Search

TPS9597 Background: RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity. Clinical data in combination with nivolumab has demonstrated a high rate of deep and durable response in patients with advanced skin cancer. Solid organ transplantation (SOT) is an important lifesaving procedure for patients with a wide range of end-organ diseases, but requires patients (pts) to undergo lifelong immunosuppression to prevent allograft rejection, and skin cancers (SCs) – including cutaneous squamous cell carcinoma (CSCC) – are common post-transplant malignancies. SC in SOT pts is generally managed with surgical resection, radiation therapy, and chemotherapy or targeted therapy. The use of immune checkpoint inhibitors in SOT recipients has improved outcomes but is associated with a high risk of allograft rejection. Thus, there is a high unmet need for a safe and effective treatment that also protects pts from allograft rejection. The objective of this study is to assess the safety and efficacy of single-agent RP1 in SOT patients with SCs, with a focus on CSCC. Methods: This study will enroll up to 65 evaluable SOT pts with locally advanced or metastatic SCs. The study has two parts. In Part A, pts will receive an initial dose of 1 x 106 plaque-forming units (PFU) of RP1. Two weeks later they will receive 1 x 107 PFU of RP1 and continue every two weeks until pre-specified study endpoints are met. In Part B, after determining the safety and tolerability in the initial cohort with kidney and liver transplants, the study may also enroll heart and lung transplant recipients. RP1 will be administered by intra-tumoral injection, utilizing image guidance as clinically appropriate. Key inclusion criteria are pts with confirmed recurrent, locally advanced or metastatic CSCC and up to 10 pts with non-CSCC SC, stable allograft function and ECOG performance status of ≤1. Pts with prior systemic anti-cancer treatment are allowed. Key exclusion criteria are prior treatment with an oncolytic therapy, active herpetic infections or prior complications of HSV-1 infection and a history of organ graft rejection within 12 months. The primary objective of the trial is to assess efficacy determined by objective response rate and safety of single agent RP1. Additional secondary endpoints include duration of response, complete response rate, disease control rate, progression-free survival and overall survival. Clinical trial information: NCT04349436.

TPS2705 Background: RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that contains insertions for the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule, CD40 ligand, and 4-1BB ligand. Together, these insertions are expected to increase oncolytic potency, cell-to-cell spread, immunogenic cell death, and systemic immune activation. RP3 has demonstrated antitumor activity in preclinical models using viruses similar to RP3 expressing murine versions of anti-CTLA-4, CD40L, and 4-1BBL both alone and in combination with PD1-1 blockade. Methods: This is an open-label, multicenter, Phase 1 study evaluating RP3 as monotherapy or in combination with nivolumab (nivo) in patients (pts) with solid tumors (NCT04735978). Part 1 evaluated escalating doses of RP3. Pts in Part 1 received IT injections of up to 10 mL RP3 into superficial, nodal, or visceral lesions Q2W x 5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then 106 PFU/mL x 4; DL2: 106 PFU/mL once, then 107 PFU/mL x4). The RP2D is 106 PFU/mL once, followed by 107 PFU/mL IT Q2W. In Part 2, pts are being enrolled into expansion cohorts of 45 patients with GI (including HCC), lung, breast, and squamous cell carcinoma of the head and neck treated with RP1 combined with nivo. Additional cohorts will enroll patients treated with RP3 followed by nivo, RP3 monotherapy to further explore biomarkers in injected and uninjected tumors, and with the potential to also open a cohort in melanoma. Pts in both Part 1 and Part 2 may receive up to 8 additional doses of RP3 if protocol-specified criteria are met. Key inclusion criteria: confirmed advanced or metastatic non-neurological solid tumors, at least one measurable tumor ≥ 1 cm and injectable tumors ≥ 1 cm in aggregate, ECOG ≤1, and adequate hematologic, hepatic, and renal function. In Cohorts 1, 2, and 4, approximately 50% of the pts with lung, breast, and GI cancer must have liver lesions intended for injection. Exclusion criteria include prior oncolytic virus treatment, need for immunosuppressive therapy, an autoimmune disease requiring systemic therapy, active significant herpetic infections or prior complications of HSV-1 infection, active or chronic HBV or HCV infection, known HIV infection, or prior active malignancy within 3 years. Clinical trial information: NCT04735978.

