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Background: High tumor GR expression is associated with poor prognosis in estrogen receptor (ER) negative early-stage breast cancer. Co-treatment with M, a GR antagonist, potentiates effects of chemotherapy in ER- breast cancer xenograft studies. Herein we describe results of a phase 1 dose-escalation study of M plus E, with an ongoing dose expansion cohort in pts with GR+ TNBC. Objectives: Determine 1) safety and tolerability, 2) recommended phase 2 dose (RP2D) of M + E, and 3) characterize pharmacokinetics (PK) and clinical activity of M in pts with GR+ TNBC. Methods: Eligibility: 1) relapsed/refractory breast, ovarian, prostate, urothelial, sarcoma, or non-small cell lung cancer; 2) 2-5 prior chemotherapy regimens for advanced disease; 3) ECOG PS 0-1; and 4) adequate end-organ function. Study used a 3 + 3 dose escalation scheme. After a 7 day lead-in of M alone, M was administered by mouth daily in combination with E given IV on days 1 and 8 of a 21 day cycle. Results: 13 pts in Part 1 Dose escalation with metastatic breast cancer (MBC) were treated with M+E: 5 TNBC, 8 GR+ tumors, 2 GR- tumors, and 3 of unknown GR status. Pts were treated at 3 dose levels (DL)[M mg/d, E mg/m2]: 3 at DL1 [600, 1.1] 4 at DL-1a [300, 1.4], and 6 at DL-1 [300, 1.1]. Median duration of treatment was 90+ days. Neutropenia leading to delay of E was dose limiting in 4 pts. CTAE Grade 3/4 neutropenia was observed in 10 pts over all DL, but easily managed (9 pts with growth factor support). Other grade 3+ toxicities were neuropathy (2 pts) and onycholysis (1 pt). No other significant toxicity was noted. RP2D was determined as 300mg/d M and 1.1mg/m2 E. At this DL there were no DLTs. PK of M and E were as predicted from published literature with no evidence of drug-drug interaction (DDI). A total of 6 pts received this dose (3 TNBC; 3 MBC). All 3 TNBC were GR+. 1 had partial response, 1 had stable disease, and 1 had progressive disease. A phase I/II study of M+E is now in progress. To date, 3 GR+ TNBC pts have been treated for a median of 28+ days. Conclusion: M + E is a novel combination designed to improve antitumor activity. It is well tolerated with evidence of clinical activity and no evidence of DDI. RP2D is 300mg M + E 1.1mg/m2. Study is ongoing in expansion phase where recruitment is limited to pts with GR+ TNBC. Additional PK and clinical data will be presented. Citation Format: Wilks S, Modiano M, Spira A, Becerra C, Walling J, Nguyen D, Baker G, Conzen SD, Nanda R. Phase 1 study of GR antagonist mifepristone (M) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients (pts) with GR-positive triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-21.

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44–1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30–0.76; P

Summary Background Highly emetogenic chemotherapy induces emesis in almost all patients in the absence of prophylaxis. Guidelines recommend use of a neurokinin-1 (NK-1) receptor antagonist in conjunction with a 5-HT 3 receptor antagonist and corticosteroid in patients receiving highly emetogenic chemotherapy. We aimed to assess rolapitant, an NK-1 receptor antagonist, for prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of cisplatin-based highly emetogenic chemotherapy. Methods We conducted two global, randomised, double-blind, active-controlled, phase 3 trials (HEC-1 and HEC-2) at 155 cancer centres (76 in HEC-1 and 79 in HEC-2) in 26 countries (17 in HEC-1 and 14 in HEC-2). We enrolled patients with cancer aged 18 years or older, who had not previously been treated with cisplatin, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly assign patients to treatment. Patients were stratified by sex and randomly allocated to either oral rolapitant (180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) about 1–2 h before administration of highly emetogenic chemotherapy. All patients received granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2–4. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients were allowed to receive the same study drug they were assigned in cycle 1, unless removed at the clinician's discretion. Patients could also choose to leave the study at any point. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a cancer centre compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (no emesis or use of rescue medication) in the delayed phase (>24–120 h after initiation of chemotherapy) in cycle 1. These studies are registered with ClinicalTrials.gov, numbers NCT01499849 and NCT01500213. Both studies have been completed. Findings Between Feb 21, 2012, and March 12, 2014, 532 patients in HEC-1 and 555 patients in HEC-2 were randomly assigned to treatment. 526 patients in HEC-1 (264 rolapitant and 262 active control) and 544 in HEC-2 (271 rolapitant and 273 active control) received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients in the rolapitant group had complete responses in the delayed phase than did patients in the active control group (HEC-1: 192 [73%] vs 153 [58%]; odds ratio 1·9, 95% CI 1·3–2·7; p=0·0006; HEC-2: 190 [70%] vs 169 [62%]; 1·4, 1·0–2·1; p=0·0426; pooled studies: 382 [71%] vs 322 [60%]; 1·6, 1·3–2·1; p=0·0001). The incidence of adverse events was similar across treatment groups. The most commonly reported treatment-related treatment-emergent adverse events in the rolapitant versus active control groups were headache (three [ vs two [ vs four [ vs three [ vs three [ vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [ vs one [ vs two [ vs two [ vs two [ Interpretation Rolapitant in combination with a 5-HT 3 receptor antagonist and dexamethasone is well-tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of highly emetogenic cisplatin-based chemotherapy. Funding TESARO, Inc.

