Time To Tumor Progression Research Articles

Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]

Survey of cetuximab activity in irinotecan-refractory metastatic colorectal cancer patients

13533 Background: The BOND study demonstrated Cetuximab (Cx) activity in irinotecan-refractory metastatic colorectal cancer (IRMCCR) patients (pts). Cx was approved in Europe early 2004 for this population. The aim of this study was to survey its efficacy in a unselected population of IRMCCR treated in 4 french academic centers. Methods: Data of all IRMCCR pts who had received Cx with or without irinotecan regimen between Jan 2004 and Sept 2005 were included in this survey. Exhaustivity of treated pts was established based on pharmacy registry. Primary end-point was time to tumor progression (TTP). Secondary end-points were overall survival (OS) and tumor response (RECIST). Results: Characteristics of the 76 included IRMCCR pts were : male/female : 44/32; median age 59.5 yrs (range 23 - 79); performance status : 0–1 (59 pts) and 2–3 (17); median number of tumor sites : 2 (1 - 5). The median number of chemotherapy regimens preceeding first Cx administration was 3 (range 1 to 5). At least one local treatment of the metastases (surgical resection and/or radiofrequency ablation) was a part of the strategy before Cx for 39 pts (51.3%). EGFR status was positive in 72 pts and negative in 4. Cx was administered : alone in 4 pts, combined with FOLFIRI in 4 and with irinotecan alone in 68 (89%). 10 pts received only one infusion Cx (early clinical progression : 6; patient decision : 2; early death : 2). Median number of Cx infusions was 10 (range 1 to 60). Median TTP (intent-to-treat) was 3.3 months [IC95% : 2.2–4.6]. Median OS since first-line chemotherapy and first Cx administration were 33.6 months [IC95% : 27.7–41.1] and 7.6 months [IC95% : 5.6–9.5], respectively. Tumor response (full population) was complete response 1.3%, partial response 19.7% (overall response 21%), stable disease 25% (disease control : 46%), progression 37% and not evaluable 17%. Conclusions: This therapeutic survey in a unselected population of IRMCCR are in accordance with the results of the BOND study for TTP, OS and tumor response. (supported by ADEBIOPHARM ER48). [Table: see text]

Phase II trial of preoperative cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy: PET scan after induction therapy may identify early treatment failure

4023 Background: Response on PET scan during preoperative chemotherapy (chemo) for esophageal cancer (EC) has prognostic significance [JCO 19:3058;2001]. Induction chemo with weekly irinotecan(I)/cisplatin(C) relieves dysphagia, and weekly I/C administered with radiotherapy (RT) is well tolerated [ProcASCO 23:Abs 4017;2005]. We completed a Phase II trial of induction I/C followed by I/C/RT followed by surgery. Repeat PET scan was performed after induction chemo and prior to RT. Methods: Patients (pts) with resectable EC/GE junction carcinoma were staged with EUS, PET, and CT scan. Induction chemo consisted of I-65 mg/m2 and C-30 mg/m2 weeks 1,2,4,5, and weeks 7,8,10,11 with RT (180 cGy daily fractions to 5040 cGy). PET scan was repeated at week 6. Esophagectomy was planned 4–8 weeks after RT. Results: 60 pts were enrolled: 6 inevaluable, 54 evaluable, 3 await surgery; 49 male (91%), 5 female (9%), 41 adenocarcinoma (76%), 13 squamous (24%), median age 59, median PS 0, EUS T3N1 35 (65%), N1 40 (74%). Of 41 pts with dysphagia, 31 (76%) had resolution/improvement with induction chemo and 3/54 (6%) required a feeding tube. Of 51 pts, 3 clinical complete responders (CR) deferred surgery (1 refusal, 2 medically inoperable). Of 48 pts, 4 progressed during induction (8%), 9 progressed during RT (19%), and 35 underwent R0 resection (73%). 9/48 (19%) achieved pathologic CR. The median overall survival was 35.4 mos (median follow up 15 mos). In exploratory analysis in 54 pts, response after induction on the week 6 PET scan measured as a decline in SUV, correlated with time to tumor progression (TTP). The mean change in SUV was 43%. A set point of 22% or greater decline in SUV (PET responder) yielded the greatest distinction in TTP (PET responders TTP 18.5 mos, vs nonresponders 5.5 mos, p = 0.03). 4 pts with progression during induction crossed over to RT with paclitaxel: 3 (2 squamous, 1 adenocarcinoma) achieved durable disease control (one pathologic CR, one pathologic PR, one clinical CR). Conclusions: Response on PET scan during induction chemo for EC may identify early treatment failures, and may direct pts to successful salvage with alternative chemo during RT. Supported by a grant from Pfizer. [Table: see text]

