Genta Incorporated was a biopharmaceutical company started in La Jolla, California, which discovered and developed innovative drugs for the treatment of patients with cancer. Founded in 1989 by a highly skilled entrepreneur, the company focused on a novel technology known as antisense, which targets gene products that are associated with the onset and progression of serious diseases. At that time, only Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (formerly Isis Pharmaceuticals until December 2015) was conducting significant research with this technology. Antisense is a short span of oligonucleotides – modified DNA structures ranging from about 12-24 bases that selectively bind to specific RNA. The intent is to block expression of an aberrant protein that contributes to the disease of interest. Genta in-licensed three different antisense molecules that blocked Bcl-2, a fibroblast growth factor (FGF), and the gene c-myb, respectively.
2555 Background: Tesetaxel (TST) has anticancer activity in patients (pts) with metastatic breast cancer (MBC) and gastric cancer when administered orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not cause hypersensitivity reactions, and may be associated with less neurotoxicity. The maximally tolerated dose (MTD) on the Q3W schedule is 27 mg/m2, and neutropenia is dose-limiting. Since taxane activity may be schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation of TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2; adequate organ function. TST was given once weekly for 3 weeks in a 28-day cycle, beginning at a total flat dose of 25 mg/cycle with progressive increases in total dose up to 75 mg/cycle. Subsequently, dosing was converted to a weight-based regimen at weekly doses of 12.5, 15, and 17.5 mg/m2 (i.e., total per cycle dose up to 52.5 mg/m2). Serial plasma samples were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The MTD was 15 mg/m2/wk (total cycle dose, 45 mg/m2). With repeated cycles, constitutional symptoms (fatigue and anorexia) rather than neutropenia proved dose-limiting at 17.5 mg/m2/wk. Only 1 pt (at 12.5 mg/m2/wk) developed grade 3 neutropenia; no other episodes of Grade 3-4 myelotoxicity were observed. One pt with MBC (who had progressed after 2 prior taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained prolonged reduction of PSA (> 57%). PK analyses showed low but progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after each succeeding dose, which was consistent with the prolonged T½ of this drug (~180 hrs). There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral TST is safe, provides long-term low-level drug exposure, and increases the total delivered dose over 12 wks by 25%. Interestingly, this regimen is not associated with significant myelosuppression. Thus, weekly TST dosing provides a highly convenient, “dose-dense”, taxane regimen that is not associated with neutropenia, which should facilitate its integration into multiple chemotherapy regimens. An ongoing study is evaluating efficacy of weekly TST dosing in MBC.
221 Background: In subjects with normal renal function, renal clearance of intact drug (ie, excretion in the urine) represents only a small portion of the total clearance for phosphorothioate oligonucleotides (Cossum et al 1993, 1994; Crooke et al 2000). This finding was similarly observed in patients with advanced melanoma who were treated with oblimersen (OBL), a phosphorothioate oligonucleotide currently being studied in combination with chemotherapy in patients with various solid tumors and hematologic cancers. OBL in subjects with renal impairment had not been formally studied; thus, a Phase I study was conducted to characterize the pharmacokinetics of OBL in subjects with normal, mildly impaired, and moderately impaired renal function. Methods: Subjects were allocated to one of 3 groups: normal renal function (creatinine clearance > 80 mL/min); mild renal impairment (creatinine clearance 50 to ≤ 80 mL/min); or moderate renal impairment (creatinine clearance 30-49 mL/min). Creatinine clearance was calculated using the Cockcroft-Gault formula and, in subjects with renal impairment, was confirmed based on measured creatinine clearance. Subjects had to be at least 18 years of age and, except for the varying degree of renal impairment, have adequate organ function. The OBL dose chosen for IV infusion (3 mg/kg/d) has been administered in previous clinical studies, including 1 large Phase III study in subjects with chronic lymphocytic leukemia. The first subject in each group received OBL for 12 hours, at which time safety data were reviewed. OBL was then administered for 48 hours to the remaining subjects in each group to ensure OBL steady-state plasma levels were reached. Blood and urine samples were collected at defined intervals. Plasma and urinary concentrations of OBL and its measurable metabolites (N-1 and N-2) will be determined using a validated analytical method. Pairwise comparisons will be performed on the primary pharmacokinetic parameters, AUC 0- τ and C max , using the two one-sided tests procedure between subjects with normal and mildly impaired renal function, normal and moderately impaired renal function, and mildly impaired and moderately impaired renal function. Results: A total of 23 subjects were treated, including 9 men and 14 women ranging in age from 21 to 66 years. Fifteen subjects were white; 6 subjects were black; and 1 subject each was Native American and Hispanic. Nine of the subjects had normal renal function and 7 subjects each had mildly impaired and moderately impaired renal function. No Grade 3, Grade 4, or serious adverse events occurred. Pharmacokinetic analyses are ongoing. Conclusions: Results of pharmacokinetic analyses will be presented.
Background: A randomized Phase 3 trial was performed to compare the efficacy and safety of fludarabine/cyclophosphamide (Flu/Cy) combined with oblimersen (OBL; Genasense®; G3139) or administered alone in patients (pts) with relapsed or refractory CLL. The primary objective was to compare the proportion of pts who achieved complete response (CR, including nodular partial response) between treatment arms.
OBJECTIVES:Our group previously demonstrated that expression of the oncogene, Bcl-2, was associated with radiation resistance. The aim of the present study was to determine whether Bcl-2 expression in radiation-resistant tumors was associated with expression of carbonic anhydrase IX (CAIX), vascular endothelial growth factor (VEGF), and pAkt and whether downregulation of Bcl-2 could modulate the expression of CAIX, VEGF, and pAkt.METHODS:Two prostate cancer cell lines, PC-3-Bcl-2 and PC-3-Neo, were injected into the subcutaneous flanks of 192 athymic male nude mice; 96 received PC-3 Bcl-2 and 96 PC-3-Neo. The mice were then treated with antisense Bcl-2 oligodeoxynucleotide (ASODN), reverse control ODN, or vehicle only (mock treatment) with or without irradiation (4 Gy). The tumors were monitored for growth (ie, volume) over time, resected at various points, and processed and sectioned for protein analyses.RESULTS:Bcl-2 ASODN treatment was associated with downregulation of Bcl-2, VEGF, pAkt, and CAIX. PC-3-Bcl-2 and PC-3-Neo prostate tumor xenografts in mice treated with the combination of Bcl-2 ASODN and irradiation were significantly (ie, one third) smaller than those in mice treated with reverse control ODN alone, Bcl-2 ASODN alone, irradiation alone, or reverse control ODN plus irradiation (P = 0.0001). An increased tumor response to the combined therapy was associated with decreased expression of Bcl-2, VEGF, and pAkt proteins.CONCLUSIONS:These findings have demonstrated an intimate relationship among CAIX, VEGF, pAkt, and Bcl-2 in prostate tumors. Thus, CAIX might prove effective as a potential marker of tumor radiation resistance. Downregulation of CAIX might lead to radiation sensitization. Consequently, the combination of CAIX reduction and radiotherapy warrants further consideration as a new strategy for therapy.
