G3 Diarrhea Research Articles

A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.

8107 Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “3+3” design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline & d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n=6), 100 mg/d (n=6), 80 mg 5d on 2d off (5/2, n=3), with gef 250 mg/d. Gp A (n=9, 1 CNS), B (n=6, 1 CNS), F:M (9:6), median age 63 (47-73) and majority >3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%), mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea. MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80 5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax (>25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12 PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1 MET amp) had clinical responses, including slight tumor shrinkage and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed. Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted. A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.

Bendamustine, Bortezomib, and Rituximab in Patients with Previously Untreated Low Grade Lymphoma: A Phase II Trial of the Sarah Cannon Research Institute

AbstractAbstract 1624 Background:Rituximab and bendamustine combination regimens have demonstrated high activity in non-Hodgkin's lymphoma (NHL). A phase III trial compared bendamustine plus R-CHOP as first-line treatment for follicular, indolent, and mantle cell lymphoma (Rummel ASH 2009). Bendamustine plus rituximab had an overall response rate of 94% and a complete remission rate of 40% compared to 94% and 31%, respectively, for R-CHOP. Phase III trials evaluating bendamustine plus rituximab as first-line therapy for patients (pts) with indolent and mantle cell lymphoma have shown equivalent or superior results when compared to R-CHOP or R-CVP as first-line treatment for indolent lymphoma. Bortezomib is a small molecule proteasome inhibitor that has shown substantial activity in multiple myeloma and lymphoma. Pre-clinical studies demonstrate significant synergy and/or ability to overcome resistance to a variety of current and investigational treatments for lymphoma. This trial evaluated the activity of bendamustine, bortezomib, and rituximab (BBR) in patients with previously untreated low-grade lymphoma. Methods:Eligible patients had histologically-confirmed follicular center cell (FCC) lymphoma (grade 1 or 2), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), or lymphoplasmacytic lymphoma (LPL); lymph node biopsy containing CD20+ B-cells; Ann-Arbor Stage 2, 3, or 4 disease; no previous systemic treatment for lymphoma; bi-dimensional measurable disease with at least 1 lesion measuring > 2.0 cm in a single dimension; ECOG PS 0–2. Treatment for all patients was given in 28-day cycles for a maximum of 6 cycles. Patients received rituximab 375 mg/m2 IV on days 1, 8, and 15 of cycle 1 (cycles 2–6, rituximab only on day 1); bendamustine 90 mg/m2 IV on days 1 and 2; and bortezomib 1.6 mg/m2IV on days 1, 8, and 15. Response evaluations were performed after cycle 3 and cycle 6. Patients were permitted to begin maintenance treatment with rituximab 6 months after completion of study treatment and after 6-month follow-up assessments have been conducted. Results:Between 1/2010 and 11/2011, 55 patients were enrolled with a median age of 62 years (range 30–89). Fifty one percent were male, 85% stage III or IV. Diagnoses were: FCC, 38pts (69%); MZL, 8pts (15%); SLL, 5pts (9%) and LPL, 4pts (7%). The median follow-up is 13 months (range: 6–26). At the time of this analysis, 78% of pts had completed 6 cycles of BRR, and 56% had continued to maintenance rituximab. Two pts remain in the first 6 cycles of BRR. Five pts (9%) discontinued treatment due to toxicity (1pt G2 neuropathy, 1 pt G2 atrial fibrillation, 1 pt G3 pancreatitis, 1 pt G3 diarrhea, 1pt G2 rash). The remaining 5 pts discontinued prematurely (1pt death due to stroke, 1pt wound complication, 1 pt lost to follow-up, 2 pts off due to request). Objective response was achieved in 89% of pts; 26pts (47%) complete response, 23pts (42%) partial response, 2pts (4%) stable disease, and 4pts (7%) unevaluable at the time of this analysis. Related grade 3/4 hematologic toxicities were: neutropenia (25%), febrile neutropenia (2%), thrombocytopenia (5%), and anemia (4%). We observed no grade 4 treatment related non -hematologic adverse events, the most common grade 3 were neuropathy (9%), diarrhea (7%), fatigue (7%), constipation (5%), and rash (5%). Time-to-event data are immature and will be the subject of a later analysis. At the time of data cut-off, 3 pts (5.5%) had progressed or relapsed and 3pts (5.5%) had died. Conclusion:BBR was well tolerated and produced high CR and OR rates. Toxicities including neuropathy were modest. Further study of this regimen in patients with previously untreated lymphoma is warranted. Disclosures:Off Label Use: Off-label bendamustine and bortezomib in first-line treatment for lymphoma. Boccia:Cephalon: Research Funding.