TPS2704 Background: RP2 is a selective replication-competent herpes simplex virus 1 (HSV-1) that contains a codon-optimized sequence for human granulocyte-macrophage colony-stimulating factor (GM-CSF), the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), GM-CSF, and an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule. These modifications are intended to increase oncolytic potency, cell-to-cell spread, tumor antigen release, and systemic anti-tumor immune activation. RP2 has demonstrated antitumor activity in preclinical models using viruses similar to RP2 expressing murine versions of anti-CTLA-4 and GM-CSF, both alone and in combination with PD1-1 blockade. Methods: This is a Phase 1 multicenter, open-label, study evaluating RP2 ± nivolumab (NCT04336241). Part 1 evaluated escalating doses of monotherapy RP2 with a modified 3 + 3 design. Patients (pts) received intratumoral (IT) injections of up to 10 mL of RP2 into superficial or visceral tumors Q2W x5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then followed by 106 PFU/mL x4; DL 2: 106 PFU/mL once, then followed by 107 PFU/mL x4). The recommended Phase 2 dose of RP2 was identified as 106 PFU/mL once, followed by subsequent doses of 1 × 107 PFU/mL. In Part 2, up to 60 evaluable pts will be enrolled, including 30 pts in Cohort 2a and 30 in Cohort 2b. Cohort 2a was designed to evaluate the safety and antitumor activity of the combination in pts with solid tumors, and is fully enrolled. Cohort 2b is open for enrollment of pts with advanced or metastatic uveal melanoma, NSCLC, breast cancer, head and neck cancer or GI cancers (NSCLC, breast or GI cancers must have at least one liver tumor suitable for injection). Pts in Part 2 receive intra-tumoral RP2 at the RP2D Q2W for up to 8 doses in combination with 240 mg nivolumab IV Q2W or 480 mg nivolumab IV Q4W for up to two years from the first RP2 dose. In Part 3 (not yet open for enrollment), up to 15 evaluable pts are able to be enrolled to evaluate RP2 monotherapy including at least 10 pts with NSCLC, breast or GI cancers with at least one liver tumor suitable for injection. Reinitiation of up to 8 additional RP2 doses is permitted if prespecified criteria are met. Pts are dosed with RP2 by direct visualization or ultrasound-guided injection into superficial, subcutaneous, or nodal tumors and by image-guided injection into deeper lesions, including visceral lesions. Key inclusion criteria include histologically confirmed advanced or metastatic non-neurological solid tumors, at least one measurable and injectable tumor of diameter ≥1 cm, ECOG ≤1, and adequate hematologic, hepatic, and renal function. Exclusion criteria include prior treatment with oncolytic viruses, acute or chronic hepatitis B or C infection, and HIV infections. Clinical trial information: NCT04336241.

The study evaluated the safety, tolerability, and pharmacokinetics of BMS-936561, a fully human monoclonal antibody-drug conjugate targeting CD70 cell-surface protein.Eligible patients had ECOG performance status 0-2 and received ≤3 prior chemotherapy regimens. An initial accelerated titration design enrolling one patient per dose level was followed by 3 + 3 dose escalation with the first observation of a grade ≥2 adverse event (AE). We tested escalating doses of BMS-936561 (0.5, 1, 2, 4, 8, 15 mg/kg) administered every 21 days in a 42 day cycle for a maximum of 17 cycles. Pharmacokinetic samples were collected in cycle 1.A total of 26 patients enrolled; 16 and 10 for the escalation and expansion cohorts, respectively. Median age was 63 years (48-74); 18 males and 25 Caucasians. There was no defined MTD per protocol, but a DLT of grade 3 hypersensitivity was recorded in 2 of 16 (13%) subjects at the highest dose of 15 mg/kg. The most frequent AEs were: fatigue (85%), nausea (54%), and decreased appetite (39%). Delayed toxicities (facial edema and pleural/pericardial effusions) occurred in 6 of 16 (38%) subjects at the 15 mg/kg dose. PK analysis showed a dose-proportional increase in active drug levels with increasing doses. There was disease stabilization in 18 of 26 patients (69%) without correlation with received dose.BMS-936561 is well tolerated over a wide range of doses in patients with advanced ccRCC and B-NHL. The 8 mg/kg dose was the highest best tolerated dose and the recommended dose for future studies.

Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors. Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1–5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects. The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine. The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.

Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS-690514. Two open-label, randomized, single-dose, 2-treatment, 2-period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a high-fat meal, and in study 2 (N = 17), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)), area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-690514 increased by 55%, 33%, and 34%, respectively, following a high-fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS-690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS-690514 was increased when given along with a meal, probably through inhibition of intestinal first-pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS-690514 in the absence and presence of food.

3017 Background: Anti-CD137 antibody was shown in both murine cancer models and in a first-in-human, phase I trial (Sznol et al., 2008) to increase peripheral activated CD8 T cells and IFN-inducibl...

2558 Background: BMS936561 is a fully human monoclonal anti-body conjugate targeting the CD70 transmembrane cell-surface protein highly expressed in ccRCC and B-NHL. The study was designed to deter...

TPS3114 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has shown antitumor activity in phase I trials in pts with solid tumors, including advanced MEL. Objective responses were observed in pts whose diseases were refractory to multiple prior therapies. We describe an ongoing exploratory, open-label, multicenter translational study designed to further investigate the immunoregulatory activity and mechanisms of action of nivolumab in advanced MEL, including ipilimumab (anti-CTLA-4) naïve and refractory pts. Methods: This study is enrolling advanced MEL pts who are either ipilimumab naive (n=40) or refractory (n=40). Eligible pts must not have received >3 prior therapies for metastatic disease and must consent to pre-and on-treatment biopsy (after 2 doses of nivolumab [Day 28]) of an accessible tumor. Nivolumab will be administered IV every 2 weeks (wks) at a dose of 3mg/kg and may continue for up to 13 cycles (104 wks) until clinically significant progression or treatment discontinuation criteria are met. Tumor responses will be assessed every 8 wks using RECIST 1.1 criteria. The primary objective is to investigate the pharmacodynamic (immunoregulatory) activity of nivolumab in the peripheral blood (PB), tumor, and tumor microenvironment. Secondary objectives include evaluation of safety and tolerability, preliminary antitumor activity, and immunogenicity of nivolumab, as well as the association between tumor PD-L1 expression and clinical efficacy. Exploratory objectives include characterization of pharmacokinetics (PK) and evaluation of the potential association between selected PB and/or tumor biomarkers and PK, clinical safety, and efficacy (eg, progression-free and overall survival). Clinical trial information: NCT01621490.

TPS3109 Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 + 6 design and cohort expansion (Part 2). In Part 1 (n=48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 μg/kg daily x 5) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 μg/kg weekly) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n=25/arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi + weekly rIL-21 or Ipi + daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 + Ipi and to define the MTD of the respective rIL-21 + Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.

8030 Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. Nivolumab, a PD-1 receptor blocking antibody, was evaluated in a phase 1 study in pts with various tumors including NSCLC (Topalian et al, NEJM 2012;366:2443). Methods: Pts with ≥1 prior chemotherapy regimen received nivolumab (1-10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. We report initial overall survival (OS) and updated safety and response data for NSCLC pts. Results: 127 pts evaluable for safety received nivolumab at 1, 3, or 10 mg/kg as of July 2012. Common drug-related AEs were decreased appetite (9%), anemia (8%), diarrhea, nausea, and pruritus (7% each). The most common G3/4 AEs were fatigue, pneumonitis, and elevated AST (2% each). Two drug-related deaths from pneumonitis occurred early in the trial and led to increased monitoring without further deaths from pneumonitis. Median OS (mOS) across all dose cohorts was 9.2 mo and 9.6 mo for squamous (sq) and non-sq NSCLC, respectively. mOS was not reached at the 3 mg/kg dose (phase 3 dose) for either histology. Sustained OS was observed, with 44%/ 41% and 44%/ 17% of pts (sq/non-sq) alive at 1 and 2 years, respectively (Table). Prolonged ORs occurred in both histologies (Table). Conclusions: In this long-term follow-up of a phase I trial, nivolumab had an acceptable safety profile and showed an encouraging sustained OS benefit across histologies in previously treated advanced NSCLC. Follow-up through a Feb 2013 data cut (≥1 yr follow-up for all pts) will be provided at presentation. Clinical trial information: NCT00730639. [Table: see text]

TPS3112 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N=160) includes a dose escalation phase (Part 1) using a 3 + 3 design followed by an expansion phase (Part 2). In Part 1 (N=60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 µg/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1–4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N=50) or non-small cell lung carcinoma (N=50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 + nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.

