7543 Background: Allovectin-7, a bicistronic plasmid formulated with a cationic lipid system and encoding HLA-B7 and β-2 microglobulin, is an immunotherapeutic designed to induce a pro-inflammatory response and express allogenic MHC-class I antigen upon intralesional administration. Methods: We have conducted a Phase 2 dose-escalation trial to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy; injectable lesion(s); ECOG PS 0–1 and adequate organ function. Patients with brain or visceral (except lung) metastases, abnormal LDH, or any lesion ≥100 cm2 were excluded. Patients with 2 or more injectable lesions were randomized to receive injections of 2 mg Allovectin-7 divided for injection for up to 5 lesions. Patients received weekly intratumoral injections of a total of 2 mg of Allovectin-7 for 6 weeks followed by 3 weeks of observation and evaluation. Overall Response (OR) was assessed using RECIST guidelines two weeks following the last injection of each cycle. Patients with stable or responding disease received additional cycles of Allovectin-7. Results: Final, audited data are presented for the 133 patients enrolled. All patients were evaluated for safety (6 patients in the dose-escalation stage and 127 patients in the 2 mg efficacy stage), and 127 patients were evaluated for efficacy. Fifteen patients (11.8%, 95% CI: 6.2–17.4) achieved an objective response lasting a median duration of 12.7 months (95% CI: 8.3 - ongoing). The responders include two patients who had lesions resected and found no evidence of melanoma. Median time to progression was 1.6 months and median overall survival was 21.3 months (95% CI: 14.8–33.4). There were no reported Grade 3 or Grade 4 adverse events associated with Allovectin-7. Conclusions: Results indicate that high-dose Allovectin-7 is an active, well-tolerated treatment for Stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions. The details of the Phase 3, follow-up clinical trial design will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vical Vical
7509 Background: A bicistronic plasmid encoding HLA-B7 and β-2 microglobulin genes formulated in cationic lipids, Allovectin-7® (A-7), is an immunotherapeutic designed to induce a pro-inflammatory response and express MHC-class I after tumor injections. Expression of HLA-B7 in tumors may result in increased immunorecognition of tumors that in turn elicits an antitumor response. Methods: We are conducting a phase 2 trial to evaluate the activity of A-7 in patients (pts) with metastatic melanoma (MM). Eligible pts have stage III or IV MM recurrent or unresponsive to prior therapy; injectable (1 to 25 cm2 cutaneous, subcutaneous, or nodal) lesion(s); ECOG PS 0–1 and adequate organ function. Pts with brain or non-lung visceral metastases or any lesion ≥ 100 cm2 are excluded. Pts with 2 or more injectable lesions are randomized to receive injections into 1 or up to 5 lesions. Pts receive weekly intratumoral injections of a total of 2 mg for 6 wks followed by 3 wks of observation and evaluation. Response is assessed using RECIST guidelines two wks following the last injection of each cycle. Pts with stable or responding disease receive additional cycles. Results: Interim unaudited data will be presented for all 133 pts enrolled. All pts were evaluated for safety (6 pts in the dose escalation stage plus 127 pts in the high-dose stage), and 127 pts are evaluated for efficacy. In an interim data analysis 12 of 91 pts (13.2%) achieved an objective response lasting a median duration of 6.4 months. Median overall survival has not yet been reached and durability of response is still accruing. One Grade 3 and no Grade 4 adverse event associated with A-7 have been reported. Conclusions: Interim results indicate that high-dose A-7 is an active, well-tolerated treatment for Stage III/IV MM pts with injectable cutaneous, subcutaneous, or nodal lesions. No significant financial relationships to disclose.