1291P - Phase I/II Dose-Finding Study of Crizotinib (CRIZ) in Combination with Erlotinib (E) in Patients (PTS) with Advanced Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background c-Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. Criz is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining criz with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and criz in pts with advanced NSCLC. Methods Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received E 100 mg QD for ≥7 days before adding criz 150 or 200 mg BID (150 + 100 and 200 + 100, respectively). Results As of March 15th 2012, 27 pts had started therapy. Median (range) duration of combination therapy in 150 + 100 (n = 19) was 7 weeks (0.1–28.0); for 200 + 100 (n = 7) was 6.9 weeks (1.9–77.6). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150 + 100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200 + 100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (96%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (73%), rash (62%) and fatigue (46%). Six pts discontinued therapy due to TRAEs (150 + 100: G3 diarrhea, G3 dehydration, and G1 hyponatremia in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n = 1 each; 200 + 100: G3 dry eyes, G1 esophagitis, n = 1 each). One partial response (200 + 100; duration 73 weeks) and 9 stable diseases (n = 7 150 + 100, n = 2 200 + 100; duration 8–62 weeks) were observed overall. Co-administration of both doses of criz with E increased E AUC by 1.8 fold; criz PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with criz was comparable to 150 mg QD from historical data. Conclusions E plus criz at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus criz 150 mg BID was defined as MTD. Disclosure S.I. Ou: Advisory relationship with Pfizer and Genentech (both compensated). Received honoraria from Pfizer, Genentech and Lilly. Research funding from Pfizer. K. Eaton: Research funding from Pfizer. A. Argiris: Advisory relationship with Pfizer. Received honoraria from Pfizer. Research funding from Pfizer. G. Otterson: Received honoraria from Genentech and Abraxis/Celgene. Research funding from Genentech, Abraxis/Celgene, Pfizer, Tragara, Amgen, Pharmacyclics, OSI and GSK. F. Robert: Research funding to the University of Alabama at Birmingham. N. Brega: Employed by Pfizer as a Director. Hold Pfizer stock. T. Usari: Employed by Pfizer as a statistician. Holds Pfizer stock. W. Tan: Employed by Pfizer. Holds Pfizer stock. All other authors have declared no conflicts of interest.

713P - Neoadjuvant Gemox Followed by Gem-Based Chemoradiation for Locally advanced Unresectable Pancreatic Cancer

ABSTRACT Purpose To asses activity, safety and secondary resectability in unresectable locally advanced pancreatic cancer (LAPC) patients (pts). Methods Unresectable LAPC pts were eligible for this phase II study. Primary endpoint was clinical benefit (CB = CR + PR + SD). A sample size of 37 pts was considered sufficient to give an 80% probability of rejecting a baseline clinical benefit rate of 55%, with an exact 5% one-sided significance test when the true disease control rate was 75%. The drug regimen would have been considered interest if at least 26 patients showed clinical benefit. Neoadjuvant induction chemotherapy (CHT) encompassed gemcitabine (GEM) 1000 mg/m2 (100-min infusion on d1) and oxaliplatin 100 mg/m2 (2-hr infusion on d2) every 2 wks, for 6 cycles. After CHT pts were restaged for surgery and/or chemoradiation (CRT) consolidation (EBRT up to a total dose of 50.4 Gy plus concomitant GEM 300 mg/m2/week). After CRT completion, pts were restaged to evaluate secondary surgery. Results From January 2005 to January 2012, 35 pts (M/F: 17/18; median age: 68 yrs, range: 46-78; ECOG PS 0-1/2: 28/7) entered the study. A median of 5 (range 1-7) CHT induction cycles were delivered. Toxicity was mild, with G3-4 neutropenia in 2 pts (6%), G3 thrombocytopenia in 1 pt (3%), G3 transaminase elevation in 5 pts (14%), and G3 diarrhea in 2 pts (6%). CHT dose was reduced or delayed in 8 and 7 pts, respectively. Nine confirmed PR and 17 SD were observed for a CB of 74% (95% confidence interval [CI], 56.7-87.5%). A decrease in serum CA 19.9 ≥50% of the baseline was observed in 14 of 23 evaluable pts. Nine-teen pts completed CRT, including 5 pts who subsequently underwent surgery; 1 pt underwent surgery without CRT. Toxicity for the CRT phase was mild, with G3 thrombocytopenia in 1 pt (3%) and G3 neutropenia in 3 pts (8%). Median overall survival (OS) and progression free survival (PFS) for all 35 patients were 10 (95% CI, 8-12) and 9 mos (95% CI, 6-12), respectively. One-yr OS and PFS rates were 26% and 30%, respectively. Conclusions The regimen under study is active and well tolerated. Although an encouraging response rate was reported, OS remains poor, calling for a better selection strategy for LAPC pts who are candidates to neoadjuvant treatment. Disclosure All authors have declared no conflicts of interest.

846P - Medical Optimization of Torisel® (MOTOR): A Phase II Trial of Temsirolimus as Second-Line Treatment for Advanced RCC by the Italian Kidney Cancer Group (GIR)

ABSTRACT Purpose The mammalian target of rapamycin (mTOR) kinase is a well-established therapeutic target in renal cell carcinoma (RCC). We explored the activity and safety of Temsirolimus as II-line treatment for advanced RCC pts in a multicenter phase II trial. Methodology in this open-label trial, Temsirolimus (25 mg/wk i.v.) was administered to advanced RCC pts with documented progression after any I-line treatment. Primary endpoint was PFS rate at 6 mos. Tumor response was assessed every 8 wks. Considering a 6-mo PFS rate of 20% unacceptable (p0 = 20%) and a 6-mo PFS rate of 40% (p1 = 40%) of interest, a minimum targeted accrual of 47 pts in the sunitinib-pretreated group was to be pursued in order to reach 90% power at a significance level of 5%. Results From May 2009 to January 2012, 76 pts were enrolled (median age: 67 yrs, range: 36-86; M/F: 58/18; ECOG PS 0/1/2: 51/19/6); I-line therapy included sunitinib (60 pts), bevacizumab (8), sorafenib (3), cytokines (2), or other (3). With 18/57 evaluable patients free from progression at 6 mos in the sunitinib-pretreated group the primary endpoint was met and trial accrual was stopped. Median PFS was 4.0 mos (95% CI: 2.7–5.3) and 4.6 mos (95% CI: 2.8–6.5) in the overall (n = 71) and sunitinib-pretreated (n = 57) populations, respectively; OS in the same groups was 13.7 mos (95% CI: 9.1–18.3) and 14.6 mos (95% CI: 8.9-20.3), respectively. Six out of 71 pts (8%) had PR and 33/71 (46%) had SD as their best response. Toxicity (n = 68) was mild with G3 anemia, neutropenia and thrombocytopenia in 2, 1, and 1 pts, respectively; G3 hyperglycemia and G3 hypertriglyceridemia in 2 and 7 pts, respectively; G4 hypercholesterolemia in 2 pts; G3 stomatitis in 5 pts; G3 asthenia in 3 pts; G3-4 pulmonary toxicity in 2 pts; G3 diarrhea in 2 pts; G3 cutaneous rash in 1 pt. Only 1 hypersensitivity reaction occurred during Temsirolimus infusion. Treatment compliance was good, with Conclusions Temsirolimus is an active and well-tolerated II-line treatment for advanced RCC; results of currently ongoing phase III trials are awaited to further define its role in this setting. Disclosure All authors have declared no conflicts of interest.

