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Grade 3 or 4 adverse events possibly related to refametinib or sorafenib, occurring in {greater than or equal to}2 patients in either cohort

Overview of dose-limiting toxicities and adverse events leading to discontinuation and relationship to study treatment

Refametinib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

Incidence of treatment-emergent adverse events, all grades, occurring in {greater than or equal to}20% of patients in either cohort

CTC enumeration and pERK analysis in course 1

pERK levels in hair follicles by dose level and course

Refametinib geometric mean (% coefficient of variation) single-dose pharmacokinetic data on day 1 of course 1

Sorafenib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

PURPOSE: Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma. METHODS: A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with intravenous infusions of PG-11047 on days 1, 8, and 15 of a 28-day cycle. PG-11047 dose escalation ranged from 50 mg to 590 mg. RESULTS: The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size. CONCLUSIONS: Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

BackgroundCytotoxic therapy for relapsed and refractory germ cell tumors or metastatic sex cord stromal tumors is rarely effective and is often accompanied by high adverse event rates. Expression of CD30 has been observed in testicular cancers, and patients with CD30-expressing embryonal carcinomas have worse progression-free survival and overall survival than those with CD30-negative tumors. The objective of this study (NCT01461538) was to characterize the antitumor activity of brentuximab vedotin in patients with CD30-expressing nonlymphomatous malignancies. Enrolled patients included seven patients with relapsed or refractory germ cell tumors or metastatic sex cord stromal tumors described in this case series.Materials and MethodsForty patients with relapsed or refractory germ cell tumors, metastatic sex cord stromal tumors, or testicular tumors were screened for CD30 expression; 14 patients had tumors that expressed CD30. Seven patients with CD30-expressing testicular cancer were enrolled in the treatment study: five patients with germ cell tumors, one patient with a Leydig cell tumor, and one patient with a Sertoli cell tumor. Patients were treated with brentuximab vedotin at initial doses of 1.8 or 2.4 mg/kg every 3 weeks. Response assessments were performed at cycles 2 and 4 and every 4 cycles thereafter while the patient was receiving treatment.ResultsTwo of seven patients achieved an objective response, including one durable complete response and one partial response at a single time point. Both responding patients had germ cell tumors. Treatment with brentuximab vedotin was generally well tolerated.ConclusionTreatment of relapsed or refractory germ cell tumors with brentuximab vedotin can induce durable responses with a manageable toxicity profile.Implications for PracticeThis case series of seven patients with relapsed or refractory CD30-expressing germ cell tumors (GCTs) or sex cord stromal tumors demonstrates that brentuximab vedotin has activity against GCTs and is well tolerated in heavily pretreated patients with these aggressive tumor types. One patient achieved a complete response that has been durable for almost 4 years since the discontinuation of treatment with brentuximab vedotin. Therefore, brentuximab vedotin may be a valuable option for physicians who care for this difficult-to-treat patient population.

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]

Purpose Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell lung cancer (SCLC). Patients and Methods Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m2/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF). Results Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m2. Conclusion Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m2 per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, ≤ 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www.clinicaltrials.gov as #NCT00142116.

Background: Gemcitabine (G) has shown activity in mantle cell lymphoma (MCL) as a single agent. The combination of mitoxantrone (M) and rituximab (R) is also active in MCL. The primary objective of this study was to determine the efficacy of G+M+R in relapsed or refractory MCL. Patients and Methods: Sixteen patients were enrolled between April 2005 and January 2007, 88% had Stage IV MCL, Median patient age was 74 years. Patients received gemcitabine 900 mg/m2 IV (30–60 min infusion) on Days 1 and 8, mitoxantrone 10 mg/m2 IV (5–10 min infusion) on day 1, and rituximab 375 mg/m2 IV on Day 1 (max 400 mg/hour) of the 21-day cycle. Patients received a median of 6 cycles (range, 1–8). Results: Best responses were CR 20% (95%CI, 0, 40.2), PR 27% (95%CI, 4.3, 49.1), SD 40% (95%CI, 15.2, 64.8), and PD 13% (95%CI, 0, 30.5). Median survival and PFS have not been reached with a median follow-up of 10.7 months. The most common Grade 3–4 toxicities were neutropenia (100%), thrombocytopenia (67%), leukopenia (53%), and anemia (33%). The study was closed early due to slow accrual owing to an alternative treatment which became available at the time. Conclusion: The combination of G+M+R in MCL was well-tolerated with manageable toxicity using growth factors to minimize neutropenia; further studies are warranted.

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. Conclusions: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368–76. ©2015 AACR.

Background This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. Methods Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300–400 μg/mL) every 28 days plus 1,000 mg/m2 gemcitabine HCl (days 1 and 15), 60 mg/m2 docetaxel, 200 mg/m2/day temozolomide, 75 mg/m2 cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*μg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*μg/mL for gemcitabine and erlotinib). Results A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. Conclusions The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.

