Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were developed, tested, and approved in record time. As patients with cancer were excluded from vaccine trials, some patients may be hesitant,1Barriere J. Gal J. Hoch B. et al.Acceptance of SARS-CoV-2 vaccination among French patients with cancer: a cross-sectional survey.Ann Oncol. 2021; 32: 673-674Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar given unanswered questions around safety and adverse reactions, especially those undergoing treatment. One study conducted among 134 patients receiving immune checkpoint inhibitors (ICIs) reported an 81% BNT162b2 vaccine uptake rate with similar rates of acute adverse reactions as reported among healthy individuals, except for higher frequency of myalgias among patients with cancer.2Waissengrin B. Agbarya A. Safadi E. et al.Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors.Lancet Oncol. 2021; 22: 581-583Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Further research is needed by tumor type and treatment to better inform clinicians and patients during the vaccine decision-making process. We report data on uptake and perspectives on SARS-CoV-2 vaccination and postvaccination adverse reactions in 208 recently diagnosed patients with cancer (median age 63 years, 52.4% women, 33.2% non-White minorities, Table 1) at a large healthcare system in Los Angeles spanning the timeline from limited vaccine availability to broader dissemination (November 2020 to July 2021). Vaccine hesitancy and perspectives were measured using a modified version of the World Health Organization Vaccine Hesitancy Scale (Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.10.005).3Domek G.J. O'Leary S.T. Bull S. et al.Measuring vaccine hesitancy: field testing the WHO SAGE Working Group on Vaccine Hesitancy survey tool in Guatemala.Vaccine. 2018; 36: 5273-5281Crossref PubMed Scopus (91) Google Scholar A self-administered symptoms questionnaire was given to vaccinated recipients after dose 1 (D1) and D2 for messenger RNA (mRNA) SARS-CoV-2 vaccines. Electronic medical records provided correlative clinical information. Chi-square tests were used to assess differences for categorical variables and a Wilcoxon rank-sum test for continuous variables (Stata v. 15.1). All tests were two-sided and considered statistically significant at P < 0.05.Table 1Demographic and clinical characteristics of patients by vaccination statusCharacteristicsaAll values are frequencies and column percentages unless otherwise specified. Missing categories do not contribute to P value estimates.Total (n = 208)Unvaccinated (n = 59)Vaccinated (n = 149)P valueAge in years, median (IQR)63 (54-72)60 (51-69)66 (56-72)0.02Sex0.37 Male99 (47.6)31 (52.5)68 (45.6) Female109 (52.4)28 (47.5)81 (54.4)Race/ethnicity0.39 White135 (64.9)36 (61.0)99 (66.4) Black/African American12 (5.8)1 (1.7)11 (7.4) Asian19 (9.1)6 (10.2)13 (8.7) Hispanic/Latinx31 (14.9)12 (20.3)19 (12.8) Other/mixed7 (3.4)2 (3.4)5 (3.4) Declined to state4 (1.9)2 (3.4)2 (1.3)Education0.03 High-school diploma/GED or less21 (10.1)5 (8.5)16 (10.7) Some college/2-year degree/4-year college85 (40.9)32 (54.2)53 (35.6) School beyond college/graduate/professional degree81 (38.9)16 (27.1)65 (43.6) Missing21 (10.1)6 (10.2)15 (10.1)Current employment status0.003 Employed64 (30.8)18 (30.5)46 (30.9) Retired68 (32.7)10 (16.9)58 (38.9) Unable to work: disability/caregiver33 (15.9)16 (27.1)17 (11.4) Unemployed17 (8.2)8 (13.6)9 (6.0) Not sure/decline to state6 (2.9)1 (1.7)5 (3.4) Missing20 (9.6)6 (10.2)14 (9.4)Income last year before taxes0.91 Less than $25 00021 (10.1)7 (11.9)14 (9.4) $25 000-$49 99918 (8.7)6 (10.2)12 (8.1) $50 000-$74 99922 (10.6)5 (8.5)17 (11.4) $75 000 or more68 (32.7)18 (30.5)50 (33.6) Not sure/decline to state51 (24.5)15 (25.4)36 (24.2) Missing28 (13.5)8 (13.6)20 (13.4)ECOG score0.15 0: fully active94 (45.2)22 (37.3)72 (48.3) 1: restricted in physically strenuous activity but ambulatory100 (48.1)35 (59.3)65 (43.6) 2: ambulatory but unable to carry out work activities8 (3.8)2 (3.4)6 (4.0) Unknown/not available5 (2.4)0 (0.0)5 (3.4) Missing1 (0.5)0 (0.0)1 (0.7)ECOG, Eastern Cooperative Oncology Group; GED, general equivalency diploma; IQR, interquartile range.a All values are frequencies and column percentages unless otherwise specified. Missing categories do not contribute to P value estimates. Open table in a new tab ECOG, Eastern Cooperative