Prognostic value of etoposide area under the curve (AUC) in lymphoma patients treated with BEAM regimen and ASCT: Multicenter study of Groupe d’Etudes des Lymphomes de l’Adulte (GELA).

8068 Background: The prospective LYMPK study primary objective was to assess the impact of etoposide pharmacokinetic (PK) parameters on toxicity and efficacy in lymphoma patients receiving the BEAM regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). We previously showed the high inter-individual variability in etoposide PKs, defined by area under the curve (AUC) and trough concentration (Cmin), among study patients treated with the same doses /m2 (You B et al, Proc. ASCO 2008). Methods: Ninety-six patients with malignant lymphoma at 1st line (n=52) or relapse (n=44) were enrolled in 5 centers. All received BEAM regimen, including high-dose etoposide (100 to 200 mg/m2 bid for 4 days), followed by ASCT. Individual etoposide AUC and Cmin were estimated by population PK approach using NONMEM program. The impact of PK parameters on toxicity and survival was assessed using linear regression and univariate/multivariate analyses. Results: Data from 90 patients were assessable after a 4.2-year median follow-up. The bi-compartment model previously reported was used to characterize PK parameters (You B et al, Proc. ASCO 2008). Etoposide AUC and Cmin correlated with mucositis duration, especially for grade 3-4 toxicity (p< 0.05), but not with other toxicities. Cmin had significant prognostic value regarding 5 year progression free survival (p=0.03). Five year overall survival (OS) was longer in patients with higher AUC (76% vs 56%, if AUC > median, p=0.04) as it was in patients with higher Cmin (78% vs 54%, if Cmin > median, p=0.02). When assessed with available IPI prognostic factors (age; performance status; LDH and stage) using Cox analysis, the only independent prognostic factors of OS and disease specific survival were etoposide AUC (HR= 0.39, 95% CI = 0.16-0.94) and Cmin (HR = 0.32, 95% CI = 0.12-0.80). Conclusions: LYMPK study results suggest that individual etoposide systemic exposure has a strong impact on survival in lymphoma patient receiving BEAM regimen and ASCT. Given the high variability in patient AUCs, plasma concentration-based adjustment of etoposide dose may be considered in future studies.

Patient (PT) participation and disaster (D) agency (AG) coordination for oncology (ONC) PT D preparedness (PREP): Analysis of the Great Southern California Shake Out (GSCSO) drill and implications for regional and national emergency (E) planning (P)

e17549 Background: PT E PREP is important (Katrina, Los Angeles fires 2007, 2008). MOASC developed the ONC PT E Network (OPEN) (www.open-central.com; Proc ASCO 2006 a6142, 2007 a17003 , and 2008 a6545). On Novermber 13, 2008, 28 organizations and sponsors (US and Cal govt and private) conducted the GSCSO drill with a Richter scale 7.8 earthquake. MOASC tested OPEN as part of GSCSO. Methods: In OPEN, PTs were given wallet cards with E information (diagnosis, stage, treatment, doses). As part of GSCSO, MOASC a) surveyed two practices in two counties to evaluate ONC PT motivation and PREP; and b) surveyed D AG to determine the triage program for ONC PTs who required CT. PTs in two offices pretended the ONC offices had been closed due to the D. They were asked to call the MOASC E line and advise an address to which they would evacuate where MOASC referred PTs to a participating physician for chemotherapy (CT). Results: 36 PTs participated. In office interviews, PTs had concerns about transportation to evacuation locations during the D, how they would find available phone lines during an E, and whether MOASC lines would be responsive in an E. Only 5 PTs (13.9%) contacted the MOASC E line within 24 hours. The 4 most available D AGs were unaware of how to triage ONC PTs requiring CT, and were unaware of MOASC and ASCO resources. They wanted to refer ONC PTs to E rooms which would be unresponsive to PT needs for CT. Conclusions: ONC PTs are not yet motivated for D PREP (concerns regarding current CT have higher priority). Responding AGs are not capable of correctly triaging ONC PTs for CT. Neither PTs nor doctors have a list of D AGs. State ONC societies, ASCO, and ACCC should create regional E phone response lines through state societies, regional E oncologist contacts, and a single national facilitating D response office, as well as coordinate regional and national D AGs so that PTs can be triaged to appropriate resources. National D AGs funded to coordinate responses should be the source of support for this process. Motivating ONC PTs for EP will require reimbursed practice participation. No significant financial relationships to disclose.