Impact of Karnovsky performance status (KPS) on outcome of elderly patients (pts) with glioblastoma (GBM) and activity of temozolomide (TMZ) as first line therapy: Retrospective analysis of a cohort

1515 Background: Due to increasing incidence of GBM in the elderly, prognostic factors and therapeutic strategies need to be considered in this population. Recently radiotherapy has shown survival improvement in patients with KPS ≥ 70 (ANOCEF, EANO 2005), while chemotherapy with TMZ may be considered as a therapeutic option (Chinot at al, Cancer 2003). Methods: We analyzed retrospectively all pts above 70 years old with GBM, who were referred to our institution from May 1998 to October 2004; all responses to TMZ were reviewed. Results: We identified 136 pts registered. Median age was 74 (range 70–87), and 43% had a KPS < 70. Surgery consisted of stereotactic biopsy (SB), 29% ; partial surgery (PS), 12%; and gross total removal (GTR), 29% of pts. Diagnosis was strongly suggested by neuroradiology in 30% of cases. Treatment consisted of TMZ (5 days standard schedule) (group A) as first-line treatment in 89 pts (65%), radiotherapy and/or nitroso-urea based regimens in 40 pts (30%) (group B) and best supportive care in 7 (5%) pts. For the all cohort, median of overall survival (OS) was 7 months (m), strongly impacted by KPS (3.9 vs 8.7 m, p<0.0001 for KPS < 70 and ≥70 respectively) and age (8.2 vs 6.0 m, p<0.007 for age < 75 years vs. ≥ 75). OS was 6.6, 7.3, and 8.4 mos in the case of SB, PS, and GTR respectively and was 5.2 for neuroradiologic diagnosis. In group A, median time to tumour progression (TTP) and OS were 4.7 & 7.3 m. KPS impacted TTP (2.9 vs. 5.1 m, p=0.0002) and OS (4.9 vs. 8.7 m, p<0.0001) for KPS < and ≥ 70 respectively. Response rates (RR) were for 71 pts evaluable 28%; SD 35%; PD 37% associated with an OS of 11.7, 7 and 3.2 m respectively. RR was 34% for histologically proven GBM, vs 22% in cases of neuroradiologic diagnosis. In group B, TTP and OS were 4.3 & 6.7 m respectively. Conclusions: KPS appeared to have a major impact on outcomes in elderly patients with GBM. Future trials designs should take this impact into consideration. TMZ appeared to be effective in elderly patients with newly diagnosed GBM. This alternative approach is currently being tested against RT alone in international trials. Impact of MGMT status in the TMZ population will be presented. No significant financial relationships to disclose.

A randomised phase II study comparing irinotecan (IRI) plus leucovorin (LV) and 5-fluorouracil (5FU) versus IRI-LV-5FU followed be oxaliplatin (OXA) plus LV-5FU in patients with previously untreated metastatic colorectal cancer (CRC)

3583 Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework supports the hypothesis that sequential administration of cytotoxic drugs at adequate doses can maximize the cell kill and overcome drug resistance. The aim of the study was to compare the response rate (RR), the time to tumor progression (TTP), the overall survival (OS) and to assess the toxicity profile of previously untreated patients with advanced CRC randomly assigned between IRI-LV-5FU (arm A) versus IRI-LV-5FU followed by OXA-LV-5FU (arm B). Methods: Intent to treat analysis was performed on 429 patients (219 in arm A and 210 in arm B) who were randomized from 31/10/2001 to 21/10/2004. The treatment schedules consisted of weekly IRI, 80 mg/m2 or OXA, 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5FU, 450 mg/m2 for 6 weeks followed by a 2-week rest period. Treatment was continued for 4 cycles, patients in arm B were treated initially with IRI-LV-5FU for 2 cycles followed by sequential administration of 2 cycles of OXA-LV-5FU. Results: The study failed to show any superiority of the sequential regimen. There were no significant differences between the two arms in the overall RR (26% versus 28%, p=0.631), TTP (Median, 7.8 versus 8.4 months, p=0.149). Toxicity profiles (grade III and IV) were equally frequent in both arms (diarrhea 13% versus 13.5%, febrile neutropenia 2% versus 1.5%, neurotoxicity 0% versus 0.5%). Conclusions: IRI-LV-5FU or IRI-LV-5FU followed by QXA-LV-5FU show equally substantial activities with manageable toxicity profile in advanced CRC. No significant financial relationships to disclose.