Oncology Group; GED, general equivalency diploma; IQR, interquartile range. Overall, 128 individuals had solid tumors and 80 hematological malignancies [median time since diagnosis 2.5 (interquartile range 1.0-5.5) years]. The majority of patients (n = 156, 75%) were within 6 months of diagnosis and receiving one or more treatments [ICI: n = 77 (37.0%); chemotherapy (CT): n = 48 (23.1%); B-cell targeted therapies (BCT): n = 64 (30.8%); aromatase inhibitor/hormone therapy: n = 38 (18.3%); allogeneic hematopoietic stem cell transplant: n = 16 (7.7%)]. Approximately 6% (n = 13) of participants had a prior SARS-CoV-2 infection. Overall, 7.3% reported intention to delay or abstain from vaccination (hematologic malignancy: 7.4% versus solid tumor: 7.3%, P value = 0.99). Among unvaccinated patients, women were more hesitant than men (35.7% versus 12.9%, P = 0.06). The most common concerns among hesitant patients were fear of adverse reactions (n = 8, 57.1%), rushed vaccine development (n = 6, 42.9%), and insufficient knowledge (n = 9, 64.3%). Eighty-three participants (39.9%) received Pfizer-BioNTech-BNT162b2, 66 (31.7%) received Moderna-mRNA-1273, and 59 were unvaccinated (28.4%) at the time of the survey. Older (P = 0.02), highly educated (P = 0.03), and retired (P = 0.003) individuals were more likely to be vaccinated (Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.10.005). Adverse reactions were common (D1: 27.6% and D2: 53.5%). There were no significant differences in adverse reactions by age, mRNA vaccine type, or prior SARS-CoV-2 infection. We found that the Eastern Cooperative Oncology Group (ECOG) score was not associated with adverse reactions after D1 (P = 0.72), but being fully active was associated with a greater number of reported adverse reactions after D2 (P = 0.005). Women experienced more pain compared with men (D2: 66.7% versus 37.3%; P = 0.002), including pain (P = 0.02) and fatigue/malaise (P = 0.003; Figure 1). Patients with solid tumors also reported more symptoms compared with those with hematologic malignancies (D2: 62.3% versus 35.1%; P = 0.006); more specifically, symptoms were less frequent among those receiving BCTs compared with those not on BCTs (D2: 35.5% versus 60.2%; P = 0.02). Fevers were more common among patients receiving ICIs compared with those not on ICIs (D2: 34.1% versus 11.4%, P = 0.003). Women on hormone therapy frequently reported muscle/bone/joint or nerve symptoms (D2: 11.5% versus 2.0%; P = 0.025). Patients on CT reported muscle/bone/joint/nerve (D1: 15.2% versus 0%; P < 0.001) and cough/chest or breathing symptoms (D2: 10.7% versus 1.2%; P = 0.02). Our study shows that postvaccination adverse events varied by tumor type and treatment. The report of adverse events in this study may be subject to recall bias and the potential influence of the media. Previous studies have suggested that patients receiving combined ICI therapy (anti-PD-1, anti-PD-L1, anti-CTLA-4) should be closely monitored for increased immune-related adverse reactions during vaccine administration.4Luo B. Li J. Hou X. et al.Indications for and contraindications of immune checkpoint inhibitors in cancer patients with coronavirus disease 2019 vaccination.Future Oncol. 2021; 17: 3477-3484Crossref PubMed Scopus (17) Google Scholar,5Maio M. Hamid O. Larkin J. et al.Immune checkpoint inhibitors for cancer therapy in the COVID-19 era.Clin Cancer Res. 2020; 26: 4201-4205Crossref PubMed Scopus (30) Google Scholar Addressing specific vaccine concerns among patients with cancer early may ensure high compliance, in particular among women. The findings discussed here may be generalizable to patients with cancer in other metropolitan, multiethnic populations. Future research is needed on patient and provider concerns regarding immunogenicity of SARS-CoV-2 vaccines among patients on various cancer therapies, especially as booster vaccinations are now recommended for individuals with underlying medical conditions including cancer. We sincerely appreciate all SeroNet-CORALE participants and each member of the study (www.corale-study.org) and biospecimen management group. We are also grateful to all the front-line health care workers in our health care system who continue to be dedicated to delivering the highest quality care for all patients. This work was supported by the National Cancer Institute at the National Institutes of Health [grant number U54CA260591].