Association between human papillomavirus (HPV) status with serum cytokine and angiogenic factor (CAF) profile after induction chemotherapy in head and neck squamous cell carcinoma (HNSCC)

6081 Background: Human papillomavirus has been implicated in the development of head and neck squamous cell carcinoma and is associated with a more favorable clinical outcome. Previously, we identified a serum hypoxia signature associated with HNSCC progression (Byers et al, Proc ASCO. 2008). We investigated the association between HPV status, serum biomarkers, and clinical outcome in patients treated with induction chemotherapy. Methods: 47 previously untreated patients with locally advanced nodal disease (T0–4, N2b/c/3, M0) received 6 weekly cycles of paclitaxel (135 mg/m2), carboplatin (AUC 2), and cetuximab (400 mg/m2 week 1; 250 mg/m2 weeks 2–6) followed by definitive local therapy. 46 (98%) patients had a complete or partial response to induction chemotherapy (Kies et al, Proc ASCO. 2006), and 6 have had tumor progression (PD) after a minimum follow-up of two years. Formalin fixed biopsies were available for HPV testing by in situ hybridization with non-radioisotopic chromogen for 25 patients (including 5/6 with PD). 38 CAFs were measured by multiplex bead assay before and during treatment. Results: 12/25 patients were HPV-positive, all male and six were never smokers; of the 13 HPV-negative patients, four were male and three were never smokers. Among those with available data, all 5 patients with PD were HPV-negative (p = 0.02). There were four study deaths, all in the HPV-negative group. Overall survival was superior in HPV-positive patients (p = 0.04). There was no significant association between HPV status and serum CAF markers. However, among HPV-negative patients, PD was associated with the CAF hypoxia signature (5/8 patients with the hypoxia signature progressed versus 0/5 signature-negative). Of the individual CAFs, osteopontin was significantly elevated in all HPV-negative patients with PD. Conclusions: HPV positivity was associated with a longer progression-free survival and overall survival. Among HPV-negative patients, only those with a serum hypoxia signature had disease progression. These data suggest that the combination of HPV status and CAF profiling may identify patients at risk for relapse after sequential therapy. No significant financial relationships to disclose.

Interim efficacy analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan (CPT-11) in resected stages II-III rectal cancers

4015 Background: The R98 trial tests the hypothesis that irinotecan (CPT-11) combined with 5FU/LV is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: 600 pts were planned to be randomized between 5FU/LV (control arm) or 5FU/LV + CPT-11. Recruitment was slow, with only 357 pts included in the study between 03/1999 and 12/2005 (178 in control arm and 179 in CPT-11) at which time the IDMC recommended closure of accrual. The primary endpoint was disease free survival (DFS), relevant events being death (whatever its cause), local or distant recurrence, and any new primary cancer. The trial was stratified by choice of control arm: either a Mayo-Clinic regimen (A: LV 20 mg/m2, 5FU 425 mg/m2 bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m2 over 2-hour, 5FU 400 mg/m2 bolus and 600 mg/m2 22-hour infusion, d1–2, q2w for 12 cycles), depending on centre decision. The experimental arm (B) consisted of LV5FU2 + CPT-11 180 mg/m2 d1 of every cycle. Results: Safety analysis was reported last year (P. Piedbois et al. Proc. ASCO 2008). We present here a first interim analysis of efficacy on half the numbers of events planned per protocol. Median follow-up is 55 months. Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. There was a trend in favor of 5FU/LV + CPT-11 in terms of DFS (77 vs 62 events in control and CPT-11 arms, hazard ratio=0.75, p=0.089) with similar effect in the Mayo-Clinic stratum (31 vs 25 events, hazard ratio=0.77) and in the LV5FU2 stratum (46 vs 37 events, hazard ratio=0.74). Conclusions: This interim efficacy analysis shows a trend in favor of 5FU/LV + CPT-11. If performed when at least 220 events are observed (projected in 2010), the next efficacy analysis would have a conditional power of about 60% to detect a true benefit of 5FU/LV + CPT-11 if the treatment effect remained the same as observed today. Study supported by Pfizer, France. [Table: see text]