Safety Verification Trials of mFOLFIRI and Sequential IRIS + Bevacizumab as First- or Second-Line Therapies for Metastatic Colorectal Cancer in Japanese Patients

Objective: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab and sequential IRIS + bevacizumab as first- or second-line therapies. Methods: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m² of irinitecan, and 80 mg/m²/day of S-1 orally from day 3 until day 16 as a 3-week course). The primary endpoint was the safety of each method until week 12, with the secondary endpoint being the comparison of the safety and efficacy of the two methods. Results: The safety of the two treatments was comparable, except that G3 anorexia and diarrhoea were less frequent with sequential IRIS + bevacizumab. The overall response rate was 62% [95% confidence interval (CI) 40.1–79.8] versus 72% (95% CI 50.6–86.2), and progression-free survival was 324 days (95% CI 247–475) versus 345 days (95% CI 312–594) with mFOLFIRI + bevacizumab versus IRIS + bevacizumab, respectively. Conclusion: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic colorectal cancer and is compatible with mFOLFIRI + bevacizumab.

Interstitial preoperative high-dose-rate brachytherapy for early stage cervical cancer: Dose–volume histogram parameters, pathologic response and early clinical outcome

To analyze dose-volume histogram parameters and pathologic response after preoperative high-dose-rate brachytherapy (HDRB) for high-risk early stage cervical cancers (ESCCs). From June 2007 to December 2011, 32 patients with a histologically proven invasive cervical cancer with high risk of local recurrence (size >2cm, adenocarcinoma type, perineural and/or lymphovascular invasion) underwent a preoperative HDRB, which delivered a total dose of 39Gy in nine fractions over 5 days. All the patients underwent hysterectomy after HDRB. With a median clinical target volume of 50cc (minimum-maximum, 42-74), the median V100 was 49cc (minimum-maximum, 42-50). Median D90 was 45Gy (equivalent dose at 2Gy per fraction, 56Gyαβ10). Median D2cc was 34Gy, 31Gy, 28Gy, and 38Gyαβ3 for bladder, rectum, sigmoid, and vagina, respectively. Twenty-eight patients (88.5%) achieved a complete histologic response after surgery, whereas for the 4 remaining patients, residual tumor cells (3 patients) and gross residual disease (1 patient) were observed in the pathologic specimen. With a median followup of 24 months (minimum-maximum, 5-48), no local recurrence was observed; 1 patient died of intercurrent cause. Early toxicity occurred within the 30 days after HDRB (Common Terminology Criteria for Adverse Events v3.0) was G1 diarrhea for 15 patients (47%) and G1 urinary frequency or urgency for 13 patients (40.6%). No G2-G3 toxicities were noticed. Preoperative HDRB for high-risk ESCCs represents a well-tolerated procedure, which leads to a high rate of postoperative pathologic response. Dose-volume histogram parameters were at least equivalent to those obtained with a low-dose-rate procedure. Long-term results will help to analyze the place of preoperative brachytherapy in the management of high-risk ESCCs.

Phase I/II dose-finding study of crizotinib (CRIZ) in combination with erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2610 Background: c Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. CRIZ is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were either sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined with E 100 mg QD (150/100 and 200/100, respectively). Results: Twenty-five pts have been treated to date. Median duration of combination therapy in 150/100 (n=18) was 6.6 weeks (0.1–25.3); for 200/100 (n=7) was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n=1 each; 200/100: G3 dry eyes, G1 esophagitis, n=1 each). One partial response (200/100; duration 61 weeks) and 9 stable diseases (n=7 150/100, n=2 200/100; duration 7–54 weeks) were observed overall. Co-administration of both doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with CRIZ was comparable to that of 150 mg QD from historical data. Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus CRIZ 150 mg BID was defined as MTD.

A phase I study of lapatinib (LPT) and cetuximab (CTX) in patients with CTX-sensitive solid tumors.