Background CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. Methods Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m2 IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. Results 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. Conclusions While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

ABSTRACT Background VEGF-mediated angiogenesis contributes to NSCLC pathogenesis. RAM is a recombinant human mAb that binds the extracellular domain of the vascular endothelial growth factor receptor-2 (VEGFR-2) and inhibits cancer growth in diverse preclinical models. Methods Pts with advanced NSCLC (Stage IIIb not suitable for locoregional therapy or Stage IV) were eligible. Squamous histology and treated brain metastases were allowed. Exclusion criteria included prior bevacizumab, blood vessel invasion, intratumor cavitation, and recent gross hemoptysis. Pts received RAM 10 mg/kg, paclitaxel 200 mg/m2, and carboplatin AUC = 6 on Day 1 of a 3-week cycle for up to 6 cycles, followed by maintenance RAM. The primary endpoint was PFS at 6 months (m); secondary/exploratory endpoints were safety, ORR, OS rate at 1 year, PK/PD profiles, and immunogenicity. Results 40 pts were treated (15M:25F; median age 60; 39 nonsquamous / 1 squamous); all have discontinued. 39 pts were evaluable for response. 22 of 40 treated pts had an objective response (1 CR, 21 PR; ORR = 55%). 14 pts had a best response of SD. Median PFS was 7.85 m (95% CI: 5.49 m-9.86 m), and the PFS rate at 6 m was 62.5% (90% CI: 48.3%-75.3%); the 1-year survival rate was 74.6% (95% CI: 57.9%-85.4%). 34 of 40 pts (85%) reported an AE at least possibly related to RAM; the most common related AEs were fatigue (53%), peripheral neuropathy (33%), nausea (28%), myalgia (23%), and epistaxis (23%). Related AEs of Gr ≥ 3 were reported for 15 pts; the most common were neutropenia (5 pts), thrombocytopenia (4 pts), fatigue, febrile neutropenia (3 pts each), peripheral neuropathy and pulmonary embolism (2 pts each). There were 5 pts with a total of 6 Gr 4 related events: febrile neutropenia, pulmonary embolism (2 pts each), neutropenia and thrombocytopenia (1 pt each). Conclusions RAM in combination with paclitaxel and carboplatin shows promising efficacy based on the overall disease control rate (CR + PR + SD) reaching 90% and PFS rate at 6 m of 62.5%, and is well tolerated by patients with NSCLC. Disclosure D.R. Camidge: I have received research funding from Eli Lilly and Company and honoraria from ImClone Systems. R.C. Doebele: Research Funding: ImClone Systems, Eli Lilly & Co., Pfizer Inc. Honoraria: Boehringer Ingelheim, Abbott Laboratories, Pfizer Inc Stock: Ariad ( M. Ballas: I now have an employment position at Bristol Myers Squibb (BMS), own T. Jahan: I have received additional research funding from Eli Lilly & Co. for other trials, as well as research funding from Morphotek, Pfizer, and Genentech. I have no speaker or consultant income to disclose. S. Yurasov: Employed by ImClone/Eli Lilly; own Lilly stock. All other authors have declared no conflicts of interest.

➢ The Phase 1 portion of the study was successfully completed; the recommended phase 2 dose (RP2D) was defined as lorvotuzumab mertansine 112 mg/m2 IV on Days 1 and 8 in combination with carboplatin AUC 5 IV on Day 1 and etoposide 100 mg/m2 IV on Days 1-3, every 21 days.➢ The combination was well tolerated with the number of patients requiring dose reductions in line with historic data6. The overall safety profile was consistent with single agent lorvotuzumab mertansine and with the standard of care regimen ie grade 1/2 peripheral neuropathy was the most common related adverse event and myelosuppressive events were the most common related grade 3 and 4 events.➢ There was no observed effect on PK parameters when LM was administered in combination with carboplatin and etoposide at RP2D.

ABSTRACT Purpose SCLC expresses CD56 almost universally. LM is a CD56-targeting antibody-drug conjugate. This study was initiated to evaluate LM for the treatment of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase 1 portion was designed to establish the recommended phase 2 dose (RP2D) of LM with C and E. PK data with the combination also was obtained. Methods Patients (pts) with advanced solid tumors were accrued to a standard 3 + 3 dose-escalation study design. Successive cohorts received escalating doses of LM IV on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21 days. LM PK was measured by an ELISA-based method. C and E levels were measured using optimized LC-MS/MS assays. PK parameters were determined by noncompartmental analysis. Results 33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C AUC6; 3 using C AUC5) at LM doses ranging from 60-112 mg/m2. The RP2D was defined as LM 112 mg/m2 with C AUC5 and E 100 mg/m2. PK samples were analyzed for Cycle 1, first dose. At the RP2D, LM exposure and maximum concentration were similar to those observed in single-agent trials, with the t1/2 of LM approaching 1 day (24.2 hours). PK findings for C/E were similar to published reports (Oguri, 1988; D'Incalci, 1982) with the observed AUC of C = 5.1 ± 0.7 min*mg/mL and E = 6921 ± 1231 min*µg/mL. The most common treatment-related adverse events (AEs) were anemia, thrombocytopenia, nausea, peripheral neuropathy, decreased lymphocytes and neutrophils, and fatigue. The majority of related grade 3/4 AEs were cytopenias which, while known to occur with C/E regimens, typically have not been associated with LM monotherapy. Among 13 pts with SCLC accrued to phase 1, 6 (46%; 4 previously treated) achieved PR after at least one response assessment. Conclusion The combination is well tolerated with no apparent drug-drug interactions. Preliminary signs of activity have been observed in this predominantly pre-treated population. The randomized phase 2 portion of the study in chemo-naive patients with SCLC has opened to accrual. Updated data will be presented. Disclosure R. Guild: Employee of ImmunoGen, Inc. R. Mastico: Employee of ImmunoGen, Inc. All other authors have declared no conflicts of interest.