Beneficial effects of elective brain irradiation (BI) in limited disease inoperable non-small cell lung cancer patients treated with combined chemo-radiotherapy (CCRT)

18033 Background: BI significantly decrease brain metastases (BM) and prolonged CNS relapse free (CRF) duration (J Neurooncol 2: 253, 1984). Studies of 5 CCRT protocols using chest irradiation with randomization to BI after 2–3 courses of chemotherapy showed that patients who had complete response (CR), partial response (PR), minor response (MR), or no change (NC) of the diseases with CCRT benefited from BI with significantly reduced BM, prolonged response (R) duration and time to progression (TTP). (Proc. ASCO 5: Abstract 728, 1986). The value of BI remains unclear. Methods: Re-evaluation of previously mentioned 5 CCRT protocols was done to determine the effects on S, duration of R, TTP, and CRF with evaluations at 75th percentiles. Results: Of 138 patients (59 BI+), there was no significant difference between BI+ and BI- in terms of characteristics and response to CCRT. The effects of BI on S, duration of R, TTP, and CRF are as above. Conclusions: 1) BI significantly improved the duration of R,TTP, and CRF; 2) Although no S benefit was found in standard evaluation, BI patients had 37 weeks S advantage at 75th percentiles; 3) Patients who had CR, PR, or MR had benefited from BI and the benefits were more when evaluated at 75th percentiles; 4) The standard study of duration curves should be modified to look at a higher percentiles if the proposed treatment had low responses; 5) Awaiting for the results of RTOG 0214, our information could possibly favor BI in these patients. [Table: see text] No significant financial relationships to disclose.

Randomized phase II trial of three dosing schedules of nanoparticle albumin-bound paclitaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer: An initial interim safety report

1104 Background: Nanoparticle paclitaxel (NP) at 260mg/m2 every 3 weeks (q3wk) is more effective than standard paclitaxel (P) (Gradishar et al, JCO 2005). Weekly, uninterrupted administration of P is superior to q3wk P in MBC (Seidman et al, Proc ASCO 2004). When added to weekly P as 1st-line therapy for MBC, bevacizumab (B) improves response rate and progression-free survival (Miller et al, Proc ASCO 2005). We initiated a randomized phase II trial of NP given at 260mg/m2 q3wk (arm A) vs. 260mg/m2 q2wk with filgrastim (arm B) vs. 130mg/m2 weekly, all with B, as 1st-line therapy for patients (pts) with HER2- MBC. Methods: 66 of planned 225 pts have enrolled. After 31 pts had been randomized and treated, investigators concerned about possible differential neurotoxicity requested this early interim safety analysis. Median age is 54 (range 40–78). 83% are post-menopausal and 100% have visceral dominant disease. 68% had prior adjuvant or neo-adjuvant chemotherapy; 35% with taxanes. Results: With 170 cycles delivered (median: 4, range 1–15) 10 dose reductions have been necessary for NP (1 in A, 5 in B, 4 in C). No hypersensitivity reactions or dose interruptions have occurred for NP; 3 doses of B have been held due to hypertension. Significant preliminary antitumor activity has been noted in all arms. One grade 4 toxicity occurred in arm C, hyperglycemia. 15 grade 3 toxicities have been reported across all arms. Pts on arm A have experienced 3 grade 3 toxicities (30%): fatigue, neutropenia, and arthralgia with no grade 3 neurotoxicity. Pts on arm B have had 7 grade 3 toxicities (58%) with 3 pts experiencing grade 3 sensory neuropathy (25%) and others experiencing fatigue, neutropenia, anemia, esophagitis, dyspnea, and ataxia. 5 arm C pts experienced grade 3 toxicities (56%) including diarrhea, dehydration, mucositis, neutropenia, hypokalemia; 2 pts have had grade 3 sensory neuropathy (22%). Conclusions: This early safety analysis does not detect any statistically or clinically significant differences in grade 3 toxicity and all arms continue to accrue. The next protocol-specified safety analysis is expected in early 2007, with mature safety data for 60 pts. Updated results will be presented. [Table: see text]