2590 Background: Preclinical research has shown that one mechanism of acquired resistance to CTX is via EGFR-ErbB2 heterodimerization, which can reactivate oncogenic pathways. LPT is a dual EGFR and ErbB2 intracellular tyrosine kinase inhibitor. A phase I translational clinical study was performed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and clinical activity of CTX and LPT in patients with EGFR-driven solid tumor malignancies that can be treated with CTX. Methods: Patients (Pts) were enrolled in a 3+3 dose escalation trial. Prior CTX therapy was allowed. CTX was given at 400mg/m2 on Cycle 1, Day 1 (C1D1), then 250 mg/m2 weekly. LPT dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg orally daily. Rash management included daily sunblock, steroid cream, and doxycycline. Cycle length was 21 days, and patients were assessed for toxicity through the end of C2, and for efficacy after every 2 cycles. Fresh tumor biopsies were obtained at baseline and at the end of C1 to compare EGFR and ErbB2 expression levels and EGFR related pathway activation. DNA from blood samples was analyzed for pharmacogenetic (PGx) variations and correlations with toxicity and pharmacokinetics (PK). Results: Between October, 2010 to January 2012, 13 pts were enrolled, with colon (4), lung (3), head and neck (3), and anal cancers (3); 10 were evaluable for toxicity. Treatment-related toxicities of any grade included: rash (67%), diarrhea (42%), fatigue (33%), nausea/vomiting (17%), and dehydration (8%). DLTs included G3 rash in 1 of 6 pts on DL1, and G3 diarrhea despite optimal therapy in 1 of 4 pts on DL2. Enrollment to DL2 continues. Of 7 pts evaluable for response, 1 had an uPR, 3 had SD, including 1 with SD of ≥4 cycles, and 3 had DP. Both patients with uPR and prolonged SD were treated on DL1. Tumor EGFR-ErbB2 and EGFR pathway phosphorylation analyses and PGx results will be presented. Conclusions: The combination of CTX and LPT is well tolerated with expected toxicities. Efficacy was seen even on DL 1. Phase II clinical studies in CTX-sensitive diseases such as colon and head and neck cancer are planned.

Cabazitaxel in patients with advanced CRPC after docetaxel failure: Results of expanded program access (EAP) in Spain: Safety and efficacy.

e15149 Background: Cabazitaxel is the new chemotherapy standard as second line in castrate resistant prostate cancer (CPRC) [Tropic Trial, Lancet 2010]. The aim of this study was to analyze the baseline characteristics and outcomes in a different cohort of patients (pts) from six hospitals in Spain within to EAP. Methods: We report a cohort of 65 pts including in EAP trial, who have progressed on or after docetaxel-based chemotherapy. Cabazitaxel was administered a standard dose of 25 mg/m2 IV q3wks. All pts had proven histology confirmation of prostate adenocarcinoma and progressive disease (radiologic and/or rising PSA) at the beginning of the treatment. Results: We collected data of 65 pts between 3-2011 to 12-2012. Median age was 63 years (range 45-83) and ECOG 0-1-2 in 26%-58%-16% respectively. Median basal PSA was 864 and Gleason grade was 7. Seventy-eight percent had bone metastases, 33% ganglionar metastases and 14% visceral metastases. Previous therapy was: hormonal, median 2 lines and chemotherapy was median of 1.6 lines. Thirty percent (20 pts) had received ketoconazole. Median of previous docetaxel dose was 1029 mg/m2(50-3750). Seventy percent of pts received G-CSF as primary prophylaxis in any cycle, 24% (16pts) had grade >3 neutropenia and 6 pts (9%) had febrile neutropenia. Other toxicities were: g3 anemia 3pts (4,6%), g3 asthenia 5pts (7,7%), g3 diarrhea 1 pt (1,5%). No toxic death was reported. The PSA response rate to cabazitaxel was 64% (31pts) and the median of cabazitaxel cycles administered was 6 at last follow-up. Median progression free survival was 4.4 months (2.7-6.1). Conclusions: These results confirm the efficacy and safety of cabazitaxel in this setting. Similar baselines parameters to Tropic trial were observed. This data reflex that Cabazitaxel in CRPC pts after docetaxel failure require the use of G-CSF in daily clinical practice.

Randomized phase II study of docetaxel plus vandetanib (D+V) versus docetaxel followed by vandetanib (D-V) in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (OC): SWOG S0904.

5015 Background: Antiangiogenesis therapy has led to antitumor effects both preclinically and clinically. Vandetanib (V) is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET. These targets are of interest in OC care, as targeting has shown anti-tumor efficacy, particularly in combination with taxanes. We explored the efficacy, safety, and toxicity of docetaxel (D) and V in women with recurrent OC. Methods: Women with resistant, refractory, or progressive/persistent OC were eligible for this randomized phase II study provided they had not received D or V for recurrent disease. Patients were allowed to receive other anti-VEGF targeted agents for primary therapy (stratification variable). Up to 3 additional cytotoxic regimens for recurrence were allowed. Patients were allocated 1:1 to D(75 mg/m2, I.V.)+V (100 mg daily, p.o.) or D(75 mg/m2). Patients receiving single agent D were allowed to crossover to V upon progression (D-V). The primary endpoint was PFS. Other objectives were: OS, objective response (ORR), and frequency/severity of adverse events. The study was designed with 84% power to detect a 1.55 PFS hazard ratio using a one-sided P of 0.1. Results: 131 patients were enrolled; 5 were excluded (1 ineligible, 4 eligible but untreated). 9% had received prior anti-angiogenic therapy. 61 patients on D+V were assessable for toxicity; 19 (31%) had treatment-related G4 events, primarily hematologic. Similarly, 17 (26%) of 65 patients receiving D alone had G4 events, primarily hematologic. 34 (52%) patients crossed over to V; no G4 events were recorded among 32 evaluable patients. G3 diarrhea was observed in 14% of D+V patients; 5% D-V patients. G3 acneiform rash occurred in 2% and 0%, respectively. The median PFS estimates were 3.0 mos (D+V) vs 3.5 (D-V); HR (PFS): 0.98 (80% CI:0.75-1.27). For OS, the median estimates were 14 mos (D+V) vs 12 mos (D-V); HR (OS):0.84 (80% CI:0.56-1.28). ORR was 14% and 17%, respectively. Crossover V response was 4% (1/27 measurable patients). Conclusions: D+V was well tolerated in this population however, did not prolong PFS with respect to D.