A randomized phase II non-comparative study of Ispinesib given weekly or every three weeks in metastatic colorectal cancer. A California Cancer Consortium Study (CCC-P)

3595 Background: Ispinesib(SB-715992) is a polycyclic, nitrogen-containing heterocycle that inhibits the mitotic kinesin spindle protein (KSP). KSP is essential for mitotic spindle assembly and function during mitosis, and is a rational target of anti-cancer therapy. This phase II study used two different dosing schedules; the primary objective was to determine the response rate (RR) and the secondary objectives were to determine time to tumor progression (TTP), progression free survival (PFS), overall survival (OS) and toxicity. Methods: Patients (pts) were randomized to receive (Arm A) ispinesib 7 mg/m2 every week for 3 weeks, every 28 days or (Arm B) 18 mg/m2 every 21 days. Response was assessed every 6 weeks. Chemotherapy was administered until disease progression or intolerance. Results: A total of 64 pts were accrued. The median number of cycles was 2 for both arms. Five pts had stable disease and 48 had progressive disease. PFS was 49 days in Arm A (44 to 51) and 37 days in Arm B (35 to 42 days). The most common grade 3/4 toxicities in arms A and B respectively included neutropenia (3 and 20), nausea and vomiting (3 and 1), neurologic (1 and 2). Of these, only 1 pt had febrile neutropenia and 1 pt had peripheral sensory neuropathy. The toxicity data is not available on 2 patients. Eleven pts are not evaluable for response yet. Conclusions: Ispinesib did not demonstrate significant activity in heavily pretreated patients with advanced/metastatic colorectal cancer at the dose and schedule employed in this trial. Correlative studies are in progress. Supported by NO1 CM17101 [Table: see text] No significant financial relationships to disclose.

Progressive low‐grade oligodendrogliomas

Loss of heterozygosity (LOH) on chromosomes 1p and 19q has been associated with chemosensitivity and improved prognosis in patients with oligodendrogliomas. The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) may induce resistance to DNA-alkylating agents. Recent studies demonstrated that temozolomide (TMZ), an oral alkylating agent, has efficacy in the treatment of patients with progressive, low-grade oligodendroglioma (LGO). However, to the authors' knowledge, limited data are available regarding the 1p/19q profile and its correlation with MGMT protein expression and response to treatment with DNA-alkylating drugs. Adult patients with magnetic resonance imaging (MRI) findings and/or clinical deterioration compatible with progressive LGO were eligible for the study if they were radiotherapy-naive. TMZ cycles were repeated every 28 days at a dose of 200 mg/m2 daily for 5 consecutive days. Clinical and MRI data were used to evaluate outcomes, and Kaplan-Meier estimates were used to assess the median time to tumor progression (TTP). The 1p/19q status was analyzed from paired tumor-blood DNA samples using polymerase chain reaction-based microsatellite analysis. MGMT protein expression was estimated semiquantitatively by immunohistochemistry using paraffin embedded tumor sections. There were 28 patients who received treatment, and the median time from diagnosis to tumor progression was 33.5 months. The median number of TMZ cycles per patient was 12.5. Marked clinical improvements were recorded in 15 patients (54%), and objective responses were recorded in 17 patients (61%). The median TTP was 31 months, and the progression-free survival rate was 70% at 24 months. Loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively). TMZ was active in patients with progressive LGO, and their response to treatment was associated with 1p deletion and low MGMT protein expression. The authors suggest the possible use of MGMT immunostaining as a surrogate marker for predicting tumor chemosensitivity.

Efficacy and Tolerability of Oxaliplatin Plus Irinotecan 5-Fluouracil and Leucovorin Regimen in Advanced Stage Colorectal Cancer Patients Pretreated With Irinotecan 5-Fluouracil and Leucovorin

Oxaliplatin has been introduced in the treatment of advanced colorectal cancer during the past few years. The pre-existing treatment of leucovorin-5-fluorouracil-irinotecan (IFL), although reasonably effective, has needed novel, active agents to increase the response rate and overall survival. We planned this phase 2 study in patients pretreated with IFL, adding oxaliplatin as second-line treatment: our objectives were to determine response rate and overall survival. All patients (median age 65) were designated to receive 6 cycles of chemotherapy: leucovorin 200 mg/m2 infused for 60 minutes, 5-fluorouracil 500 mg/m2 bolus at 30 minutes from the start of the previous infusion, irinotecan 135 mg/m2 infused for 90 minutes, and oxaliplatin 135 mg/m2 for 90 minutes, infused sequentially on day 1 and repeated every 3 weeks. Standard ondansetron antiemetic treatment and dexamethasone 8 mg were administered to all patients. No prophylactic recombinant human granulocyte colony-stimulating factor was permitted. Fifty-seven patients were recruited and 54 were evaluable for response, survival, and toxicity. All patients had advanced, inoperable, metastatic disease in the liver and/or lungs, abdominal cavity, and multiple sites. All patients had undergone IFL pretreatment and had no response; 40 had disease progression and 14 had stable disease when entering the present study; 302 chemotherapy cycles (mean 5.92) were administered. There was no treatment delay caused by toxicity (either neutropenia or diarrhea). Irinotecan and oxaliplatin were reduced by 25% in 6 (11.1%) patients. No complete responses were observed; 21 (38.9%) patients achieved partial response, 26 (48.2%) had stable disease, and 7 (13%) had disease progression. Median duration of response was 6 months, time to tumor progression (TTP) 8 months, and median overall survival after the initiation of second-line treatment was 10 months (95% confidence interval [CI], 7.5-12.6). The addition of oxaliplatin to IFL as second-line treatment rendered a prolongation of survival and a response rate of 38.9% in patients in whom IFL pretreatment had failed.