2501 Background: Aberrant HH pathway signaling has been suggested to play a role in the development of multiple solid tumors and hematological malignancies. BMS-833923 is a potent, oral, small molecule antagonist of the HH signaling component Smoothened. Methods: The trial is designed to identify a maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics. All subjects receive a single dose 1 week prior to continuous daily dosing, which allows for single dose PK collection for 1 week. To identify the pharmacologically active dose range, skin samples are collected prior to day 1 and again on day 22 of the first cycle to assess GLI1 protein expression levels. Results: As of October 21, 2009, eighteen subjects (mean age of 56 [range 21-78]; ECOG performance 0--1) have been treated at four dose levels: 30 mg (n=5), 60 mg (n=3), 120 mg (n=3), and 240 mg (n=7). No subjects in the first three dose cohorts experienced drug-related CTCAE adverse events greater than grade...

Background: The human folate receptor (FR) is selectively overexpressed in a number of human epithelial malignancies, including ovarian, renal, and prostate cancers. Folate-conjugated therapies provide a strategy for targeting patients with FR expressing tumors. Identification of patients with FR expressing tumors is important to increase the opportunity for clinical benefit from folate conjugated therapies. The goals of this study are to determine the prevalence of FRα expression in various solid tumors, and to determine the concordance of FRα expression between primary and matched metastatic tumors. This concordance could help to determine if primary tumor samples would be suitable for assessing FR expression in metastatic tumors. Little information on this is currently available. Methods: FRα expression was analyzed by immunohistochemistry (IHC) in 339 primary tumors covering a wide range of human tumor types. Concordance of FRα status in 86 archived primary and matched metastatic breast, renal, endometrial and ovarian tumors was assessed by IHC. Results: FRα expression prevalence was moderate to high in primary tumors of lung (13/29; 45%), renal (66/115; 57%), colon (17/27; 63%), prostate (8/12; 67%) and ovarian (22/29; 76%). FRα expression frequency was found relatively low in breast tumor (26/127; 20%) which is consistent with previous reports. Furthermore, for the first time, we showed a good concordance (81.4%) of FRα expression between paired primary and metastatic ovarian, endometrial, renal and breast malignancies. Conclusions: FRα is frequently overexpressed in ovarian, prostate, colon and renal tumors, suggesting these tumor patients might benefit more from folate conjugated therapies. New findings from this study show that FRα expression is maintained in metastatic tumors, indicating the utility of archived primary tumor samples for determining the FR positivity of metastatic tumors in patients receiving a folate conjugated agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3752.

Background: The hedgehog pathway is dysregulated in basal cell carcinoma, medulloblastoma, pancreatic, lung, gastric, and a variety of other cancers. BMS-833923 is a potent, oral, small molecule antagonist of hedgehog signaling. Methods: Subjects with advanced or metastatic solid tumors were enrolled into a multiple ascending dose study to identify a maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-833923. All subjects receive a single dose one week prior to continuous daily dosing. The single dose window allows for single dose PK collection for one week. To identify the pharmacologically active dose range surrogate tissue was collected prior to Day 1 and again on Day 22 of the first cycle. Results: As of August 14, 2009 sixteen subjects have been treated at four dose levels: 30 mg (n=5), 60 mg (n=3), 120 mg (n=3), and 240 mg (n=5); with mean patient age of 56 (range 21–78) and ECOG performance 0–1. No subjects in the first three dose cohorts experienced drug-related CTCAE AEs greater than Grade 2. One subject with medulloblastoma in the 30 mg dose cohort continues on study for more than 10 months with stable disease. Treatment of patients in the fourth cohort at 240 mg continuous daily dosing is still on-going. In this cohort one subject experienced drug-related CTCAE Grade 2 lipase elevation and pancreatitis that quickly resolved when drug was withheld. This subject has a diagnosis of Gorlin Syndrome, which is caused by germline mutations in the hedgehog pathway genes Patched or Smoothened. This subject experienced a partial response (PR) that is still ongoing. BMS-833923 PK properties showed dose proportionality between the 30, 60, and 120 mg dose cohorts with a Cmax of 30 ng/ml, 56 ng/ml and 102 ng/ml respectively. The terminal half-life was greater than 7 days and drug accumulations were observed. Conclusion: BMS-833923 is generally well tolerated at daily doses of 30, 60, 120 mg. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A55.