PurposeSCLC expresses CD56 almost universally. LM is a CD56-targeting antibody-drug conjugate. This study was initiated to evaluate LM for the treatment of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase 1 portion was designed to establish the recommended phase 2 dose (RP2D) of LM with C and E. PK data with the combination also was obtained.MethodsPatients (pts) with advanced solid tumors were accrued to a standard 3 + 3 dose-escalation study design. Successive cohorts received escalating doses of LM IV on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21 days. LM PK was measured by an ELISA-based method. C and E levels were measured using optimized LC-MS/MS assays. PK parameters were determined by noncompartmental analysis.Results33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C AUC6; 3 …

265 Background: Gemcitabine (G) is the standard treatment for first- line PanC. PanC is one of the most hypoxic solid tumors. TH-302 is an inert prodrug of brominated isophosphoramide mustard and undergoes selective activation in deep hypoxia. As a single agent, tumor responses were reported in patients (pts) with metastatic melanoma, SCLC, and head/neck cancer at TH-302 weekly doses of 480-575 mg/m2. METHODS Eligible pts for the PanC expansion of this phase I/II study ( NCT00743379 ) had ECOG <1, locally advanced or metastatic PanC previously untreated with systemic chemotherapy other than adjuvant G, 5FU, and/or radiation. IV TH-302 was dosed at 240-575 mg/m2 (240 or 340 in expansion) with standard dose G (1000 mg/m2) on days 1, 8 and 15 of a 28-day cycle. Serum protein and microRNA hypoxia biomarkers were analyzed at baseline, start of cycle 3 and end of study. RESULTS 46 PanC subjects (12 locally advanced, 34 distant mets); median age: 63 (range 41-83); 24 male; ECOG 0/1 in 29/17 pts; RECIST response rate (RR) of 21%, median PFS of 6.1 mo (95%CI 4.8, 7.7) and median survival of 11.4 mo (95%CI 6.0, not reached) were observed. RR was 23% with median survival of 7.4 mo in pts with distant mets. 52% of pts had a >50% decrease in CA19-9. Common adverse events were skin or mucosal toxicity, nausea, fatigue and vomiting; most grade 1/2. Grade 3/4 neutropenia, thrombocytopenia and anemia in 68%, 64%, and 20% of pts respectively. The dose intensities at 240 mg/m2 and 340 mg/m2 were similar and related to hematologic toxicities. Skin toxicities were less common at 240 mg/m2. A TH-302 dose response was present with higher RR and PFS at 340 mg/m2. Initial serum hypoxia biomarkers did not identify a preferential pt population. CONCLUSIONS The activity and clinical benefits of the combination of TH-302 with G in first line PanC are promising as compared to previous studies of G alone. TH-302 adds to the hematologic toxicity of G, but the regimen is well tolerated. The safety and activity provided rationale for comparing TH-302 plus G versus G alone in a randomized phase II trial ( NCT01144455 ) and indicate TH-302 may complement G by penetrating into the hypoxic regions of the PanC tumors where activation induces cytotoxicity. No significant financial relationships to disclose.

2609 Background: Liposomal (LIPO) docetaxel (DOCE) formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic DOCE exposure. ATI-1123 is a novel LIPO DOCE formulation utilizing human serum albumin that facilitates LIPO tumor targeting. We studied safety, tolerability, pharmacokinetics (PK) and tumor response of ATI-1123 in patients (pts) with advanced solid tumors.METHODSPts enrolled had progressive disease after standard therapy, measurable disease (RECIST), ECOG ≤ 2, survival ≥ 3 mo. Dosing (1 hr infusion) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. Dosing was continued until pts had progressive disease or unacceptable toxicities. Plasma was analyzed for encapsulated / non-encapsulated DOCE using a validated assay. PK was determined by model independent methods.RESULTSTo date, 19 pts were enrolled (median age 62 yr; range 40-80 yr; 58% male; 5 (26%) NSCLC; 5 (26%) pancreas; 4 (21%) prostate; 3 (16%) other and 2 (11%) ovary. Doses studied (mg/m2) were 15 (2 pts), 30 (1 pt), 60 (3 pts), 90 (7 pts) and 110 (5 pts). Two DLTs were noted at the 110 mg/m2 cohort (Gr 3 mucositis; Gr 3 neutropenic fever) and the 90 mg/m2 cohort expansion is ongoing. At Cycle 1, 5 (26%) pts had hypersensitivity reactions (all Gr 2). One reaction required ATI-1123 discontinuation; the remainder were managed with test dose, prolonged infusion time and/or premedication. No new toxicities were noted relative to standard DOCE. PR was seen in 1 NSCLC pt. SD was noted in 4 of 9 pts (44%) for which protocol-defined followup was available (prostate, 2; pancreatic, 1; cervix, 1). Two prostate ca pts had pronounced PSA (>95% reduction) response following multiple treatment cycles. PK results demonstrated linear and dose proportional PK. Compared with standard DOCE PK Cmax and AUC0-24 ratios were 1.60-3.32 and 1.80-4.11 fold higher, and DOCE clearance was 1.68-4.10 fold lower with ATI-1123.CONCLUSIONSATI-1123 exhibited acceptable tolerability, a favorable PK profile and antitumor activity that warrant exploration in larger Phase 2 trials.