BACKGROUND Rolapitant, a novel neurokinin‐1 receptor antagonist, provided effective protection against chemotherapy‐induced nausea and vomiting (CINV) in a randomized, double‐blind phase 3 trial of patients receiving moderately emetogenic chemotherapy or an anthracycline and cyclophosphamide regimen. The current analysis explored the efficacy and safety of rolapitant in preventing CINV in a subgroup of patients receiving carboplatin. METHODS Patients were randomized 1:1 to receive oral rolapitant (180 mg) or a placebo 1 to 2 hours before chemotherapy administration; all patients received oral granisetron (2 mg) on days 1 to 3 and oral dexamethasone (20 mg) on day 1. A post hoc analysis examined the subgroup of patients receiving carboplatin in cycle 1. The efficacy endpoints were as follows: complete response (CR), no emesis, no nausea, no significant nausea, complete protection, time to first emesis or use of rescue medication, and no impact on daily life. RESULTS In the subgroup administered carboplatin‐based chemotherapy (n = 401), a significantly higher proportion of patients in the rolapitant group versus the control group achieved a CR in the overall phase (0‐120 hours; 80.2% vs 64.6%; P < .001) and in the delayed phase (>24‐120 hours; 82.3% vs 65.6%; P < .001) after chemotherapy administration. Superior responses were also observed by the measures of no emesis, no nausea, and complete protection in the overall and delayed phases and by the time to first emesis or use of rescue medication. The incidence of treatment‐emergent adverse events was similar for the rolapitant and control groups. CONCLUSIONS Rolapitant provided superior CINV protection to patients receiving carboplatin‐based chemotherapy in comparison with the control. These results support rolapitant use as part of the antiemetic regimen in carboplatin‐treated patients. Cancer 2016;122:2418–2425. © 2016 American Cancer Society., The efficacy of rolapitant, a neurokinin‐1 receptor antagonist with a long duration of action, was examined in a subgroup of 401 patients with cancer who received carboplatin‐based chemotherapy in a phase 3 trial. In this population, a single oral dose of rolapitant (180 mg) combined with granisetron and dexamethasone provided statistically superior protection against chemotherapy‐induced nausea and vomiting in the delayed and overall phases in comparison with granisetron and dexamethasone alone, and it was well tolerated.

Purpose This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer. Methods Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor. Treatments were as follows: arm 1 was doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles followed by paclitaxel 175 mg/m2 every 3 weeks for four cycles (ie, AC-P); and arm 2 was doxorubicin 50 mg/m2 plus paclitaxel 200 mg/m2 every 3 weeks for four cycles followed by paclitaxel 80 mg/m2 weekly for 12 weeks. Results Overall, 1,830 patients were enrolled and 1,801 were treated: arm 1 (n = 906; AC→P) and arm 2 (n = 895; AP-WP). Overall, patients had a PS of 0 (88%), had estrogen receptor and progesterone receptor–positive disease (52%), had one to three positive nodes (46%), and were postmenopausal (57%); the median age was 52 years. Currently, 1,640 patients (90%) are alive. The 6-year DFS was 79% to 80% in both groups. Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2. Overall 6-year survival rates were 82% and 87% in arms 1 and 2, respectively. Reasons for patients being taken off study treatment included toxicity (13% in arm 1 v 20% in arm 2), progressive disease or recurrence (7% v 5%), and consent withdrawn (9% v 8%), respectively. The most frequent toxicities were hematologic, including neutropenia and leukopenia followed by neuropathy, myalgia, nausea, fatigue, headache, arthralgia, and vomiting. Conclusion The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer. The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen.

Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m² intravenously (IV) over 30 min days 1–5, 15–19 and gemcitabine 800 or 1,000 mg/m² IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280–1,300 mg/m² IV over 30–60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m² IV over 30 min on days 1, 8, and 15 every 28 days). One hundred five patients received 340 treatment cycles (median 2, range 1–16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. The recommended phase II dose of imexon is 875 mg/m² with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

Purpose. To perform a phase I and pharmacokinetics study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) a new ribonucleotide reductase inhibitor using a single intravenous (2-h) schedule every 4 weeks. 3-AP was given at a starting dose of 5 mg/m2 with escalation based on a modified Fibonacci scheme. Patients and methods. A total of 27 patients with advanced cancer were entered into the study. Doses of 3-AP ranged from 5 mg/m2 to 105 mg/m2. Blood and urine samples were collected and 3-AP was measured by HPLC. Results. A total of 46 courses were evaluable. One patient developed grade 4 thrombocytopenia at the lowest dose level, and one patient had grade 3 anemia. Two patients developed grade 3 coagulation abnormalities. The only other toxicities of more than grade l occurring in more than 10% of patients were fever and asthenia. No toxicities were observed at the highest dose level. Peak serum concentration of 3-AP increased linearly with dose. No tumor responses were observed in this heavily pretreated population, although eight patients had stabilization of their disease. Conclusions. Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m2 on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.