A phase II study to determine if sensory neuropathy of nab-paclitaxel can be reduced by prolonging infusion in patients with non-small cell lung cancer (NSCLC)

18087 Background: We have previously reported that nab-paclitaxel (ABI-007; Abraxane) administered at 125 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days has a response rate (RR) of 30% and median survival of 11 months [Rizvi, Proc. ASCO 2006]. We also observed 15/40 (38%) patients developed grade 2/3 sensory neuropathy with a 30 minute infusion. We hypothesize that a longer infusion with nab-paclitaxel may reduce peak plasma levels and accordingly reduce sensory neuropathy. Methods: After enrollment of 40 patients at 125 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days, we amended the protocol to study an additional 25 patients with chemotherapy naïve stage IV NSCLC with a 2 hour infusion. The enrollment criteria and treatment schedule otherwise remained the same. Our goal was to detect 1 to 2 grade improvement of peripheral neuropathy with 80% power at the two sided p=0.10 significance level compared to the 40 patients treated with this dose given over 30 minutes. Results: To date, 22 of 25 planned patients have been treated with a 2 hour infusion. The mean number of doses administered was 11 for the initial 40 patients treated with a 30 minute infusion and 10 for the 22 patients treated with the 2 hour infusion. We observed 9/40 grade 2 and 6/40 grade 3 sensory neuropathy with the 30 minute infusion and 2/22 grade 2 and 1/22 grade 3 sensory neuropathy with the 2 hour infusion. The combined grade 2 and 3 toxicities were less with the 2 hour infusion (3/22, 14%) compared with the 30 minute infusion (15/40, 38%; p=0.078, Fisher’s exact test). Conclusions: Prolonging the infusion rate of nab-paclitaxel from 30 minutes to 2 hours is associated with a significant decrease in grade 2 and 3 sensory neuropathy. Efficacy data is presently being evaluated. [Table: see text]

Compliance with oral topotecan in patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)

7092 Background: Compliance with chemotherapy can affect treatment efficacy and patient safety. Selecting an oral chemotherapy regimen with good tolerability in appropriate patients is important. To determine general level of compliance of oral topotecan, a retrospective analysis was conducted on 3 international open-label, multicenter, 2-arm randomized, phase III studies of patients with NSCLC and SCLC. Methods: Patients were randomized to receive oral topotecan d1–5 q21d as follows: Study 387 (Ramlau et al, Proc ASCO, 2005) 2.3 mg/m2/d second-line vs IV docetaxel for NSCLC; Study 389 (Eckardt et al, Proc ASCO, 2005) 1.7 mg/m2/d first-line with cisplatin vs etoposide/cisplatin for extensive-disease SCLC; and Study 478 (O’Brien et al, Lung Cancer 2005) 2.3 mg/m2/d second-line vs best supportive care for SCLC. Oral topotecan was administered to the patient in the clinic on day 1 of each course and the patient was responsible for self-administering the oral capsules the remaining 4 days of dosing. Patient compliance was defined as 100x(sum of number of caps taken across courses)/(sum of number of caps dispensed across courses), where number of caps taken = number of caps dispensed-number of caps returned. Results: Accrual per arm was (387), 414 patients; (389) 389; (478) 71. In the treated population for all three groups, adherence to oral topotecan was high, with >90% of patients recording at least 90% overall compliance (Table). Mean age (% ≥65 years/%PS 2) was (387) 58.8 years (29.2%/14%), (389) 59.7 (32.6%/13%), and (478) 59.8 (33.8%/27%). Median oral topotecan dose intensity (% target) for each course was (387) 87%, (389) 95%, and (478) 98%. The most common reason for dose reductions or delays was hematological toxicity. Conclusions: Oral topotecan can be administered on an outpatient basis with a high degree of patient compliance in the treated population, which included those ≥65 years and those with poor PS. [Table: see text] [Table: see text]