Summary Background Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. Methods In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m 2 ) or docetaxel (75 mg/m 2 ) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m 2 at first dose and 250 mg/m 2 weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. Findings Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7–3·2) versus 2·8 months (2·5–3·3) with pemetrexed (HR 1·03, 95% CI 0·87–1·21; p=0·76). The most common grade 3–4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. Interpretation The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. Funding Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.

4069 Background: BBI608, a first-in-class CSC inhibitor that works through inhibiting Stat3, has shown potent synergistic anti-tumor and anti-metastatic activity with paclitaxel in vivo. In a phase...

327 Background: Brentuximab Vedotin (BV) is a novel antibody drug conjugate that combines the agent mono-methyl auristatin E (MMAE) to a CD-30 specific monoclonal antibody by a protease-cleavable linker. It is approved by the FDA for treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). In addition to HL and ALCL, CD-30 expression has been reported on malignant tumors of non-lymphoid origin including testicular embryonal carcinoma (EC). Here we report our initial experience in three heavily pre-treated patients with CD30-positive EC who were treated as part of an ongoing phase 2 open-label multicenter study designed to evaluate the antitumor activity of BV in patients with CD30-positive non-lymphomatous malignancies. Methods: Three men with relapsed or refractory, histologically confirmed CD-30 positive testicular cancer received BV until progression or toxicity. CD-30 expression was assessed by immunohistochemistry. All 3 patients were dosed at 1.8 mg/kg IV every 21 days and followed for response at cycles 2, 4. Results: Three patients were enrolled at 2 sites in the US. Median age was 26 years (range 24-33). All 3 patients progressed after high dose chemotherapy with peripheral blood stem cell transplant. Two patients received BV as 4th line and 1 patient as 3rd line therapy. Tumor sites included lungs, liver, retroperitoneal, mediastinal and supraclavicular lymph nodes. The first patient baseline hCG was 5571. After 2 cycles of therapy, hCG nadir was 45 with a radiologic partial response (PR) by RESICT that lasted 2 months. He then had serologic and radiographic progression in the liver while on therapy. Patient 2 was serologic marker negative and had a radiographic PR by RECIST in lung and mediastinum after cycle 2 and continues on therapy. Patient 3 had a baseline hCG of 10400, with nadir at 110 after 2 doses and continues to have serologic response. By RECIST he currently has stable disease. The treatment was well tolerated in all 3 patients with no grade 3-4 toxicities. Conclusions: All 3 patients with heavily pretreated CD-30 positive EC had clinical benefit after treatment with brentuximab vedotin. The treatment was well tolerated. The enrollment is ongoing in this Phase 2 study. Clinical trial information: NCT01461538.

Abstract 3800 Introduction: Treatment of anemia in pts with myelodysplastic syndromes (MDS) may require packed red blood cell transfusion. Transfusion dependence in MDS is associated with poorer clinical outcomes and reduced overall survival (OS). This US registry prospectively collected data on clinical outcomes in chelated and non-chelated, transfused, lower-risk MDS pts. OS, leukemic transformation, and clinical events are reported for non-chelated and chelated pts at 36 mos on study. Methods: This 5-year, non-interventional registry enrolled 600 pts from 107 US centers. Pts were ≥18 years old with lower-risk MDS (WHO, FAB, and/or IPSS) and transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ≥6 units every 12 weeks). The chelated group included all pts who had ever used iron chelation; sub-analysis was performed on pts with ≥6 mos chelation. Assessments were every 6 mos for 5 years or until death and included demographics, survival, disease status, comorbidities, causes of death, and MDS therapy. Results: Baseline demographics and IPSS risk status were similar between groups, although transfusion burden trended higher in chelated pts (Table 1). As of April 30, 2012, 169 pts continued on registry, and 431 discontinued (345 died, 57.5%; 61 lost to follow-up, 10.2%; and 25 other, 4.2%). In all, 264 (44%) pts received chelation therapy; 200 had ≥6 mos chelation. OS and time to acute myeloid leukemia (AML) transformation were significantly longer, and percentage of deaths was significantly lower in chelated ≥6 mos vs. non-chelated pts (P Conclusions: At 36 mos, chelated pts had significantly longer OS and time to AML transformation, as well as significantly fewer deaths. Trends toward fewer AML transformations and cardiac disorders were observed in chelated pts. Baseline characteristics and IPSS risk status were similar between groups, with the exception of more prevalent cardiac and vascular comorbidities in non-chelated pts. Additional assessments over the 5-year duration of this registry will provide further information on the association between chelation and clinical outcomes. Disclosures: Lyons: Novartis: Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Telik: Research Funding. Paley:Novartis: Employment. Esposito:Novartis: Employment. Garcia-Manero:Novartis: Research Funding.