Extended Follow-Up and Analysis with Central Radiological Review of Patients Receiving FavId® (Id/KLH) Vaccine Following Rituximab.

Background: Idiotype vaccination (Id/KLH) is a promising approach to the treatment of patients (pts) with B-cell malignancies. Our experience suggests that Id/KLH may function best in pts with lower tumor burden who are less heavily pretreated. We have conducted a phase II trial of Id/KLH following cytoreduction with rituximab in patients with treatment naive (TN) or relapsed/refractory (R/R) follicular NHL (FL).Treatment: Pts received rituximab, 375mg/m2, IV, weekly x 4, wk 1–4. Pts with without progression received Id/KLH, 1 mg, SQ, monthly x 6, starting on wk 12, with GM-CSF, 250 mcg, SQ, on days 1–4. Pts could receive booster Id/KLH on a reduced schedule until disease progression.Results: One hundred three pts were enrolled and received rituximab; 89 pts received Id/KLH. The last patient was registered in Dec 2003. Among these 89 evaluable pts, 55 were R/R to prior therapy, and 34 were TN. The overall response rate (ORR) following rituximab (assessed at month 3 based on a centralized read of CT scans) was 49% (44/89). Following Id/KLH, the ORR improved to 64% (57/89). The median time for improved response following initiation of Id/KLH treatment was 6.6 months (range 5.8 – 23.4 months) which was consistent with the time required to demonstrate an immune response in those pts tested. Prognostic factors for time to tumor progression (TTP) were evaluated and demonstrated a significant negative relationship for liver involvement (hazard ratio; HR = 9.3, p=0.0017) and 3 or more prior regimens (HR=4.7, p=0.0035). Median TTP has not been reached in the TN group (N=34) and in pts who relapsed after prior chemotherapy (N=26), with an actuarial 18 month progression free survival rate of 69% and 70%, respectively. The group of pts who would be eligible for the ongoing phase 3 randomized registration study (N=71) of rituximab followed by Id/KLH have also not reached median TTP. T-cell responses to both Id and KLH were observed in 80% and 86% of pts respectively (N=15) and were seen after a median of 2 doses of Id/KLH. Likewise, antibody responses to Id and KLH were seen in 13% and 69% respectively (N=23) and developed after a median of 5 to 6 doses of Id/KLH.Conclusion: Id/KLH, administered following rituximab to pts with FL, appears to result in an increase in the response rate and TTP compared to that reported for rituximab alone. We also observed a high rate of cellular immunity against idiotype following Id/KLH. These data support the design of an ongoing PIII clinical study of Id/KLH following rituximab which excluded pts with poor prognostic indicators.

A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide [Revlimidä (R), CC-5013] in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma.

Introdution:Lenalidomide (Revlimid™) is Celgene's lead clinical compound in a new group of drugs called IMiDs, which have immunomodularory properties. The drug has been evaluated in phase-I, II, and III clinical trials for the treatment of multiple myeloma (MM). Lenalidomide shows substantial anti-tumor activity in patients with refractory or relapsed MM and significantly prolongs time to tumor progression (TTP) compared to standard therapy in these patients. Lenalidomide was well tolerated in these trials, the only dose limiting toxicity in a phase-I trial was myelosuppression. In order to further improve therapeutic efficacy and to overcome drug resistance we are currently evaluating Lenalidomide (Revlimid™) in combination with doxorubicin and dexamethasone (RAD) for the treatment of patients with refracrory or relapsed MM in a phase-I/II trial.Methods:Patients with relapsed or refractory multiple myeloma recieve a fixed dose of either 10 mg or 15 mg Revlimid Revlimid™ given daily for 21 days (d 1–21) in combination with doxorubicin (adriamycin) and dexamethasone, to be repeated on day 29. Three dose levels of doxorubicin (adramycin) are planned: 4 mg/m2 day 1–4, 6 mg/m2 day 1–4 and 9 mg/m2 day 1–4. 40 mg dexamethasone is given orally day 1–4 and day 17–20 at a fixed dose. 3– 6 cycles are applicated unless severe toxicity or disease progression occurs.Results:RAD treatment was well tolerated at dose level 1 and dose level 2. Therefore, current dose escalation is continued. All patients treated at the first two dose levels (6/6) responded to RAD treatment. Further updated results on this trial will be presented.