Phase II study of docetaxel and vinorelbine plus GM-CSF in malignant melanoma

18017 Background: Patients having locoregional or metastatic melanoma have a poor prognosis, with 50% to 10% of patients dying from the disease within 5 years. Current chemotherapy regimens offer limited benefits to these patients and more effective and less toxic treatments are needed. Methods: We developed a phase II clinical trial to evaluate the activity of an every two week schedule of docetaxel (40mg/m2, d1), vinorelbine (30 mg/m2, d1) IV and sargramostim (GMCSF, 250 ug/m2 sq d2–11). This regimen was developed based on preclinical synergistic activity of paclitaxel plus vinorelbine (Neale et al. Melanoma Res 11:601, 2001), and evidence that the docetaxel plus vinorelbine combination can be given safely to lung cancer patients (Sanchez et al. Lung Ca 38:309, 2002). Sargramostim was included based on preliminary clinical data that it delays time to progression in stage IV melanoma patients resected for cure (Spitler, JCO 18:1614, 2000). We report here an interim analysis for the initial 21 patients with stage IV melanoma treated in first or second line. Results: The primary endpoint was time to progression. Grade III/IV toxicities included anemia (12.5%) and neutropenia (5%), with one patient requiring 25% dose reduction. To date, median time to progression (TTP) is 7 months, with 30% of cases showing greater than 8 months TTP. Conclusions: This result compares favorably with biochemotherapy, which has a median TTP of 5 months and overall survival of 8.4 months (Atkins Proc ASCO 22:708. 2003), while being significantly less toxic. Based on these favorable findings, we are continuing to accrue patients to this trial. [Table: see text]

22 year phase 1/2 study of single agent carboplatin in metastatic seminoma: Potential for acceleration by a new surrogate end point, 72 hr PET scan response?

14565 Background: That metastatic seminoma may be more chemo-curable than non-seminoma was first suggested by Samuels (1980 Proc ASCO 21 abst 415) 4 of 5 patients durable CR to single agent cisplatin and by Oliver (1984 Proc ASCO 3. Abst 636) 9 of 10 durable responses. Carboplatin proved less effective and in randomised trials involving 361 patients relapse free survival was 72% with Carbo and 92% with cisplatin-based combination. Prompted by successful dose escalation of carboplatin in ovarian cancer, the initial phase 1 study that preceded the UK randomised trial was reopened and dosage escalated to AUC 8 and then 10. This abstract updates this study and provides more prolonged follow up of the previous reported cases. Methods: Initially patients received Carboplatin 450 mg/m2 (1983–7) and then AUC 7 (88–94), 8 (95–6) and 10 (97–06). The treatment was repeated q21 when possible and if delayed because of toxicity blood counts were repeated every 24 hours. Results: 60 metastatic seminoma patients have been treated between 1983 and 2006. 79%/95% of 19 receiving 450 mg/m2, 88%/94% of 17 receiving AUC 7 or 8 and 92%/100% of 24 receiving AUC 10 are progression free/alive. Overall 58 (97%) are alive and with 28 patients followed more than 10 years there have been no relapses after 26 months. Mild and rapidly recovering (med 14 d) transaminitis in 64% of AUC × 10 (med 93 range 51–541) suggests this may be the upper limit for safe use. As a pilot study 5 seminomas receiving AUC × 10 and 6 non-seminomas receiving BEP had PET scan before and at 72 hours after treatment. The only patient failing to respond substantially was a seminoma who showed increased PET activity on AUC × 10 but achieved complete remission of PET activity after one course of BEP. Conclusion: This data confirms the need for more studies of single agent platinum analogues in seminomas and reinforces the view that it may be preferable to radiotherapy for patients electing adjuvant treatment. With increasing attention being paid to late events, minimizing treatment toxicity and finding a fast track approach to proving safety is an increasing need. The data presented demonstrates the potential of early PET scan as a surrogate for response and could have accelerated the phase 1/2 study reported. No significant financial relationships to disclose.