2612 Background: S‐1 is a new oral fluoropyrimidine that combines tegafur (FT), a prodrug of 5-FU, with two modulators, gimeracil (CDHP), and oteracil (Oxo). CDHP inhibits 5-FU degradation by DPD inhibition, and Oxo inhibits 5-FU phosphorylation in the GI tract. CDHP and Oxo are mainly renally excreted, however, FT is metabolized in the liver. Hepatic impairment (HI) could influence both the conversion process of FT to 5‐FU by CYP2A6 and the catabolism of 5-FU by DPD. Methods: Patients (pts) with advanced solid tumors, ECOG ≤2, adequate renal and heme function were stratified into 4 HI cohorts: normal, mild, moderate, and severe, using NCI ODWG Criteria. Six pt cohorts received the same dose of S-1, 30 mg/m2 PO BID for 14 days followed by 7-day off period in 21 day cycles. Blood PK and urine analysis of S-1 components, metabolites (5-FU, FBAL, CA, uracil) were performed during cycle 1. Objectives were to provide a recommended dose (RD) and characterize safety, for different HI cohorts. Results: 27 pts received S-1, 5 pts required 1 dose reduction. Median age was 55 (25-72), 14 pts were male. The majority of pts had GI tumors. HI cohorts(pt #): normal(6), mild(8), moderate(7), severe(6). Most common treatment-emergent AEs reported over all cycles for all pts: nausea (52%), diarrhea (37%), vomiting (37%), fatigue (33%), stomatitis (22%), and rash (15%). 1 grade 3 HFS in mild cohort. 1 pt in the mild HI cohort experienced 1 DLT – grade 3 elevated ALT on day21 which resolved after 8 days. After single and multiple doses of S-1, there was considerable variability in plasma PK data with no trends observed in the magnitude of PK parameters as a function of HI. No effect of HI on FT, Oxo, or FBAL for AUC or Cmax following single- or multiple-dose administration was observed. No accumulation of S-1 components or metabolites. SD was seen in 11 pts (CRC, gastric, appendix, lung and melanoma) and 1 PR (pancreas) in the mild HI cohort. Conclusions: S-1 was generally well tolerated in this pt population with a safety profile consistent with previous reports. Clinical and PK results suggest that RD for S-1 for pts with mild, moderate, or severe HI is 30 mg/m2 BID for 14 days followed by a 7-day off period. Dose adjustment based on severity of HI is not warranted.

3062 Background: LDE225 is a potent and selective inhibitor of Smo, a key regulatory protein in the Hedgehog (Hh) signaling pathway, which is linked to the pathogenesis of many human cancers. This open-label, dose-escalation study aims to evaluate the tolerability, safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of LDE225. Methods: Patients (pts) with advanced cancer (n=76) received oral doses of LDE225, ranging from 100 to 3,000 mg QD and 400 and 750 mg BID, on a continuous 28-day dosing schedule, with a single dose PK run-in period. Dose escalations were guided by a Bayesian logistic regression model. Clinical assessments for safety and antitumor activity were performed. Blood was sampled for PK, as were skin and tumor biopsies for PD analysis. Results: LDE225 was well tolerated up to 800 mg QD. At QD doses ≥ 1,000 mg and BID doses ≥ 400 mg, dose-limiting CTCAE G3/4 increases in plasma creatine phosphokinase (CK) associated with myalgia were observed. Treatment-related G1/2 AEs in > 10% of pts include nausea, vomiting, dysgeusia, decreased appetite, myalgia, muscle spasms and fatigue. Systemic exposure of LDE225 increased with increasing dose but was less than dose-proportional. Steady-state concentrations were achieved after 28 days, with a mean effective half-life of approximately 6 days (range: 1–14 days). An association between high systemic drug exposure and dose-limiting CK elevation was identified. Exposure-dependent reduction in Gli-1 mRNA expression was observed in skin and tumor biopsies (up to 95% and 99%, respectively). A link between Hh target gene expression and antitumor activity was demonstrated in pts with medulloblastoma (1 PR and 1 metabolic PR) and advanced basal cell carcinoma (BCC; 1 CR with histologic clearance and 4 PRs). Disease stabilization (> 4 months) in 5 pts (lung adenocarcinoma, spindle cell sarcoma, breast cancer, and BCC [x2]) was also observed. Conclusions: The MTD of LDE225 is 800 mg QD. LDE225 exhibits exposure-dependent target inhibition, a promising antitumor activity that is linked with Hh pathway inhibition, and evidence of histologic clearance in BCC.