Abstract LB-226: mTOR inhibition by Temsirolimus as second-line treatment for advanced RCC: The Medical optimization of Torisel® (MoTOR) phase II trial by the Italian Kidney Cancer Group (GIR)

Abstract Background: The mammalian target of rapamycin (mTOR) kinase is an essential regulator of growth and response to hypoxic and metabolic stress and a well-established therapeutic target in renal cell carcinoma (RCC). The mTOR inhibitor Temsirolimus (CCI-779, Torisel®) is the first-line treatment of choice for RCC patients with poor-risk features. Preclinical and clinical evidence indicates that mTOR inhibitors may be effective in controlling RCC growth, even after resistance to agents targeting the VEGF/VEGFR axis ensues. Thus we designed a multicenter phase II trial to assess the activity and safety of Temsirolimus as II-line treatment for advanced RCC patients (pts). Methodology: This was an open-label, multicenter, phase II trial of Temsirolimus (25 mg/wk i.v.), administered to advanced RCC pts with documented progression after I-line treatment. Primary endpoint was PFS rate at 6 mos. Tumor response was assessed every 8 wks. Considering a 6-mo PFS rate of 20% unacceptable (p0=20%) and a 6-mo PFS rate of 40% (p1=40%) of interest, a minimum targeted accrual of 47 pts in the sunitinib-pretreated group was to be pursued in order to reach 90% power at a significance level of 5%. Pts who underwent any other I-line treatment were allowed on study until the target accrual in the sunitinib-pretreated group was met. Results: From May 2009 to January 2012, 76 pts were enrolled (median age: 67 yrs, range: 36-86; M/F: 58/18; ECOG PS 0/1/2: 51/19/6); I-line therapy included sunitinib (60 pts), bevacizumab (8), sorafenib (3), cytokines (2), or other (3). With 18/57 evaluable patients free from progression at 6 mos in the sunitinib-pretreated group the primary endpoint was met. Median PFS was 4.0 mos (95% CI: 2.7-5.3) and 4.6 mos (95% CI: 2.8-6.5) in the overall (n=71) and sunitinib-pretreated (n=57) populations, respectively; OS in the same groups was 13.7 mos (95% CI: 9.1-18.3) and 14.6 mos (95% CI: 8.9-20.3), respectively. Six out of 71 pts (8%) had PR and 33/71 (46%) had SD as their best response. Toxicity (n=68) was mild with G3 anemia, neutropenia and thrombocytopenia in 2, 1, and 1 pts, respectively; G3 hyperglycemia and G3 hypertriglyceridemia in 2 and 7 pts, respectively; G4 hypercholesterolemia in 2 pts; G3 stomatitis in 5 pts; G3 asthenia in 3 pts; G3-4 pulmonary toxicity in 2 pts; G3 diarrhea in 2 pts; G3 cutaneous rash in 1 pt. Only 1 hypersensitivity reaction occurred during Temsirolimus infusion. Treatment compliance was good, with <10% of weekly administrations omitted and 15/67 (22%) pts requiring dose reductions (to 20 mg/wk and 15 mg/wk in 11 and 4 pts, respectively). Mean number of weekly administrations received was 15. Conclusions. Temsirolimus is an active and well-tolerated II-line treatment for advanced RCC, particularly in sunitinib-pretreated pts, and may constitute a suitable therapeutic option in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-226. doi:1538-7445.AM2012-LB-226

Abstract 741: Sunitinib plus hormone ablation and radiation therapy for patients with high-risk localized prostate cancer: Results from a multi-institutional phase I study

Abstract Background: Novel strategies are needed to improve the long-term outcomes of patients (pts) with high-risk prostate cancer treated with hormonal ablation and external beam radiation therapy (XRT). Preclinical data suggest that angiogenesis inhibitors normalize vasculature, reduce hypoxia, and improve the therapeutic index of XRT. To assess the feasibility of combined VEGFR/PDGFR inhibition in combination with XRT, a Phase I study with sunitinib was initiated. Methods: Seventeen men with adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or PSA > 20ng/ml received initial hormonal ablation (leuprolide 22.5mg every 12 weeks + oral bicalutamide 50mg daily) for 4-8 weeks prior to oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks post XRT (prostate and proximal seminal vesicles received 75.6 Gy in 42 fractions with at least 50 Gy for the distal seminal vesicles). A 3+3 sequential dose-escalation design was employed to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose (MTD) of sunitinib. Results: The first 4 pts enrolled on 37.5 mg experienced a DLT during lead-in. *With 2 pts unexpectedly experiencing Grade 3 neutropenia and a third experiencing Grade 3 thrombocytopenia, a drug-interaction with bicalutamide was suspected. The protocol was revised to replace these pts and omit concurrent bicalutamide. Of these first 4 pts, 3 were dose reduced to 25 mg and successfully completed full treatment, while 1 pt withdrew. Of the next 3 pts subsequently enrolled at 37.5 mg, 2 of 3 on concurrent therapy have experienced DLTs (G3 diarrhea with concomitant sunitinib-induced thyrotoxicosis; G3 proctitis). Conclusions: Using a daily dosing regimen and a lead-in phase, the MTD of concurrent sunitinib, hormonal ablation and XRT was 37.5mg daily. The recommended Phase 2 dose of sunitinib for further study is 25mg daily. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 741. doi:1538-7445.AM2012-741