e12550Background: GR is highly expressed in TNBC and is associated with a poor prognosis in estrogen receptor-negative (ER-) early stage breast cancer. Treatment with MIFE potentiates the effects of chemotherapy (ctx) in TNBC xenografts. Here we describe the results of an ongoing trial including outcomes to date in all patients with GR+ TNBC treated at the recommended Phase 2 dose (RP2D). Objectives: To determine the safety, tolerability, pharmacokinetics (PK) and clinical activity of the MIFE+E combination in pts with GR+ TNBC at the RP2D. Methods: Eligibility: Phase 1, pts with solid tumors; Phase 2, pts with GR+ TNBC; up to 5 prior ctx regimens for advanced disease; ECOG PS 0-1; adequate end-organ function. Design: 3 + 3 dose escalation scheme. After a 7-day lead-in of oral daily MIFE alone, MIFE was continued daily and E was given on days 1 and 8 of a 21-day cycle. Results: 16 pts with metastatic breast cancer were enrolled in Phase 1 (3 with GR+ TNBC). MTD/RP2D was MIFE 300 mg/day + E 1.1 mg/m2. To d...

BACKGROUND: Pixantrone dimaleate (pixantrone) has been shown to have antitumor activity in leukemia and lymphoma in vitro models and to lack delayed cardiotoxicity associated with mitoxantrone in animal models. FND-R, a combination regimen of fludarabine, mitoxantrone, dexamethasone, and rituximab, has been shown to be an effective regimen for low-grade lymphomas. METHODS: This dose-escalation study, with an expansion cohort, was conducted to evaluate the safety and preliminary efficacy of FPD-R, in which pixantrone was substituted for mitoxantrone in the FND-R regimen, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL). Escalated doses of pixantrone were administered to newly enrolled patients on day 2 of each 28-day cycle of FPD-R. RESULTS: Twenty-eight of 29 enrolled patients received at least 1 cycle of FPD-R (median, 5 cycles). Pixantrone 120 mg/m2 was identified as the recommended dose in this regimen. Grade 3-4 adverse events were primarily hematologic; grade 3-4 lymphopenia occurred in 89% of patients and leukopenia in 79%. No patients developed congestive heart failure or grade 3-4 cardiac adverse events. Left ventricular ejection fraction decreases occurred in 8 (29%) patients, and most were grade 1 or 2, transient, and asymptomatic. The overall response rate was 89%. Estimated survival was 96% after 1 year and 92% after 3 years. CONCLUSIONS: The FPD-R regimen was well-tolerated and highly active in patients with relapsed or refractory indolent NHL. Cancer 2011;. © 2011 American Cancer Society.

The purpose of the study was to evaluate the safety, efficacy, and pharmacokinetics of pixantrone (BBR2778) when substituted for etoposide in the ESHAP regimen in patients with aggressive relapsed or refractory non-Hodgkin's lymphoma. Nineteen patients received protocol therapy, consisting of pixantrone 80 mg/m2 over 1 h on day 1, methylprednisolone 500 mg on days 1 - 5, cisplatin 25 mg/m2 on days 1 - 4, and cytarabine 2000 mg/m2 on day 5. Cycles were repeated every 21 days, in the outpatient setting. Dose limiting toxicity, consisting of bone marrow suppression, occurred at the first dose level (80 mg/m2), which was defined as the recommended dose. Grade 3 and 4 toxicities were mainly hematologic. Only one patient had grade 4 febrile neutropenia. No significant decreases in ejection fraction greater than 20% occurred. Overall response rate was 58%, with 37% complete and 21% partial responses. Six of the 11 responders (55%) underwent stem cell transplant. Median time to progression and overall median survival were 5.7 months and 14.5 months, respectively. There is no significant interaction between pixantrone and the combined drugs. The recommended dose of pixantrone in combination with methylprednisolone, cytarabine, and cisplatin (PSHAP) is 80 mg/m2. PSHAP is an active salvage regimen and should be further evaluated as a pretransplant cytoreductive regimen.

209 Background: Rolapitant, a novel NK-1 receptor antagonist, showed efficacy in CINV prevention in patients (pts) receiving MEC (anthracycline/cyclophosphamide (AC) and other regimens) in a global phase 3 trial. Recent anti-emetic guidelines consider AC based regimens to be highly emetogenic. In this post hoc analysis, the efficacy and safety of rolapitant was assessed in Cycle 1 in pts receiving non-AC MEC, and in the subset of pts receiving carboplatin-based MEC. Methods: In a double-blind, active-controlled study, pts were randomized to oral rolapitant 180 mg or placebo 1–2 hours before MEC. All pts received granisetron 2 mg oral on days 1-3 and oral dexamethasone 20 mg on day 1. Complete response (CR = no emesis + no use of rescue medication), no emesis, and no nausea were assessed in overall (0-120 h), acute (0-24 h), and delayed ( > 24-120 h) phases. Results: CR was significantly (P < 0.01) higher with rolapitant than active control in overall and delayed phases in the carboplatin subset and in all 3 phases in the non-AC population (Table). No emesis rates were significantly (p < 0.05) higher with rolapitant in the carboplatin subset in the overall phase. No nausea rates were significantly (P < 0.05) higher with rolapitant in the overall and delayed phases in carboplatin-based MEC. Incidences of treatment-related AEs in Cycle 1 with rolapitant vs. active control were 11.3% vs. 6.7% in the carboplatin-based subset. Most common AEs with rolapitant and active control were constipation, fatigue, and headache. Conclusions: Rolapitant was superior to active control in preventing CINV in pts receiving non-AC MEC, including in the subgroup receiving carboplatin. Rolapitant was well tolerated with low incidence of AEs. Clinical trial information: NCT01500226. [Table: see text]