3080 Background: Dinaciclib is a potent and selective inhibitor of CDKs 1, 2, 5, and 9 with anti-tumor activity in multiple tumor cell lines and xenograft models. METHODS Dinaciclib is administered every 3 weeks in pts with advanced malignancies. Part 1: accelerated titration design to establish the RP2D of a 2-hr IV infusion. Part 2: 8 and 24-hr continuous IV infusions. Part 3: determined effect of the CYP3A4 inhibitor aprepitant on PK. PD assessments: ex vivo lymphocyte proliferation assay; FDG-PET/CT scans; and skin and/or tumor biopsies for IHC of cdk targets. RESULTS 81 pts treated. Part 1: Doses 1.85 to 58 mg/m2. RP2D 50 mg/m2. DLTs: non-neutropenic sepsis (1), neutropenic fever (2), neutropenia with pneumonia (1), hypotension (1), and rise in transaminases (3). Part 2: 7.4 and 10.4 mg/m2 well tolerated as 8- and 24-hr infusions, respectively. DLTs seen at lower doses with 8-hr and 24-hr vs 2-hr infusions. 8-hr DLTs: neutropenia with or without fever (5), hypotension (1), syncope (1), and elevated transaminases (2). 24-hr DLTs: rise in bilirubin (1) and delirium (1). Part 3: pts received dinaciclib 29.6 mg/m2 by 2-hr infusion +/- aprepitant. Among all pts, the most common treatment-related adverse events were nausea, vomiting, diarrhea, neutropenia, and fatigue. Dinaciclib was rapidly eliminated with a t1/2 of 1.4-3.3 hrs. Coadministration of aprepitant had no significant effect on PK. PD: Dose and infusion time correlated with degree and durability of suppression of lymphocyte proliferation. Tumor metabolic changes occurred in some pts by FDG-PET at day 8 but were not predictive of response. No objective responses by RECIST; SD ≥6 cycles (range 6-30) achieved in 10 pts. Pre/post tumor biopsies from 2 pts with melanoma show reduced phospho-Rb [pT356] post-treatment; total Rb was preserved. In 1 pt, p27 and p53 increased post-treatment, consistent with cdk2 and cdk9 inhibition. Analysis of skin biopsies ongoing. CONCLUSIONS Dinaciclib has an acceptable safety profile at 50, 7.4 and 10.4 mg/m2 for 2-, 8- and 24-hr infusions, respectively, without PK interaction with aprepitant. Prolonged SD was achieved in some pts. Trials are ongoing in hematologic malignancies and melanoma.

7073 Background: Amrubicin (AMR), a 3rd-generation synthetic anthracycline has shown promising activity in solid tumors, including small cell lung cancer (SCLC) without cardiotoxicity. This intensive PK and safety study also investigated the effect of AMR on QT interval. Methods: Pts with solid tumors and an ECOG PS score ≤ 1 were eligible. AMR 40 mg/m2 IV was given on days 1–3 of a 21-day cycle. Serial blood samples and time-matched triplicate ECG were collected on days 1–9, including an 11 h continuous ECG within 5 days prior to study initiation, and on days 1 and 3 of cycle 1. Urine was also collected for PK analyses. Results: 24 pts with different primary cancers (most common SCLC [5 pts]), median age 55 yrs; 46% male; 71% Caucasian) were enrolled. All received the intended AMR dose. AMR concentrations followed biphasic elimination with an initial 80% reduction within 10 min and a T1/2 of 4 h. The active metabolite of AMR, amrubicinol (AMROL), reached a peak concentration at 2–4 h. Blood AMROL had a terminal half-life of 51 h and an accumulation ratio of 1.7 after 3 doses. The AMROL to AMR molar ratio for AUC24 after 3 doses averaged 0.64. Mean urinary excretion of AMR or AMROL over 24 h was < 8% of the AMR dose. The upper 1-sided 95% CI for the time-matched, baseline-adjusted mean difference in QT interval (QTcF) on days 1 and 3 relative to the off-drug day (ΔΔQTcF) was below 10 ms at 20/21 time points, and was marginally above 10 ms at a single time point (day 1, 10 h). No correlation was observed between blood AMR or AMROL levels and ΔΔQTcF. No patients exceeded the clinically relevant thresholds of 480 ms for absolute QTcF or 60 ms for QTcF increase from the time-matched value on the off-drug day. There were no clinically significant findings in QTcF changes from baseline beyond day 3. The most common Gr 3/4 adverse events were neutropenia (45.8%), leukopenia (37.5%) and thrombocytopenia (37.5%). Gr 3/4 infections occurred in 16.7% of patients. Conclusions: The full AMR PK profile was defined for US patients. Therapeutic doses of AMR did not cause clinically significant prolongation of QTc interval in pts with solid tumors. The safety profile of AMR is consistent with earlier findings in SCLC.