Abstract LB-222: Lapatinib has antiproliferative effects in both HER2 positive (+) and HER2 negative (-) breast cancer (BC): results from the MAPLE short-term pre-surgical trial (CRUK E/06/039)

Abstract Not all patients (pts) with HER2 positive (+) breast cancer (BC) benefit from treatment (tx) with EGFR/HER2 tyrosine kinase inhibitor lapatinib (L) & it is not known whether HER2 over-expression or amplification are obligate requirements for L response. Assessment of in vivo biomarkers of drug activity, e.g. change in Ki67, after short-term pre-surgical tx may elucidate the differential molecular profile of sensitive vs. resistant tumors. Aims: i) Determine whether L induces anti-proliferative effects in HER2+ & HER2 negative (-) BC & ii) identify biomarkers of sensitivity/resistance to anti-proliferative effects of L. Methods: Women with newly diagnosed BC were randomized (3:1) to receive 10-14 days of pre-operative L (1500mg/day) or placebo (P) in a multicentre phase II trial (ISRCTN68509377). Paired core biopsies before & after tx were analyzed for Ki67, TUNEL, HER2, EGFR, ER, PgR, pAkt, pErk, & stathmin (candidate marker of PI3K/Akt activation) by IHC +/− FISH. HER2, HER3 & ligands EREG, AREG & NRG1 mRNA was measured by RT-PCR. The primary endpoint was change in Ki67. HER2+ was defined as 3+ or 2+ by IHC and FISH+. Differences in geometric means were assessed by Mann-Whitney & correlations by Spearman rank. Results: 121 pts (L=94, P=27) were randomized between 12/2007-04/2011, 70% were ER+/PgR+, 13% ER+/PgR- & 17% ER-; 22% were HER2+ (including one 2+/FISH+) & 26% were EGFR+. L pts reported significantly more frequent G1-2 (64%) or G3 (6%) rash, & G1 diarrhea (56%); the only other G3 toxicity was infection in 1 pt. There were no delays in surgery. Paired samples containing tumor were obtained for 98% (118/121) of randomized pts. Ki67 fell significantly in the L group (relative reduction in post- vs. pre-tx samples = -31%, 95%CI: -44 to -16; p<0.001), but not in the P group (-3%, 95%CI: -16 to 13). There was no increase in apoptosis (-21%, 95%CI: -39 to 2.2). While Ki67 reduction in the L group was greatest in HER2+ BC (- 46%, 95%CI: -63 to -23; p<0.01), there was also a significant Ki67 fall in HER2- BC (-27%, 95%CI: -42 to -8; p<0.05) with 13% (9/72) of HER2- BC demonstrating ≥50% Ki67 reduction with L. Both pERK & stathmin were also significantly downregulated by L. Among HER2+ pts, there was a trend for high nuclear pAkt to predict for Ki67 response (R=−0.4; p=0.1). Among HER2- pts, neither moderate HER2 nor EGFR expression nor any other biomarker correlated with Ki67 fall. The only biomarker change associated with Ki67 fall among HER2- L-treated pts was stathmin (R=0.4; p=0.001); stathmin did not correlate with pAkt at baseline or with tx. RT-PCR analyses of HER2, HER3 & ligands are ongoing. Conclusion A short-term pre-surgical study for an agent such as L where the main endpoint is molecular rather than clinical, is feasible & safe. Whilst L is currently used exclusively in HER2+ disease, MAPLE has shown it also has antiproliferative effects in a subset of HER2- BC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-222. doi:1538-7445.AM2012-LB-222

Phase I study of biweekly liposome irinotecan (PEP02, MM-398) in metastatic colorectal cancer failed on first-line oxaliplatin-based chemotherapy.

613 Background: PEP02 (MM-398) is a nanoliposomal formulation of irinotecan (CPT-11) that has improved pharmacokinetics (PK) and tumor distribution of CPT-11 and its active metabolite, SN-38. PEP02 single agent q3w has shown preliminary efficacy and safety in Phase II pancreatic and gastric cancer studies. Since irinotecan is approved for metastatic colorectal cancer (mCRC) and biweekly regimens are widely used, the aims of this study are to determine the maximum tolerated dose (MTD), characterize the PK and pharmacogenetics (PGx), and explore the efficacy of PEP02 q2w in mCRC. Methods: Patients (pts) with disease progression after 1st-line oxaliplatin-based chemotherapy, ECOG PS 0-1, and without prior exposure to irinotecan were eligible. PEP02 was given on day 1 and 15 of each 28 day treatment cycle. The starting dose was 80 mg/m2 and escalated by 10 mg/m2 to the target dose of 100 mg/m2. PK was evaluated during the 1st cycle and the tumor response was assessed by RECIST. Results: A total of 18 pts (M/F 9/9; median age 57.5) were enrolled, with 6 at each dose level. Dose-limiting toxicity manifested as G3 diarrhea was observed in one pt per dose level. The target dose of 100 mg/m2 was determined to be the MTD. Nine pts had dose delayed (4, 3, 2 at 80, 90, 100 mg/m2), mostly because of neutropenia. The PK and PGx are being analysed. As of August 2011, there are 3 pts still on study treatment and 17 pts evaluable for tumor response. Four pts (2 at 80 mg/m2, 1 each at 90 and 100 mg/m2) showed partial response (3 after 2 cycles and 1 after 8 cycles) and 8 pts (3 each at 80 and 90 mg/m2, 2 at 100 mg/m2) maintained stable disease for at least 2 cycles, which resulted in a response rate (RR) of 23.5% and a disease control rate (DCR) of 70.6%. Current median progression-free survival (PFS) is 4 months and 8 pts (47%) had PFS ≥ 6 months. Conclusions: The MTD of biweekly PEP02 is 100 mg/m2. As a 2nd-line monotherapy after oxaliplatin-based chemotherapy, the efficacy results indicate the potential benefit of PEP02 for mCRC (FOLFIRI-1 achieved only 4% RR, 34% DCR, and 2.5 months PFS in FOLFOX pretreated pts). A randomized Phase II study evaluating PEP02 plus 5-FU/LV (FUPEP regimen) vs. FOLFIRI is currently ongoing in France.

Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

Abstract 991▪▪This icon denotes a clinically relevant abstractSmoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease.In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis.Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly).The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria).According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%.After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 13 out of these 28 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). Estimated 3-years overall survival (OS) from the inclusion in the trial was 98% for Len-dex arm and 82% for no treatment arm (p=0·05) and this difference was more evident if we evaluate the OS from the moment of diagnosis (HR: 6.7; 95% IC (0.7–57); p=0.03).As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developed G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. Two patients in the Len-dex arm developed second primary malignancies (SPM): one developed polycythemia vera JAK2+, but the analysis of a frozen DNA sample obtained at the moment of inclusion in the trial demonstrated that JAK2 was already positive. The second-one was a prostate cancer in a patient with previous history of prostate enlargement plus elevated prostate specific antigen (PSA) who was closely followed by the urologist.In conclusion, this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·2), with a trend to improve the overall survival; in addition, tolerability is acceptable and concerning SPM, no safety warnings are at the present time. Moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures:Mateos:Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Baquero:Celgene: Employment. Quintana:Celgene: Employment. García:Celgene: Employment.

Abstract A177: Phase 1, dose-escalation, safety, pharmacokinetic and pharmacodynamic study of single agent PF-03758309, an oral PAK inhibitor, in patients with advanced solid tumors.

Abstract Background: P21 activated kinase (PAK), a family of serine-threonine kinases, is a downstream effector of the Rho family and functions as a signaling node for various oncogenic pathways. The capability to transform cell cultures and the consistent anti tumor response associated with PAK inhibition in preclinical studies has raised the interest of PAK as a potential target for oncology. PAK consists in 6 isoforms divided into 2 subgroups. PAK isoforms 1 and 4 have been more frequently related to cancer biology. PF309 is a potent ATP-competitive inh of PAK1, 4, 5 and 6. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design. Oral PF309 was given on a continuous daily dosing. Tumor response was assessed at baseline and every 8 wks thereafter. AEs were recorded according NCI CTC v3.0. PK assessment was a study objective and PD endpoints (downstream substrates of the PAK pathway, eg: GEFH1, p-PAK4, p-cofilin) were to be explored in pre and post-treatment tumor biopsies as well as in surrogate tissue (hair follicles). Results: 33 pts (17 M and 16 F) were treated with PF309 among 8 dose levels (1 mg QD to 60 mg BID). Median age was 62.0 years (range 24–80) and median ECOG PS was 1. The most frequent tumors were CRC (16 pts), NSCLC (4 pts), breast cancer (2 pts), osteosarcoma (2 pts) and pancreatic cancer (2 pts). Median number of cycles was 3 (range 1 to 10). All subjects experienced treatment emergent AEs; 9 subjects experienced G3–4 AEs, and 2 SAEs were reported from 2 subjects: abdominal pain and hemoptysis (both at 60 mg BID). One patient died while on study due to PD. At the time of this report 2 patients experienced DLTs at 60 mg BID: G3 diarrhea (1 pt), and G2 nausea, vomiting and diarrhea, and G1 abdominal cramping leading to the administration of less than 80% of the planned dose during C1 (1pt). As a result 60 mg BID is the maximum administered dose (MAD). Treatment-related AEs were mainly from the GI tract: G3 diarrhea (1 pt), G1–2 diarrhea (10 pts), G1–2 vomiting (8 pts), G1–2 nausea (8 pts each), abdominal pain (5 pts) and fatigue (3 pts). G1–2 QTcF prolongation was observed in 11 pts (G1 in 6 pts, G2 in 5 pts), 6 of whom had an abnormal pre-treatment QTcF. No QTcF increase &amp;gt; 60 ms above baseline was observed in any patient. G3 lab abnormalities were rarely reported and included hyponatremia, thrombocytopenia, neutropenia and increased bilirubin (1 pt each). The PK data demonstrated that after attainment of Cmax within 5 hours after dosing, PF309 plasma concentrations declined in a multi-exponential manner with an average terminal half-life of 12.4 to 17.8 hs across doses. There was a lack of dose proportionality in the dose range of 10 to 60 mg, likely due to the high inter-patient variability. The inter-patient variability of AUCtau and Cmax at steady-state ranged from 21 to 177% and 45 to 184%, respectively, across doses. So far no tumor responses have been observed. A total of 10 pts have been on study treatment for ≥ 12 weeks. One heavily pretreated pt with CRC and progressive increase of the CEA serum level experienced a decrease in the CEA value from 1343.3 to 625.2 ng/ml, and remained on study for 4 months. Conclusions: GI toxicity is the most relevant toxicity associated with PF309 and 60 mg BID is the MAD. MTD confirmation is ongoing. Clinical development of PF309 is on hold due to PK findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A177.