Apurinic/Apyrimidinic Endonuclease Activity Is Associated with Response to Radiation and Chemotherapy in Medulloblastoma and Primitive Neuroectodermal Tumors

Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy. Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP). Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P < or = 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasic site repair. Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.

CXCL12 Expression is Predictive of a Shorter Time to Tumor Progression in Low-Grade Glioma: A Single-Institution Study in 50 Patients

The clinical course of 50 patients with low-grade glioma (31 male, 19 female) undergoing surgery at a single Institution from 1992 to 1996 was analyzed in relationship with known prognostic factors as far as time to tumor progression (TTP) and survival time (ST) are concerned. Moreover, microvessel density (MVD) and expression of the angiogenesis-related chemokine CXCL12 were investigated in surgical specimens. Age at diagnosis ranged from 1 to 68 years (median 30). Histology revealed 11 fibrillary, 6 protoplasmatic, 5 gemistocytic astrocytoma, 18 oligoastrocytoma and 10 oligodendroglioma. Mean follow-up was 86 months. Four patients were lost to follow-up. Of the remaining 46, twenty-four have shown disease progression and 14 have died. Median overall survival was not achieved; an estimated 75% percentage of survivors was found at 78 months. Complete gross tumor removal was associated to a longer TTP (P = 0.04 logrank). Of the investigated immunohistochemical parameters, while MVD was not predictive of subsequent TTP, expression of CXCL12 was associated with a significantly shorter TTP (P = 0.01 logrank): this predictive value remained significant (P = 0.02) at multivariate analysis. The data suggest the possible prognostic value for CXCL-12 (an angiogenesis- and tumor-growth-related chemokine) on TTP in low-grade gliomas.

Robustness of response: A new measure of response assessment: Its impact on metricies of response in colorectal cancer

3569 Background: To illustrate a new method of quantifying and comparing response assessment techniques known as robustness of response (ROR) and to evaluate unidimensional measurement (RECIST criteria) versus bidimensional measurement (WHO criteria) with respect to their impact on assessment including response classification, time to tumor progression (TTP) and time to best overall response (BOR) in patients with colorectal cancer. Methods: 68 patients with metastatic colorectal cancer on clinical trials of HAI Floxuridine and Dexamethasone with systemic oxaliplatin with 5FU/LV and/or Irinotecan were retrospectively reviewed. The studies of a total of 2735 measurements included 68 baselines and 200 follow-up CT examinations of the chest, abdomen and pelvis. Response assessment and progression-free survival were calculated with RECIST and WHO. ROR was determined and compared among and between discordant and concordant cases. Results: There was a 92.6% agreement rate and a 7.4% disagreement rate in BOR between RECIST and WHO. The median TTP assessed by RECIST was 5.83 months compared to 5.40 months assessed by WHO (P=0.006). Time to BOR was not significantly different comparing RECIST and WHO (P=0.82). Mean percentage decrease in tumor size among the 27 unidimensional responders and 28 bidimensional responders was 65.0% and 79.7%, respectively. Mean increase in size among the 36 unidimensional progressors and 48 bidimensional progressors was 61.8% and 139.1%, respectively. The average robustness value was -35.3% by RECIST and 53.9% by WHO among the 17 discordant pairs and -25.9% by RECIST and 78.9% by WHO among the 51 concordant pairs. A comparison of ROR in time to BOR found an average robustness value of 35.7% by RECIST versus 24.8% by WHO among the 10 discordant cases, and 5.3% by RECIST versus 60.6% by WHO among the 58 concordant cases. Conclusions: In colorectal cancer, time to tumor progression was different between WHO and RECIST. This may impact clinical trials whose results are interpreted with RECIST and WHO. A new method of measuring “ROR” may indicate disease sites or therapies that are affected by measurement technique, and help to define the degree of response or progression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Byrne Foundation and NIH Cancer Chemotherapy Program Project (CA05826-35), Experimental Therapeutic Center

Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer

3508 Background: Cetuximab (Cetux), a monoclonal antibody (mab) that targets the epidermal growth factor receptor (EGFR), has shown antitumor activity both alone and in combination with irinotecan (IRI) in IRI-refractory colorectal cancer (CRC). Bevacizumab (Bev), a mab against vascular endothelial growth factor (VEGF), improved the response rate, PFS, and overall survival in CRC patients treated with first line IFL. We evaluated the safety and efficacy of concurrent administration of these two monoclonal antibodies in patients with metastatic CRC. Methods: This is a randomized phase II study in patients with IRI-refractory CRC. All patients were naive to both bev and cetux. EGFR expression was not required for study entry. Arm A received IRI at the same dose and schedule as last received prior to study, plus Cetux 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bev 5 mg/kg given every other week. Arm B received the same Cetux and Bev as arm A, but without IRI. Results: 76 patients have been randomized, 75 of whom received treatment. Median age is 60 (range 25–86). Median number of prior regimens is 3 (range 1–7). Median performance status is ECOG 1 (0–1). Interim toxicity data have been previously presented (ASCO GI Symposium, 1/05). No toxicities were encountered that would not have been expected from the single agents alone. As of 12/04, the median time to tumor progression (TTP) for arm A (Cetux/Bev/IRI) is 5.8 months, with 16 patients currently on treatment. For Arm B (Cetux/Bev) the median TTP was 4.0 months. Response data are shown in the table. Conclusions: The combination of Cetux/Bev, alone or with IRI, is tolerable. The response rates and TTP seen with the addition of Bev to either Cetux or Cetux/IRI appear favorable compared to historical controls of Cetux or Cetux/IRI without Bev. Studies of Cetux/Bev in conjunction with front line combination chemotherapy regimens are warranted and have now been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Access, Genentech, Pfizer, Roche, Sanofi, Taiho Bristol-Meyers Squibb

Satraplatin: A new treatment option for patients with hormone refractory prostate cancer

4802 Background: There is no chemotherapeutic agent specifically approved for second-line treatment for hormone-refractory prostate cancer (HRPC). Satraplatin (S) is a third-generation oral platinum compound studied in a variety of tumors, including HRPC. Results of previous phase II and III trials suggested activity in HRPC. A randomized trial conducted by the EORTC in 50 patients evaluated S as first-line therapy in HRPC. The median progression-free survival (PFS) was longer in the satraplatin + prednisone (S + P) arm than in the P alone arm. This difference was statistically significant (p = 0.023). Furthermore, a >50% decrease from baseline PSA value was seen in 9 of 27 patients (33%) in the combination arm compared to 2 of 23 (9%) patients in the P arm (p = 0.046). We have initiated a randomized phase III trial evaluating S as second line therapy for HRPC. Methods: The primary objective is to compare time to tumor progression (TTP) and PFS in patients with HRPC, randomized to either S + P or placebo + P, after failure of 1 prior chemotherapy regimen. Eligible patients include men ≥ 18 years with stage D2 metastatic HRPC with progressive disease after a minimum of 2 courses of 1 prior cytotoxic chemotherapy regimen. The final analysis will be performed after 637 events of disease progression have been observed. Using a significance level of 0.034, the trial has 85% power to detect a 30% improvement in TTP. Results: Accrual is ongoing. Conclusions: Results of 2 studies, SWOG 99–16 and TAX327, demonstrated a survival advantage for the docetaxel-containing arm, and docetaxel is approved for use in HRPC. However, the duration and response to first line chemotherapy is limited, and there is an unmet medical need for agents that provide palliation and improve survival. S has demonstrated in vitro activity against taxane-resistant cell lines and significantly prolonged PFS for untreated HRPC patients in a randomized setting. These observations formed the scientific rationale for GPC Biotech to initiate an international multi-center, double-blind, randomized phase III trial comparing S + P to placebo + P as second-line cytotoxic therapy for men with HRPC. The trial is open and actively accruing patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GPC Biotech AG, GPC Biotech GPC Biotech GPC Biotech GPC Biotech GPC Biotech

Perfusion and diffusion MRI in the assessment of the antivascular effect of arsenic trioxide combined with radiotherapy for glioblastoma multiforme: NABTT phase I study