9044 Background: There has been evidence to show that the combination of paclitaxel and carboplatin is clinically active in the treatment of metastatic melanoma. ABI-007 is a unique protein formulation of paclitaxel which was developed primarily to reduce the toxicities associated with paclitaxel and the Cremophor-EL/ethanol vehicle while maintaining or improving chemotherapeutic effect. ABI-007 demonstrates single agent activity in the treatment of metastatic melanoma. The current study explores the clinical activity of the combination of ABI-007 and carboplatin. Methods: A one stage phase II clinical trial was conducted in patients with unresectable stage IV melanoma, who were chemotherapy naive. A treatment regimen consisting of ABI-007 (100 mg/m2) and carboplatin (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs. ≥35% with this combination. With α=β=0.10, we reject CR + PR ≤ 15% if ≥ 9 responses among first 35 patients enrolled. Eligible patients, were at least 18 years of age, with ECOG PS of 0–2 and adequate organ function. Exclusion criteria included: any chemotherapy in the metastatic setting, any prior treatment with a platinum or taxane agent, uncontrolled infection or CHF, existence of peripheral neuropathy ≥ grade 2, history of malignancy within the last 5 years, or prior untreated brain metastasis. Pregnant or nursing women were not eligible. Results: Forty patients were enrolled from November 2006 thru June 2007, one patient cancelled prior to starting treatment. Among the 39 evaluable patients, 56% were male, median age was 58 years (range: 23–91), 49% had M1c disease and 62% had a PS of 0. The median number of cycles administered was 3 (range 1–11). Nine partial responses (25.7%) were seen among the first 35 patients enrolled (90% CI: 14.1–40.6%). Among all 39 evaluable patients the median PFS was 4.3 months. The median overall survival was 10.1 months. The most common severe toxicities (CTCAE ≥ grade 3) included neutropenia (27%), thrombocytopenia (5%) and neuro-sensory (5%). Conclusions: This weekly combination of ABI-007 and carboplatin appears to be well tolerated with promising clinical activity as first-line therapy in patients with metastatic melanoma. No significant financial relationships to disclose.
Meeting abstracts T-VEC is an oncolytic immunotherapy derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM, a randomized Phase III trial of T-VEC vs GM-CSF in patients with unresected
The wide range of functions attributed to GTP-binding regulatory proteins (G proteins) is reflected in the structural diversity which exists among the a, B, and y subunits of G proteins.Recently two cDNA clones encoding 0 subunits, B1 and &, were isolated from bovine and human cDNA libraries.We report here that the B2 gene encodes the 35-kilodalton (kDa) component of the @sa/@sa subunit of G proteins and that the B1 gene encodes the 36-kilodalton component.The in vitro translation product of the & cDNA co-migrates with the 35-kDa 6 subunit 0 , while the in vitro product of the cDNA co-migrates with the 36-kDa fi subunit GBsa) on denaturing polyacrylamide gels.In addition, antisera generated against synthetic flz peptides bind specifically to the f l S 8 component of isolated G proteins and to a 36-kDa protein in myeloid cell membranes.Our results suggest that the two B subunits could serve distinct functions, as they are derived from separate genes which have been highly conserved in evolution.G proteins are heterotrimeric proteins which bind guanine nucleotides, possess an endogenous GTPase' activity, and function as intermediaries in transmembrane signaling pathways (1).A general model for G protein action, extrapolated from the mechanism of activation of adenylate cyclase and the mechanism of photoreceptor function, has been proposed.It is suggested that binding of ligand to a transmembrane receptor (or activation by light) induces the a subunit of the G protein to bind GTP.The a subunit with bound GTP then dissociates from the / 3 and y subunits and activates an intracellular effector molecule (1, 2).In this model, the / 3 and y subunits remain associated in a complex which anchors the a subunit in proximity to a transmembrane receptor and se-
Evidence was found for the existence of four tumor peptides with corticotropin-releasing-factor-like (CRF) activity, two isolated from a pancreatic tumor (P-CRF-1, P-CRF-2) and two from the primary tumor and metastases of an oat-cell carcinoma (L-CRF-1, L-CRF-2). Tumor tissue was extracted for ACTH, and both tumors were demonstrated to certain ectopic ACTH. A peptide similar in size to ACTH and another, smaller than vasopressin, were isolated from each tumor. All four fractions appeared to be homogeneous on high-voltage electrophoresis at pH 6.5. Assays in hypophysectomized rats demonstrated that these peptides were devoid of direct adrenal-stimulating activity. CRF assays in the rat treated with chlorpromazine-morphine-pentobarbital showed ACTH-releasing activity comparable to the ACTH-releasing ability of 20 to 40 mU pressor activity of standard lysine vasopressin but no antidiuretice activity. Amino acid content indicates that these products are peptide in nature and different in composition from ACTH.
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