A phase I study of continuous hepatic arterial infusion of Irinotecan in patients with locally advanced hepatocellular carcinoma

Purpose Aim of this phase I study was to identify the maximum tolerated dose and dose limiting toxicity of continuous infusion of Irinotecan through a port-a-cath placed in the hepatic artery in patients with hepatocellular carcinoma and cirrhosis to explore new strategies in advanced hepatocellular carcinoma. Response rate and time-to-progression were analysed. Methods Irinotecan was delivered as a five-day continuous infusion every 21 days, with increases of 2.5 mg/m 2/day every three patients, starting from 7.5 mg/m 2/day. Dose limiting toxicity corresponded to one patient in each triplet developing G4 haematological or G3 non-haematological toxicity, confirmed in two triplets. Twenty-eight patients (17 Child-Pugh A, 11 B) received treatment and tumour response was assessed after three courses completed by 22 patients. Results Dose limiting toxicity was G3 diarrhoea in two patients, reached at 27.5 mg/m 2/day and the recommended dose was set at 25 mg/m 2/day. Nineteen of 30 patients experienced adverse events related to porth-a-cath placement and one died from liver ischemia and sepsis. Median time-to-progression was 11.3 months. Conclusion Intrarterial infusion of Irinotecan is feasible in patients with hepatocellular carcinoma on cirrhosis at a recommended dose of 25 mg/m 2/day, with no major adverse drug-related events, but with some concerns about the insertion and management of the intra-arterial device.

Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

BackgroundCyclooxygenase-2 overexpression is associated with poor outcome and resistance to platinum-based chemotherapy in ovarian cancer. We evaluated the antitumor activity and safety of the combination carboplatin plus the COX-2 inhibitor celecoxib in recurrent heavily-treated OC patients.MethodsPatients were administered oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). A Simon's two-stage design was employed.Results45 patients were enrolled: 23 (51.1%) presented platinum-resistance, and 27 (60%) had received at least 3 prior regimens for recurrence. The response rate was 28.9% with 3 complete and 10 partial responses (median duration of response = 6 months). Only one (0.4%) G4 non-febrile neutropenia was observed; G3 neutropenia, anemia, or thrombocytopenia, were observed in 2.5%, 1.7%, and 1.7% of the cycles, respectively. G3-4 vomiting was reported in only 1.7%, and 0.4% of the cycles were associated with G3 dyspepsia or diarrhea or constipation. Only one patient experienced G3 hypertension associated to G2 hypersensitivity reaction. No differences in baseline versus post-treatment Quality of Life scores were observed. Median progression free survival and overall survival were 5 and 13 months, respectively.ConclusionsCelecoxib combined with carboplatin showed promising activity and it is well tolerated in heavily-treated recurrent ovarian cancer patients.Trial registration numberNCT01124435 (ClinicalTrials.gov Identifier) and 935/03 (study ID numbers).

Phase I study of sunitinib in combination with gemcitabine/capecitabine for the first-line treatment of metastatic or unresectable renal cell carcinoma.

e15095 Background: Gemcitabine (G) plus Capecitabine (C) have demonstrated a modest activity in metastatic renal cell cancer (mRCC) patients (pts). The combination of Sunitinib (S) and C resulted in an acceptable safety profile in pts with advanced solid tumors. We hypothesized that the addition of S to G+C in advanced/mRCC would be synergistic and could increase the therapeutic efficacy. Methods: This is an open-label, phase I, dose-escalation study to assess the maximum-tolerated dose (MTD), safety and antitumor activity (in terms of response rate) of S in combination with C and G in naive pts with advanced mRCC. Advanced RCC pts with adequate organ function, performance status (ECOG 0-1), age >18 years, were eligible. Treatment consisted on iv G day 1 and 8, oral C bid days 1–14, and oral S continuous daily dosing (CDD) schedule, for six cycles (21 days per cycle), followed by sunitinib monotherapy, at the investigator’s discretion if clinical benefit was maintained. Dose level 1 G 1000 C 850 S 37.5; dose level 0 G 1000 C 650 S 37.5 (dose level -1 G 850 C 500 S 37.5). Results: 16 pts were enrolled in the study, median age: 67 yrs, histology: 9 clear cell, 4 papillar and 1 sarcomatoid have been treated at the first two dose levels. In DL1, two out of 4 pts had DLT, consisting on G3 diarrhea and mucositis, and G4 thrombocytopenia. Decision was made to reduce down to level 0; only 1/12 pts experienced DLT at this DL (mucositis G3 and thrombocytopenia G3). Other non-DLTs adverse events were asthenia, hand-foot syndrome, mucositis, diarrhea, infection, neutropenia, epistaxis, low gastrointestinal tract bleeding and hypertension. Dose reductions were frequent (58% of pts) and only 7 pts were able to receive the 3 drugs for > 3 cycles. One death was reported as possibly related to study drugs. A partial response was achieved in 3 pts, and stable disease in 6 patients. Conclusions: Although a low rate of DLT were observed at dose level 0, the safety profile of the combination does not seem to be manageable in most patients. In this trial there are no signs of a synergistic activity for the combination therapy of S plus G/C in therapy naïve pts with mRCC.