e12070 Background: GR expression is associated with a poor prognosis in estrogen receptor-negative (ER-) early stage breast cancer. Co-treatment with MIFE potentiates the effects of chemotherapy (ctx) in ER- breast cancer xenograft studies. Here we describe the results of a phase 1 dose-escalation study of MIFE+E, with an ongoing dose expansion cohort in pts with TNBC. Objectives: To determine the safety and tolerability of MIFE+E, the recommended phase 2 dose (RP2D) of MIFE+E, and to characterize pharmacokinetics (PK) and clinical activity of MIFE+E in pts with GR+ TNBC. Methods: Eligibility: relapsed/refractory advanced solid tumors; up to 5 prior ctx regimens for advanced disease; ECOG PS 0-1; and adequate end-organ function. Design: 3 + 3 dose escalation scheme. After a 7 day lead-in of oral daily MIFE alone, MIFE was continued daily and E was given on days 1 and 8 of a 21 day cycle. Results: To date, 13 pts with metastatic breast cancer (5 have TNBC) have been treated with MIFE+E: 7 GR+ tumors, 3 GR-...

144 Background: PSMA is a validated target that is overexpressed selectively on prostate cancer cells. PSMA ADC is a fully human IgG1 antibody conjugated to the microtubule disrupting agent MMAE which binds to PSMA-positive cells, inducing cytotoxicity. A phase 1 study showed activity and tolerability at doses from 1.8-2.5 mg/kg. We have enrolled 119 mCRPC pts who progressed following abi/enz in a phase 2 trial of PSMA ADC. Methods: mCRPC pts (83 taxane experienced (TE) and 36 chemo-naïve (CN)) were administered PSMA ADC 2.5 or 2.3 mg/kg IV Q3 wk for up to 8 cycles. 95% of pts received prior abi and/or enz treatment. Safety, antitumor activity (including PSA, CTCs, and tumor imaging) and exploratory biomarkers were assessed. Results: In all treated pts, PSA declines of ≥30% and ≥50% were 30% and 14%, respectively (n=113); CTC counts showed a decline of ≥50% in 78% of pts and conversion from ≥5 to

Purpose Exatecan mesylate is a hexacyclic, water-soluble, topoisomerase-1 inhibitor. Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer. A multicenter, randomized, phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted. Patients and Methods Eligibility criteria included Karnofsky performance status ≥ 60%, locally advanced or metastatic pancreatic adenocarcinoma, and no prior chemotherapy. Radiation alone for locally advanced disease was permitted. Patients were randomly assigned on a 1:1 basis. For the exatecan plus gemcitabine arm, exatecan 2.0 mg/m2 and gemcitabine 1,000 mg/m2 were administered on days 1 and 8, every 3 weeks. Gemcitabine alone was dosed at 1,000 mg/m2 up to 7 weeks in the first cycle, then once a week for the first 3 weeks of a 4-week cycle. Tumor assessment was performed every 6 weeks. The primary end point was overall survival. An intent-to-treat analysis was used. Results From August 2001 to January 2003, 349 patients were randomly assigned, 175 to exatecan plus gemcitabine and 174 to gemcitabine alone. Twenty-four patients (6.9%) were not treated. The median survival time was 6.7 months for exatecan plus gemcitabine and 6.2 months for gemcitabine alone (P = .52). One complete response (CR; < 1%) and 11 partial responses (PRs; 6.3%) were observed in the exatecan plus gemcitabine treatment group, and one CR (< 1%) and eight PRs (4.6%) were observed in the gemcitabine-alone group. Grade 3 and 4 toxicities were higher for the exatecan plus gemcitabine arm versus the gemcitabine alone arm; neutropenia (30% v 15%) and thrombocytopenia (15% v 4%). Conclusion Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer.