Background: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib. Methods: Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies. Results: Erlotinib dose escalation to 200–475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P =0.051). Neither rash severity nor response correlated with erlotinib exposure. Conclusion: Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.

2524 Background: ANA773 is an oral prodrug of a small molecule, TLR7-selective agonist which has demonstrated pharmacological activity in preclinical studies. In a study in healthy volunteers, dose-related increases in markers of interferon-alpha dependent responses (e.g. oligoadenylate synthetase (OAS), neopterin, and OAS1 and other Interferon Stimulated Gene mRNAs) were observed after administration of ANA773 with little or no increase in circulating IFN-alpha. This study aimed to determine the MTD, pharmacodynamics (PD), pharmacokinetics (PK), and anti-tumor activity in pts with advanced cancer. METHODS Phase I dose escalation in pts with advanced solid tumors. Pts were treated with ANA773 dosed orally every other day for 14 days followed by a 14 day rest period, on continuous 28-day cycles. A minimum of 3 pts were enrolled at each dose level. Endpoints included safety, PK, biomarkers of immune activation and tumor response by RECIST. RESULTS 20 pts have been treated at 5 dose levels (50, 100, 200, 400, and 800mg QOD). ANA773 was well tolerated; the MTD was not reached in this trial. CTC grade 1-2 AEs considered possibly treatment related included fatigue, nausea, diarrhea, headaches, vomiting and weight loss. One pt had gr 3 fatigue. One pt had DLT; a pt with malignant melanoma experienced grade 3 neutropenia at 800mg QOD and was dose reduced to 600mg QOD starting in cycle 2. This pt achieved a PR and continued treatment for 19 cycles. 4 pts had stable disease (SD): adenocystic carcinoma (13 cycles), prostatic carcinoma (6 cycles), uveal melanoma (7 cycles) and uveal melanoma (11 cycles). PK analysis indicates that exposure to the active TLR7 agonist is dose proportional. At 400 and 800 mg QOD an increased expression for interferon-responsive genes (OAS1, ISG15, IFIT1 and IFI27) was demonstrated in PBMCs. Consistent with ongoing TLR7 activation, substantial induction of all four genes occurred on D13. CONCLUSIONS ANA773 was well tolerated in pts with advanced solid tumors. Continued clinical development is supported by the early evidence for its activity, including evidence of TLR7 agonist-mediated pharmacology and responses observed in pts with melanoma.

3074 Background: Amuvatinib is an oral multi-targeted TKI which inhibits the mutant forms of c-kit, and PDGFRα. It also disrupts DNA repair probably through suppression of Homologous Recombination protein Rad51. METHODS Adults with cancer diagnosis appropriate for one of the 5 SOC regimens to be studied received amuvatinib (dry-powder capsules) in combination with SOC. The 5 SOC regimens were: paclitaxel/carboplatin (PC), carboplatin/etoposide (CE), topotecan (T), docetaxel (D), and erlotinib (E). Amuvatinib doses were escalated until the MTD of the drug in combination with SOC agents was reached. The primary objectives of the study were to determine the MTD, DLTs, and quantify the effects of amuvatinib on the PK of SOC agents. Other objectives included pharmacodynamic parameters and tumor response. RESULTS 100 patients, mean age of 58 (range, 25-84) years were enrolled. M/F:35/65. ECOG PS 0/1/2:15/78/7, respectively. 90% of patients had prior cancer treatment. Patients were treated with amuvatinib plus: PC (23 patients); CE (22); T (20); D (15), and E (20). Amuvatinib doses were escalated from 100 mg PO QD to 400 mg PO BID on a continuous basis. Amuvatinib did not alter the PK of SOC agents, except D. The MTD was not reached and amuvatinib-related DLTs were not identified in this study. Most common (≥ 15% of patients) adverse events (AEs) related to treatment were expected AEs of SOC: neutropenia, fatigue, alopecia, diarrhea, thrombocytopenia, and anemia. Overall, 12 PRs and 44 SDs by RECIST criteria were observed for an overall disease control rate of 56% (95% CI, 46-66). The PC and CE combination arms with amuvatinib showed the most activity with 6 and 5 PRs, respectively. Small Cell Lung Cancer (SCLC) and Neuroendocrine (NE) tumors were the most sensitive with 5 of 11 SCLC or NE patients achieving PR. Rad51 modulation and increased DNA damage (53BP1 foci) was observed in skin punch biopsies. CONCLUSIONS Amuvatinib is well tolerated in combination with 5 SOC regimens. Several PRs were observed. The results support further investigation of amuvatinib in combination with CE or PC in SCLC and NE tumors.