1538 Background: Significant tumor control and prolongation of survival have been demonstrated by combined use of radiosurgery and antivascular agent, Arsenic Trioxide (ATO), in rodent gliosarcoma model in rats. This agent is now undergoing clinical evaluation in the NABTT Brain Tumor Consortium in a Phase I trial with ATO dose escalation in combination with fractionated radiation therapy. Since this agent showed rapid effect on the tumor vasculature in the animal studies, MRI perfusion and diffusion studies were performed shortly following ATO administration. Methods: The patients were treated with external beam radiotherapy 60 Gy in 6 weeks with ATO at a starting dose of 0.25 mg/kg once a week during the course radiotherapy. ATO dose was escalated by 0.05 mg. The perfusion images were acquired using a Echo Planar Image (EPI) sequence. Perfusion parameters were Mean Transit Time (MTT), relative Cerebral Blood Volume (rCBV), and relative Cerebral Blood Flow (rCBF). The perfusion parameter values under regions of interest (ROI) from the enhancing and non-enhancing portions of the lesion were then followed serially during treatment. Results: There was a delay on mean transit time (MTT) and relative cerebral flow (rCBF) by ATO and radiotherapy, compared to counterpart normal brain. This effect was apparent within 24 hours of ATO infusion. The extent and duration of these changes will be correlated with conventional measures of outcome, such as lesion volumes, response, and time to tumor progression (TTP). There were no dose limiting toxicities with doses of ATO as high as 0.35 mg/kg once a week. Conclusions: A total of 12 patients were treated with this phase I trial. At the doses studied thus far, ATO combined with radiotherapy appears safe in the treatment of glioblastoma multiforme. ATO induced a differential delay of blood flow in the tumor compared to the normal brain. ATO showed the immediate effects and serial evaluation highlights the dynamic nature of the intratumoral vasculature in response to ATO, antivascular agent. No significant financial relationships to disclose.

An open label, phase II, multicenter, study to evaluate the efficacy and safety of pertuzumab (P) in chemotherapy naïve patients (pts) with hormone refractory prostate cancer (HRPC)

4609 Background: P is the 1st of a new class of targeted therapeutics known as HER-dimerization inhibitors (HDI). P is a human monoclonal antibody that blocks ligand-associated heterodimerization of HER2 with other HER kinase family members, thereby inhibiting intracellular signaling. Preclinical activity of P in prostate cancer xenografts has been demonstrated. Methods: P was administered IV once every 3 weeks at 420 mg (with a loading dose of 840 mg) or 1050 mg (without a loading dose) in consecutive cohorts. An interim analysis was performed for each cohort after inclusion of 23 evaluable pts. In case of > 3 responses, 27 additional pts were to be enrolled in that cohort. The 1050 mg cohort was only to be opened, if the 420 mg cohort showed ≤ 3 responses. Eligibility criteria were: progressing chemotherapy naïve HRPC, LVEF ≥ 50%. The primary endpoint in this study was PSA (prostate specific antigen) response rate (RR) at 24 weeks after start of single agent P. Secondary endpoints were safety profile, overall RR by RECIST, time to tumor progression (TTP), and overall survival (OS). Results: 23 evaluable pts in each cohort were included in the interim analysis. No PSA responses were observed with a median TTP (PSA) of 5 weeks. One unconfirmed 75% decrease in PSA was found after the interim analysis. P was well tolerated. Most common adverse event in the 46 pts was grade 1 & 2 diarrhea (48%). Nausea was reported for the 420 mg- and 1050 mg dose level respectively in 22 & 9% and asthenia in 35 & 13%. No LVEF decreases of ≥ 15% and to below 50% were observed in either cohort. No congestive heart failure was reported. Conclusions: P is safe and well tolerated. No difference in toxicity was observed between the two dose levels. There is insufficient evidence of activity in this prostate cancer study. A combination (either chemo or hormonal) or pt selection strategy may be investigated in the future. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche AstraZeneca, Boehringer Ingleheim, Celgene, Novartis

A phase II study of gemcitabine (G) and capecitabine (C) in advanced cholangiocarcinoma (CC) and gall bladder carcinoma (GBC)

4230 Background: CC and GBC are rare but lethal cancers. Although surgery can be curative, most patients are inoperable at diagnosis. Median survival with standard chemotherapy (CT) is 6 months. The goal of therapy is palliative, aimed at improving quality of life, pain and symptoms of biliary obstruction. The impact of CT on quality of life (QOL) in these patients is not reported. We performed a phase II study to determine the clinical benefit response [CBR= partial response (PR) + stable disease (SD)], time to tumor progression (TTP) and overall survival (OS) in patients with advanced CC and GBC treated with a combination of G +C as first line therapy and assessed the effect of CT on QOL, using the EORTC QLQ-C30-PAN 26. Methods: G (1000mg/m2) IV over 30-minutes was administered on days 1 and 8 and C was given orally (650mg/m2) twice a day for 14 days, both repeated every 21 days. Tumor response was measured using standard RECIST criteria. All patients filled QOL questionnaires on day 1 of each cycle. Cumulative QOL scores were calculated. The design was 2-stage for 17 patients to evaluate confirmed CR/PR (CRR) rate at 9 weeks. Results: Total of 12 patients with the following characteristics were enrolled: 11 CC and 1 GBC; median age 54 years (range 46–85 years), 5 males (42%) and 7 females (58%); ECOG PS 0 (n=4) or 1 (n=8). Median 8 cycles per patient (range 0 to 19 cycles) were completed. The 90% 1-sided confidence interval on the CRR was (0, 17%). The CBR based on best response [2PR (17%) + 5SD (42%)] was 59%. With median follow up of 8.6 months, median TTP was not reached. Due to limited number of deaths (4/12 patients), median OS was not reached. Median time to treatment failure (TTF) was 5.4 months with 3 patients still on treatment. 8/12 patients had either grade 3 or 4 toxicities. There were no treatment related deaths. Using a threshold of 5% above baseline to indicate decreased QOL, all patients with PR and 2/5 patients with SD had improved or stable QOL scores with G+C. Conclusions: G + C given in this dose and schedule is well-tolerated, effective and leads to QOL benefit for some patients with advanced CC and GBC. CBR may be a better endpoint to assess response in this disease. No significant financial relationships to disclose.