LBA8003 Background: PemC and PCB are regimens used for first-line treatment of advanced NS-NSCLC. The primary objective was to compare progression-free survival without Grade 4 toxicity (G4PFS) between two vs three drug regimen arms. Methods: Patients ≥18 years, Stage IV NS NSCLC, AJCC (v7.0), and ECOG PS 0/1 were enrolled. Patients were randomized (1:1); received 4 cycles of induction (PemC: Pem, 500 mg/m2 and C, AUC = 6; PCB: P, 200 mg/m2, C, AUC = 6, and B, 15 mg/kg) followed by Pem (PemC Arm) or B (PCB Arm) maintenance therapy in the absence of progressive disease or discontinuation. Secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The study was powered for G4PFS; assuming hazard ratio (HR) of 0.75; there was 80% power to detect superiority of PemC over PCB with a 2-sided type I error of 0.10. Efficacy data were analyzed by intent-to-treat principle using the log-rank test for time-to-event variables, and an exact test for ORR and DCR. Safety data were evaluated using CTCAE v3 for patients who received ≥1 dose of study treatment. Results: Patients were randomized to PemC (N = 182) or PCB (N = 179). Baseline factors were balanced between arms: median age 66/66 years; % female 42/42; % PS=0, 47/47; % stage IV M1a 29/30; for PemC vs PCB, median G4PFS (months) was 3.91/2.86 (HR = 0.85, 90% CI 0.7, 1.04, p = 0.176); PFS and OS had HR = 1.06 (95% CI 0.84, 1.35), p = 0.610, and HR = 1.07 (95% CI 0.83, 1.36), p = 0.616, respectively. The ORR (%) 23.6/ 27.4 and DCR (%) 59.9/57.0 were for PemC vs PCB, respectively. Significantly more drug-related grade 3/4 anemia (18.7% vs 5.4%), and thrombocytopenia (24.0% vs 9.6%) were seen on PemC; significantly more grade 3/4 neutropenia (48.8% vs 24.6%) and grade 1/2 alopecia (28.3 % vs 8.2%) were seen on PCB. Conclusions: PemC was not superior to PCB in G4PFS; no difference in PFS or OS was observed for the two- vs three-drug regimens. There were no unexpected toxicities; the toxicity profiles demonstrated distinctions by arm, and both regimens demonstrated tolerability. Clinical trial information: NCT00948675.

LBA8003 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

7541 Background: AFL is a recombinant human fusion protein that acts as a decoy receptor and prevents the interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor with their receptors. This study evaluated the efficacy and safety of AFL in combination with first-line chemotherapy of C and P in NSCLC. Methods: This phase II, single arm, open label, multicenter trial in patients with previously untreated, locally advanced, or metastatic NSCLC excluded patients with squamous histology, cavitating lesions, ECOG > 1, uncontrolled hypertension, or brain/CNS metastases. All patients received IV AFL 6 mg/kg, P 500 mg/m2, and C 75mg/m2, every 3 weeks for up to 6 cycles. For those who completed the combined chemotherapy, Q3W administration of AFL was to continue until disease progression, intolerable toxicity, or any other cause for withdrawal. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Planned sample size was 72 patients. Results: The study was closed prematurely due to 3 confirmed cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 54.8% were male, 85.7% white and 50% ECOG 0. A median of 4 cycles of AFL was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. The 3 patients with RPLS were Caucasian women. Two had a history of hypertension and both experienced elevated BP and reduced CrCl. Of the 38 patients evaluable for response, ORR was 26.3% (95% CI, 12.3-40.3%) and median PFS was 5 months (95% CI, 4.3-7.1). Conclusions: The rate of RPLS observed in this study with AFL + C + P was higher than anticipated. A meta-analysis of safety from three large placebo-controlled studies reported no RPLS among 1333 patient treated with AFL + chemotherapy, and none was reported in prior combination studies of AFL + P or AFL + C + docetaxel. Though the study was stopped early, ORR and PFS were in accordance with most historical first-line NSCLC studies.

253 Background: Apricoxib is an oral, selective inhibitor of COX-2. COX-2 and EGFR signaling regulate the dominant ERK/MAPK, AKT and ß-catenin pathways in pancreatic cancer; combinations of COX-2 and EGFR inhibitors are of particular interest in this disease. ß-catenin activity is implicated in gemcitabine resistance. In addition, apricoxib has been demonstrated to potently reverse EMT in xenograft models of pancreatic cancer. In a completed Phase II study NSCLC patients were selected based on a decrease in PGEM, a urinary biomarker of COX-2 activity. As pancreatic cancer patients overwhelmingly over express COX-2 PGEM was measured for the purpose of secondary analysis in this study. Methods: Pts with locally advanced or metastatic adenocarcinoma of the pancreas were treated with erlotinib 100 mg PO daily and apricoxib/placebo 400mg PO daily and gemcitabine per previously published schedule (Burris JCO 2007). The primary objective PFS. Results: 109 patients were randomized (70 AP/GE:39 P/GE). Characteristics were balanced between the arms, 63% had elevated baseline PGEM. Most common adverse events included; rash (69%), diarrhea (59%), nausea (59%) and fatigue (57%). Drug-related SAEs included GI bleeding, MI and CVA and were more numerous on the apricoxib arm. The primary study endpoint was not met, HR 0.7; 95% CI (NA, 1.2). Trends in OS favoring the addition of apricoxib were demonstrated in 2 subgroups; elevated baseline PGEM and pts with a ≥ 50% drop from baseline PGEM. Conclusions: This study is the first randomized placebo controlled trial combining chemotherapy with COX-2 inhibition and EGFR kinase inhibition. The apricoxib containing arm had increased GI toxicity including GI hemorrhage. Although the primary endpoint was not met, overall survival in patients with a PGEM response to COX-2 inhibition favored addition of apricoxib. Further study in a biomarker selected population is warranted. [Table: see text]

