone (M) in patients (pts) with AIPCa. Methods: Twenty-one pts with progressive AIPCa received 63 cycles of B plus M given once weekly 4 weeks out of 5 using dose escalation with a continuous reassessment method. Three pts were treated at dose level 0 (B=1.4 mg/m2, M=2 mg/m2), and 18 at dose level 1 (B=1.4, M=3.0). Results: Median age was 63 yrs (range: 47–78). Nineteen pts received prior systemic chemotherapy (median # regimens: 2, range 0–7); 17 received prior taxane-based therapy. Therapy was well tolerated with only one G4 toxicity (unrelated basal cell cancer). G3 toxicities mainly included fatigue and neutropenia (4 each). Six pts required dose reduction: 4 due to G3 neutropenia (2 in cycle 1), and 2 due to Plt < 75,000. Only 1 pt had G2 neuropathy. Of the 18 pts completing at least 2 cycles and assessable for response, 3 (17%) pts with measurable disease achieved PR (both by PSA and in lymph nodes) and completed 5, 6, and 8 cycles of treatment. Two responders received prior chemotherapy; 1 progressed on non-taxane therapy, the other had 6 prior regimens of which 3 contained a taxane. Two additional heavily pre-treated pts (4 prior chemotherapy regimens each) achieved SD - the first pt had SD throughout all 8 cycles, while the other pt had a minor response in lymph nodes after 2 cycles, and continues on therapy. Conclusions: This schedule of bortezomib with mitoxantrone is well tolerated, and shows evidence of antitumor activity. Accrual to a cohort receiving bortezomib 1.4 mg/m2 and mitoxantrone 3.0 mg/m2 is ongoing. These observations may have broader implications in the development of proteasome inhibitors in combination with cytotoxic chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millenium Johnson & Johnson Pharmaceutical Research & Development