A multicenter phase II study of irinotecan (CPT), cisplatin (CIS), and bevacizumab (BEV) in patients with unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma

4025 Background: BEV is an anti-VEGF-monoclonal antibody that improves survival in colorectal cancer. CPT/CIS is an active combination in the treatment of gastric and GEJ cancers with a median time to tumor progression(TTP) of 4.5 months. We performed this study to evaluate the efficacy and safety of the combination of CPT, CIS, and BEV in the treatment of gastric and GEJ cancers. Methods: Patients with previously untreated metastatic gastric and GEJ adenocarcinomas are eligible. The primary endpoint is to improve median TTP to 7.5 months. Response, survival, and safety are secondary endpoints. Evaluable or measurable disease was required. Patients received BEV 15mg/kg on day 1, CPT 65mg/m2 and CIS 30mg/m2 on days 1 and 8, every 21 days. Response is assessed by RECIST criteria, and CTCv 3.0 was used for toxicity assessment. Results: We have enrolled 24 patients with the following characteristics: median age 55(range 25–67), KPS 80%(70–90%), Male:Female 19:5. We have observed only 3 patients with progression at a median follow up of 3.4 months. The progression free survival at 3 months is 89%(95%CI: 81–100%), and at 6 months, is 76%(52–100%). Median TTP has not been reached. In 16 patients with measurable disease, we have observed 12 confirmed partial responses(75%, 95%CI:47–92%), 3 minor responses(15–29% reduction) and 1 stable disease. The combination therapy has been well tolerated, without an increase in CPT/CIS related toxicity: i.e. grade 3/4 neutropenia, nausea/vomiting, or diarrhea in 8% of patients. However, thromboembolic events were seen in 25% of patients(95%CI:11–45%): 4 patients with asymptomatic pulmonary embolism and 2 patients with deep vein thrombosis. Of 20 patients with their primary tumor in place, 2 patients had a gastric perforation, and another had a near perforation. There was no significant bleeding or toxicity related death. Conclusions: The combination of CPT/CIS/BEV appears active in gastric and GEJ cancers. Though preliminary, the high rates of response and disease control are noteworthy. The combination appears safe, although thromboembolic phenomenon are concerning. Accrual continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Advanced stage mucinous epithelial ovarian cancer: The Hellenic Cooperative Oncology Group experience

Objective Mucinous epithelial ovarian cancer (mEOC) representing about 10% of all EOC are known to be possibly resistant to platinum-based chemotherapy and bear a poorer prognosis with respect to other subtypes of EOC. This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stages III and IV mEOC and serous EOC (sEOC). Methods A retrospective analysis was performed in 47 patients with advanced stage of mEOC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 6/7/1983 and 25/2/2003. The outcome was compared to that of 94 patients with sEOC treated with the same protocols during the same study period (ratio mucinous: serous 1:2). Results One hundred forty-one patients (47 stages III and IV mEOC, 94 stages III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for mEOC was 38.5% (complete remission 18%) (95% CI 23.4–55.4%) and 70% (complete remission 47%) (95% CI 58.5–80.3%) for sEOC ( P = 0.001). After a median follow-up of 77.8 months, median survival and time to tumor progression (TTP) were not significantly different between the two groups (33.2 months [95% CI 23.3–43.1 months] vs. 38.0 months [95% CI 26.8–49.2 months], P = 0.46, 11.8 months [95% CI 7.2–16.4 months] vs. 20.0 months [95% CI 15.7–24.2 months], P = 0.18, respectively). Conclusion Patients with mEOC have significantly lower response to first-line platinum-based chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in inferior TTP or survival. Our data indicate that a new strategy for chemotherapy in mEOC should be adopted, one that focuses on new agents without cross-resistance to platinum agents.