Retinoids, the natural and synthetic analogs of vitamin A, are growth-inhibiting and differentiation-inducing agents and show clinical promise as chemopreventive and antineoplastic agents. Fenretinide, a new synthetic retinoid, has antitumor activity in certain in vitro and in vivo model systems and was relatively nontoxic in phase I trials. Based on these data, we designed a phase II study of Fenretinide involving 31 patients with advanced breast cancer [15] and melanoma [16], two cancers shown to be responsive to this agent in preclinical models. Fenretinide was inactive in patients with advanced disease. Toxicity was mild, and reversible. Mucocutaneous side effects occurred in 16 (52%) patients. Nyctalopia developed in three patients one of whom developed decreased B-wave amplitude of the scotopic electroretinogram. The minimal toxicity and significant activity in preclinical studies make this an attractive agent for future breast cancer chemoprevention studies.

15058 Background: Imexon for inj. (Amplimexon®, AMP) is an aziridine-containing iminopyrrolidone which causes G2 arrest, accumulation of reactive oxygen species, and induction of apoptosis in pancreatic cancer cells. AMP demonstrated synergy with gemcitabine (GEM) in preclinical pancreatic cancer models. This phase I study of AMP plus GEM was undertaken to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary endpoints were pharmacokinetics for both agents (PK) and tumor response. Methods: Patients (pts) with previously untreated advanced pancreatic adenocarcinoma received one of two dosing regimens. The first 19 received 30 minute AMP IV days 1–5 and 15–19 followed by 30 minute GEM IV days 1, 8 and 15 Q4 wks (Regimen A). Dosing was modified after 19 pts to administer both AMP and GEM over 30 minutes days 1, 8 and 15 every 4 weeks (Regimen B). Dose levels (AMP/GEM, in mg/m2) for Regimen A: 200/800, 280/800, 200/1000, and 280/1000, and for Regimen B: 280/1000, 335/1000, 390/1000, 540/1000, and 750/1000. The current cohort is 1000/1000. Pts were assessed for response after cycles 2, 5 and 8. PK and pharmacodynamic (plasma thiol depletion) measurements were obtained during cycle one. Results: Forty-six pts have been treated to date, with 36 having complete toxicity data and evaluable. Pt characteristics: M/F (24/12), Age (mean 60.4 years, range 43–75), ECOG PS 0/1 (56%, 44%), metastatic/locally advanced (91%, 9%). The 36 pts have completed 122.5 cycles of therapy (median 2, range 0.5–12). Common toxicities: anemia (77%), fatigue (71%), nausea (60%), fever (54%), and leukopenia (54%). DLT were 1/6 at 280/1000 (Regimen A - febrile neutropenia), 1/6 at 280/1000 (Regimen B - gr 3 hypotension, gr 4 renal failure), and 1/9 at 390/1000 (gr 3 hyperbilirubinemia). Accrual continues at 1000/1000. Of 36 pts, 4 have had partial responses and 14 stable disease. PK and plasma thiol analysis are ongoing. Conclusions: Imexon can be administered safely with full dose gemcitabine. Accrual continues to define the combination MTD. The response rate in this phase I study compares favorably with historical gemcitabine monotherapy, and further phase II evaluation of this combination in advanced pancreatic cancer is warranted. No significant financial relationships to disclose.

Background: Pixantrone (P) is a novel aza-anthracenedione that has substantially less delayed cardiotoxicity than either doxorubicin or mitoxantrone in animal models, with greater efficacy than either against murine lymphoma and leukemia in in vivo models. In patients (pts) with relapsed or refractory indolent NHL, P + rituximab (R) delayed the time to tumor progression compared with single agent R (395 vs. 245 days, log rank p-value Methods: Pts received P (day 2) with F (25 mg/m2/day, days 2–4), D (20 mg/day, days 1–5), and R (375 mg/m2/day, day 1) in a 28 day regimen. This was a dose escalation study; once the RD was determined, the next cohort of pts was to be treated at that dose. Results: Three pts were treated with P at 80 mg/m2 and 25 pts at 120 mg/m2, which was the RD determined in the Phase I portion of the study. The median age was 63 (range 32–78); all pts had WHO performance status 0–1. All pts had received at least one prior chemotherapy regimen (median 1, range 1–4). The median number of cycles received was 5 (range 1–8). The overall response rate (response of any duration) was 89% for 27 evaluable pts, with 17 (63%) complete responses (CR), 2 (7%) unconfirmed complete responses (CRu), and 5 (19%) partial responses (PR). Seventy percent of pts experienced a CR/CRu/PR that lasted at least 8 weeks, with a median duration of response of 25 months, (range 2.4 to 43). Grade 3/4 hematologic toxicities were neutropenia 23 (82%), thrombocytopenia 6 (21%), febrile neutropenia 3 (11%), and anemia 1 (4%). Non-hematologic adverse events were primarily grade 1 or 2 in severity. A total of 7 of 28 (25%) pts evaluable for safety had a decline in LVEF ≥ 10% to ≤ 20%. No pt had a decline in LVEF > 20 %. In 4 pts the decline in LVEF was transient and returned toward baseline with continued follow-up. Five of the 7 pts with a decline in LVEF were asymptomatic. Two pts reported transient shortness of breath with spontaneous resolution without treatment. No episodes of CHF were reported. Conclusions: The RD of pixantrone in the FPD-R regimen is 120 mg/m2. The primary toxicity is hematologic; no serious cardiotoxicity was observed. This treatment is highly active and is associated with major, durable responses. The regimen can be given on an outpatient basis and is well tolerated in relapsed and refractory indolent NHL pts.