Abstract 2800 Introduction: Many patients with MDS require regular transfusions. Several reviews have documented poorer clinical outcomes and overall survival (OS) in transfusion-dependent MDS patients. A US registry of 600 lower-risk MDS patients prospectively collected data on clinical outcomes in chelated and non-chelated transfused patients. This 24-month interim analysis reports on cardiac events, leukemic transformation and OS. Methods: This is a 5-year, non-interventional registry in MDS patients (aged ≥18 years) with lower-risk MDS (based on WHO, FAB and/or IPSS criteria) from 107 US centers. Patients had to have transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ongoing transfusion requirement of ≥6 units every 12 weeks). Follow-up was every 6 months for up to 60 months or death. Use of chelation therapy was not required. Chelated patients were those who had ever used iron chelation; a sub-analysis was done on patients with ≥6 months chelation. Assessments included demographics, disease status, MDS therapy, comorbidities, and causes of death. Differences between non-chelated and chelated patients are reported. Results: 600 patients enrolled; as of May 26, 2011, 249 continued in the registry. 351 patients discontinued due to: lost to follow-up (n=51, 8.5%); death (n=278, 46.3%); other (n=22, 3.7%). 263/600 patients received chelation therapy, of whom 191 received ≥6 months. Leukemic transformation and cardiac events were more common in non-chelated patients (Table 2). Time to leukemic transformation was significantly shorter in non-chelated versus chelated patients. A greater percentage of deaths occurred in non-chelated patients; time to death was significantly shorter in non-chelated versus chelated patients. The most frequent reasons for death were MDS/AML, cardiac, and infection. At baseline, non-chelated patients had a higher incidence of cardiac disorders than chelated patients (51.3% vs 35%). While on the registry, non-chelated patients had a higher incidence of comorbidities than did chelated patients, predominantly vascular, cardiac and endocrine. Lifetime use of MDS therapies (pre- and on-registry) was lower among non-chelated versus chelated patients (88.4% vs 94.3%). Conclusions: At the 24-month analysis, use of chelation was associated with lower AML transformation, fewer cardiac events, and better OS. The two patients groups had similar age, gender, and risk status breakdown (IPSS); however the non-chelated group had a higher prevalence of cardiac comorbidities. Ongoing follow-up for the 5-year duration of this registry will provide further data on differences in outcomes between chelated and non-chelated patients. Disclosures: Lyons: Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Sharma:Novartis: Employment. Paley:Novartis: Employment. Esposito:Novartis: Employment.

4035 Background: C, a death receptor 5 agonist, and A, an insulin-like growth factor receptor 1 antagonist, are investigational, fully human monoclonal antibodies with preclinical activity in PC mo...

4501 Background: AMG 655 is an investigational, fully human agonist monoclonal antibody (IgG1) that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. In preclinical PC models, cooperative activity is observed when G is added to AMG 655. We performed a multi-center phase I trial to evaluate AMG 655 + G in metastatic PC pts. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included toxicity, pharmacokinetics, antibody formation, objective response rate, progression-free survival (PFS), 6-month and overall survival. Methods: Eligible pts had previously untreated metastatic PC and ECOG PS 0 or 1. Pts enrolled into sequential cohorts and received AMG 655 3 or 10 mg/kg IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. CT scans were obtained Q8 weeks. Results: 13 pts (3 mg/kg cohort = 6; 10 mg/kg cohort = 7) enrolled from 7/07–11/07. Pt characteristics: females 61%; ECOG PS 1 69%; median age 65 (range 35–81); liver metastases 77%. Median number of cycles: 6 (range 2–12). There were no DLT. Nine (69%) pts had grade 3–4 toxicity, the most common were: thrombocytopenia (4 pts), neutropenia (2 pts), and abdominal pain (2 pts). No anti-AMG 655 antibodies were detected. After one 3 or 10 mg/kg dose of AMG 655 after G, the Cmax and AUC of AMG 655 were similar to those in the first- in-human single-agent study (LoRusso JCO 2007; 25: abstract 3534). Preliminary data indicate no effect of AMG 655 on PK of G. Partial response 31% (4 pts, 2 unconfirmed); stable disease 38%. Median PFS: 5.3 months (95% CI, 3.5, 6.2); 6-month survival rate: 76.2% (95% CI: 42.7%-91.7%). Conclusions: AMG 655 + G is well-tolerated and may have activity in metastatic pancreatic cancer. A randomized phase II trial of G ± AMG 655 at 10-mg/kg is currently enrolling. [Table: see text]