Dummer, R.a; Rodon, J.b; Tawbi, H.c; Amakye, D.d; Shou, Y.d; Granvil, C.d; Feng, W.d; Gobbi, S.a; Thomas, A.e; Garcia-Patos, V.b; Mita, A.C.f Author Information

7570 Background: Iniparib, a novel agent with poly(ADP-ribose) polymerase inhibitory activity, has demonstrated anticancer activity when combined with DNA-damaging chemotherapy such as C in certain clinical and preclinical settings. Combination of iniparib with CP was well tolerated at recommended doses in a phase Ib study in patients (pts) with advanced solid tumors (Mahany et al. ASCO 2008). This study was expanded to further evaluate the efficacy and safety of iniparib in combination with CP in pts with NSCLC. Methods: Eligible pts were ≥18 years of age, had a histological or cytological diagnosis of stage IIIB (with pleural effusion) or IV NSCLC not amenable to curative therapy and an ECOG status of 0 or 1. Prior systemic treatment for NSCLC with chemo- or immunotherapy, biologic response modifiers, or other investigational agents were not allowed. C (starting dose AUC 6; IV; day 1), P (200 mg/m2; IV; day 1) and iniparib (5.6 mg/kg; IV; days 1, 4, 8, and 11) were given on a 21-day cycle. The primary endpoint was objective response rate (ORR) per RECIST. Secondary endpoints were safety, laboratory changes, and adverse events (AEs). Results: Between July 2008 and January 2011, 18 pts (of 20 planned) were enrolled. Of the first 13 evaluable pts, baseline characteristics were: M/F, 7/6; median age, 63 years (range 40–73); ECOG PS 0/1/NA, 4/8/1. The ORR was 23%, consisting of 3 confirmed partial responses. Eight pts (62%) had stable disease (SD) as best response, with 3 SDs through 12 weeks and 2 SD through 18 weeks. Only two patients had progressive disease as best response. Toxicities were similar to those reported with CP alone. The most common AEs were mild/moderate and included fatigue (33%), anorexia (25%), dyspnea (17%) and alopecia (17%). Grade 3/4 AEs were neutropenia (17%) and anemia (17%). Median follow-up time was 16 weeks (range, 4-24). Updated efficacy and safety results will be presented. Conclusions: Iniparib + CP was well tolerated and shows promising activity in pts with advanced NSCLC, with increased ORR compared with a previous study of CP alone (23% vs. 15%; Sandler A, NEJM 2006). These findings support further study of iniparib + CP in NSCLC. Clinicaltrials.gov, NCT00422682.

7592 Background: Plinabulin (NPI-2358) is a vascular disrupting agent (VDA) that acts on the cytoskeleton to destabilize tumor vascular endothelial cell cohesion with additional cytotoxic activity,...

7588 Background: VEGF-mediated angiogenesis contributes to NSCLC pathogenesis. Ramucirumab is a recombinant human MAb that binds the extracellular domain of the vascular endothelial growth factor receptor 2 (VEGFR-2) and inhibits cancer growth in diverse preclinical models. Methods: Approximately 40 pts with advanced NSCLC (stage IIIB not suitable for locoregional therapy or stage IV) are planned for enrollment. Squamous histology and treated brain metastases are allowed. Exclusion criteria include prior bevacizumab, blood vessel invasion, intratumor cavitation, and recent gross hemoptysis. Pts receive ramucirumab 10 mg/kg, paclitaxel 200 mg/m2, and carboplatin AUC = 6 on Day 1 of each 3-week cycle for up to 6 cycles, followed by maintenance ramucirumab. Tumor evaluations occur every 6 weeks. The primary endpoint is progression free survival at 6 months; secondary/exploratory endpoints include safety, objective response rate (ORR), pharmacokinetic/pharmacodynamic profiles, and immunogenicity. Results: 31 pts have been enrolled to date, 22 are evaluable for safety (7M:15F; median age 59 [37-79]). None had squamous histology and 1 had treated brain metastases. 1 pt discontinued due to an adverse event (AE) (pneumothorax) and 2 pts reported serious AEs possibly related to ramucirumab: G4 febrile neutropenia and G2 pneumothorax. 15 pts are evaluable for best response. 10 of 15 pts had an objective response (1 complete response, 9 partial responses: ORR = 67%). 50% of responses have been confirmed, and in all cases, where repeat scans are available, initial response was confirmed. 5 of 15 pts had SD, 4 with tumor shrinkage. Preliminary median PFS is 5.7 m (95% CI: 5.62-5.75), with 14 of the 15 pts still on therapy as of December 4, 2009. Conclusions: Ramucirumab in combination with paclitaxel and carboplatin is well tolerated in NSCLC pts. Preliminary results do not highlight any unusual safety concerns. Preliminary efficacy data are encouraging. Updated safety and efficacy data and the relevance of pharmacodynamic markers to outcomes will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems ImClone Systems ImClone Systems