Background: Fludarabine-mitoxantrone-dexamethasone-rituximab (FND-R) is a combination chemotherapy with significant activity in untreated and relapsed indolent B-cell lymphoma patients (pts). Pixantrone is a novel aza-anthracenedione that has no delayed cardiotoxicity in animal models and has single agent activity in NHL. We conducted an outpatient phase I/II trial, to define the recommended dose (RD) of pixantrone when substituting for mitoxantrone in the FND-R regimen, and the safety and efficacy of this regimen in pts with relapsed or refractory indolent NHL. Methods: Pts received pixantrone with fludarabine (25mg/m2/day, days 1–3), dexamethasone (20mg/day, days 1–5), and rituximab (375mg/m2/day on day 1) in a 28 day regimen (FPD-R). Based on previous single agent clinical studies, the starting dose of pixantrone was defined as 80mg/m². The RD was established to be 120mg/m2 and the protocol was amended to treat patients in the phase II part. Results: 9 pts (6 males) with a median age of 65 years (range 41–78) were included in the dose-finding part of the study. Following the protocol amendment, 23 pts (11 males) of WHO performance status 0–1, median age 61 (range 32–78) have been enrolled in the currently ongoing phase II part. Pathology included SLL/CLL, follicular grade I, follicular grade II, MALT, marginal cell, and other indolent B-cell lymphomas. All pts had received a prior anthracycline-containing regimen (median number 1, range 1–4). The study regimen was well tolerated; median number of courses received was 5 (range 2–8). Grade 4 toxicities were neutropenia in 10 pts, leukopenia in 5 pts, and thrombocytopenia in 1 pt. No clinically significant cardiac events or decreases in LVEF ≥20% were noted. However 4 pts went below 50% LVEF including 1 pt who was below 50% at baseline. Non-hematologic adverse events were primarily grade 1 or 2 in severity. Response rate was 75% for the 20 pts evaluable for response, with 11 (55%) complete remission [7 confirmed (CR), 4 unconfirmed (CRu)], and 4 (20%) partial remission (PR). Two responders went onto bone marrow transplant (BMT): one had a CRu and one a PR. A third patient was pending BMT after CR. At a median follow-up of 345 days, the median duration of response has not been reached, as only two pts have progressed: the first progression occurred at 113 days, and the second pt progressed at 699 days. The remaining pts are still in remission. Conclusions: The RD of pixantrone in the FPD-R regimen is 120mg/m2. The primary toxicity is hematologic. The regimen can be given on an outpatient basis, is associated with major responses, and is very well tolerated in relapsed and refractory indolent NHL pts.