8103 Background: Amrubicin (AMR), a third-generation synthetic anthracycline and potent topoisomerase II inhibitor, is approved in Japan for the treatment of lung cancer. Patients (pts) with SCLC, who are refractory to first-line chemotherapy or progress within 3 months (mos) of treatment completion, are less likely to respond to additional chemotherapy and have an expected median survival of 3–5 mos. Here, we investigate the efficacy and safety of single-agent AMR in the treatment of Western pts with refractory ED-SCLC. Methods: In this phase II trial, pts with ED-SCLC refractory to prior 1st-line platinum-based chemotherapy (defined as progression (PD) while on therapy or relapse within 90 days of treatment completion) and ECOG performance status (PS) ≤2 were eligible. Patients were treated with intravenous AMR 40 mg/m2/day x 3 days every 21 days until PD or intolerable toxicity. The primary endpoint was response rate (ORR, by RECIST), with a goal to demonstrate an ORR ≥18% (point estimate). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: In all, 75 pts were enrolled with a median age of 63 years (range 43–88), 52% female, 17% PS 2. Response to 1st-line therapy was 5% complete remission (CR), 36% partial remission (PR) and 28% PD. Median time from completion of 1st-line therapy to PD was 1.3 mos. Sixty-nine pts received AMR for a median of 4 cycles (range 1–12). Six pts died or discontinued before receiving treatment. The primary endpoint was met with an ORR of 21% (16/75, 95% confidence interval [CI] 13.6% - 31.9%), including CR in 1 pt (1%) and PR in 15 pts (20%). Stable disease was achieved in 40% of pts. Two pts with PD as best response to 1st line chemotherapy achieved a PR. Median OS was 6.0 mos (95% CI 4.8–7.1 mos). Median PFS was 3.2 mos (95% CI 2.4–4.0 mos). The most common grade 3 or 4 adverse events were neutropenia (65%), thrombocytopenia (39%), and leukopenia (35%). Seven (10%) patients experienced febrile neutropenia. Dose reductions were required in 26 patients (38%). Conclusions: AMR shows promising activity, with an ORR of 21%, and an acceptable safety profile in patients with refractory ED-SCLC, and warrants further study in these pts. [Table: see text]

14529 Background: Malignant transformation and invasive capacity is highly correlated with the expression on tumor cells of N-cadherin (N- cad), a cell signaling and adhesion molecule. ADH-1, a cyc...

5172 Background: Vidaza (azacitidine, Pharmion Corp), a demethylating agent that activates genes repressed by promoter methylation, may induce responses in malignancies. Preclinically, demethylatin...

Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin’s lymphoma that usually presents as disseminated disease. Prognosis is poor, and responses to chemotherapy are less durable than those achieved in other types of lymphoma. New treatment options are desperately needed. Gemcitabine has shown activity in MCL as a single agent. In addition, the combination of mitoxantrone and rituximab has also been shown to be active in MCL. However, the use of these drugs in combination has not been evaluated in the treatment of MCL. The primary objective of this study was to determine the efficacy of gemcitabine+mitoxantrone+rituximab in relapsed or refractory MCL; secondary objectives were duration of response, survival at 1-year, progression-free survival (PFS), and toxicity, especially myelotoxicity. Sixteen patients were enrolled between April 2005 and December 2006, and only 15 were evaluable due to one patient’s withdrawal of consent. Patients received gemcitabine 900 mg/m2 IV (30–60 min infusion), mitoxantrone 10 mg/m2 IV (5–10 min infusion), and rituximab 375 mg/m2 IV on Day 1 (max 400 mg/hr). Patients also received gemcitabine 900 mg/m2 on Day 8 of the 21-day cycle. Medication was administered in the following order: gemcitabine→mitoxantrone→rituximab. Patients were to be treated for a maximum of 8 cycles or until the patient had evidence of a response, progressive disease, or intolerable toxicity. The median patient age was 74 years, 100% were white, and 69% were male. Of all patients, 86% had Stage IV MCL at baseline. Patients received a median of 6 cycles (range, 3 – 8). Efficacy results for the evaluable population are CR 13%, PR 27%, PD 13%, and SD 47%. Median PFS was 8.72 months (range, 1.84 – 23.49); median overall survival was 10.03 months (range, 2.50 – 23.49). Grade 3–4 treatment related toxicities reported in >1 patient were neutropenia (93%), leukopenia or thrombocytopenia (53% each), anemia (20%), and asthenia (13%). 60% of patients are currently alive as of July 2007; 9 patients discontinued study treatment due to disease progression (13%), toxicity (27%), MD request (7%), or withdrawal of consent (13%). 7 patients had normal study completion (44%). The study was closed early due to slow accrual owing to alternative treatment which became available at the time. The combination of gemcitabine, mitoxantrone, and rituximab in MCL was well-tolerated with manageable adverse events in spite of 93% neutropenia. Supplemented growth factor use was able to minimize neutropenia. No Grade 3–4 infection was reported. This regimen holds promise in patients with MCL and further studies are warranted. Updated data will be presented.