References (/) BAJETTA E, NEGRETTI E, GIANNOTTI B, ET AL: Phase II study of interferon alpha-2a (rIFN alpha-2a) and dacarbazine (DTIC) in meta- static melanoma (MM). Proc ASCO 8:286, (2) KERR R, PIPPEN P, MENNEL R, ET AL: Treat- ment of metastatic malignant melanoma with a combination of interferon alpha-2a (Ifn alpha- 2a; Roferon) and dacarbazine (DTIC). Proc ASCO 8:288, 1989 (3) VOROBIOF D, FALKSON G, VOCES CW: DTIC versus DTIC and recombinant interferon alfa 2b (rIFNa 2b) in the treatment of patients (PTS) with advanced malignant melanoma (MM). Proc ASCO 8:284, 1989 (4) KIRKWOOD JM, ERNSTOFFMS: Potential appli- cations of the interferons in oncology: Lessons drawn from studies of human melanoma. Semin Oncol 13:48-56, 1986 (5) KIRKWOOD JM, ERNSTOFF MS, GIULIANO A, ET AL: Clinical trials of interferon alfa-2B (Intron A, alpha IFN) in melanoma: Review of phase I, II, and III studies. Presented at the Fourteenth International Cancer Congress, Budapest, August 1986 Ocular Toxic Effects of Fenretinide Manuel R. Modiano,* William S. Dalton, Scott M. Lippman, Leonard Joffe, Ann R. Booth, Frank L. Meyskens, Jr. Retinoids, the natural and synthetic analogues of vitamin A, inhibit growth and induce differentiation in many ani- mal and human malignant cell types, and they show clinical promise as chemopre- ventive antineoplastic agents (1-3). Isotretinoin has been the most widely used synthetic retinoid in cancer treat- ment and cancer prevention trials. How- ever, its toxic effects, primarily mucocu- taneous and teratogenic, make it difficult to tolerate, since continued exposure to the retinoid is required to maintain its effect (1,2). We have recently completed a phase II trial of fenretinide in advanced malig- nancies (4). Fenretinide was adminis- tered in doses of 300-400 mg/day to 16 patients with advanced, metastatic, re- fractory breast cancer, 15 with mela- noma, five with Kaposi's sarcoma, and one with mycosis fungoides. Although fenretinide was inactive in advanced dis- Vol. 82, No. 12, June 20, 1990 ease, its toxic effects were mild and reversible. Toxic effects included a 45% elevation over baseline of serum triglyc- erides in 6% of the patients, a 13% elevation of serum cholesterol in 20% of patients, and mild mucocutaneous toxic effects in 52%. In addition, 10% suffered from nycta- lopia (decreased night vision), which resolved when treatment was discontin- ued. One of these patients had reversible electroretinographic changes consisting of a significant decrease in the amplitude for scotopic (dark-adapted, or rod-medi- ated) vision on electroretinogram, which did not occur until after 1 month of treatment. This decrease was observed predominantly in the B-wave for rods on the electroretinogram and developed while the patient was receiving the higher dose of fenretinide (400 mg/day). Amplitude decreases for this patient's right eye were as follows: the pretherapy A-wave amplitude (normal, 150-250 (JLV) was 190 |xV, decreasing to 160 LIV after 2 months of treatment, and the B-wave amplitude (normal, 365-550 (JLV) dropped from 430 to 290 [iM after 2 months of therapy. No changes in the A-wave amplitude were recorded for the left eye, but the B-wave amplitude dropped from 430 to 340 (JLV after 2 months on fenretinide. These changes reversed after fenretinide was discontin- ued. Patients were given fenretinide for 15-300 days (mean, 52). Kaiser-Kupfer et al. (5) have also looked at the effect of fenretinide on the electroretinogram. They reported on electroretinograms for three of five pa- tients with basal cell carcinoma who were receiving fenretinide at a dose of 800 mg/day. In two of these patients, dark-adaptation thresholds were elevated and the electroretinogram shows that am- plitude for rod-mediated vision was de- pressed. Both developed nyctalopia within 3 weeks of treatment. Costa et al. (6) also found reversible nyctalopia in one of 25 patients treated with 300 mg of fenretinide per day over 6 months. These comparisons suggest that the ocular toxic effects of fenretinide may be dose related. The ocular side effects of fenretinide, which resemble those of other synthetic retinoids (7), may be-due to the interference of these agents with vitamin A metabolism. This hypothesis is supported by a recent pharmacokinetic evaluation of patients receiving this treatment (8), which re- vealed that fenretinide caused a reduc- tion in serum retinol levels. References (/) LIPPMAN SM, KESSLER JF, MEYSKENS FL JR: Retinoids as preventive and therapeutic anti- cancer agents (part I). Cancer Treat Rep (2) LIPPMAN SM, KESSLER JF, MEYSKENS FL JR: Retinoids as preventive and therapeutic anti- cancer agents (part II). Cancer Treat Rep (3) LIPPMAN SM, MEYSKENS FL JR: Retinoids for the prevention of cancer. In Nutrition and Cancer Prevention: The Role of Micronutrients (MoonTE, Micozzi E, eds). New York: Mar- cel Dekker, 1987, pp 243-271 (4) MODIANO MR, DALTON WS, LIPPMAN SM, ET AL: Phase II study of fenretinide (N-[A- hydroxyphenyl]retinamide) in advanced breast cancer and melanoma. Invest New Drugs. In press (5) KAISER-KUPFER MI, PECK GL, CARUSO RC, ET AL: Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Opthalmol 104:69-70, 1986 (6) COSTA A, MALONE W, PERLOFF M, ET AL: Tolerability of the synthetic retinoid fen- retinide (HPR). Eur J Cancer Clin Oncol (7) EDWARDS L, ALBERTS DS, LEVINE N: Clinical toxicity of low-dose isotretinoin. Cancer Treat Rep 70:663-664, 1986 (8) PENG Y-M, DALTON WS, ALBERTS DS, ET AL: Pharmacokinetics of /V-4-hydroxyphenyl-reti- namide and the effect of its oral administration on plasma retinol concentrations in cancer pa- tients [published erratum appears in Int J Can- cer 44:567, 1989]. Int J Cancer 43:22-26, Received April 16, 1990; accepted April 17, M. R. Modiano, W. S. Dalton, L. Joffe, A. R. Booth, University of Arizona, Arizona Cancer Center, Tucson, AZ. S. M. Lippman, The University of Texas M. D. Anderson Cancer Center, Houston, TX. F. L. Meyskens, Jr., University of California, Irvine Clinical Cancer Center, Irvine, CA. *Correspondence to: Manuel R. Modiano, M.D., Department of Cancer Prevention and Con- trol, Arizona Cancer Center, 1515 N. Campbell Ave., Rm. 1995, Tucson, AZ 85724. BRIEF COMMUNICATIONS