Long, Harry J.

SUMMARY Results of systolic time interval recordings obtained serially on 104 female New Zealand White rabbits were analyzed for reproducibility, variation with respect to changes in heart rate (hr), and interrelationship of the various systolic time intervals. A table of values for systolic time intervals in the healthy rabbit was constructed. The preejection period (pep), left ventricular ejection time (lvet), and pep/lvet ratio were 0.040 ± 0.008 s, 0.119 ± 0.014 s, and 0.337 ± 0.066 respectively. The major systolic time intervals, pep and lvet, varied with respect to hr according to the regression equations: pep = 0.057 − 0.000078 hr and lvet = 0.175 − 0.000251 hr. The QS2 interval, S1S2 interval and isovolumic contraction time also varied with changes in hr.

SUMMARY Systolic time interval recordings were performed serially on 104 healthy female New Zealand White rabbits and 51 rabbits with congestive heart failure (chf) induced by chronic anthracycline drug therapy. The results were analyzed and the comparisons were made with studies of systolic time interval recordings of chf in persons. In the rabbit, chf is manifested by prolongation of the isovolumic contraction time, the preejection period (pep), and by shortening of the left ventricular ejection time (lvet). The ratio of pep/lvet was a sensitive indicator of left ventricular failure, with values in excess of 0.466 reflecting significant cardiac dysfunction at the 95% confidence level. The mean pep/lvet = 0.337 ± 0.66 in healthy rabbits and pep/lvet = 0.502 ± 0.075 in rabbits with chf. The pep index increased from 0.057 ± 0.007 in healthy rabbits to 0.074 ± 0.007 in rabbits with heart failure. The lvet index decreased from 0.173 ± 0.007 in healthy rabbits to 0.166 ± 0.010 in rabbits with chf.

3 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

5028 Background: Edmonston vaccine strains of MV have significant antitumor activity against ovarian cancer xenografts (Peng et al, Cancer Res, 2002). Oncolytic selectivity is due to overexpression of the MV CD46 receptor in ovarian cancer cells. Furthermore, engineering the virus to express the marker peptide CEA (MV-CEA) allows real time monitoring of viral gene expression/propagation in vivo. Methods: We are conducting a Phase I trial of MV-CEA in patients (pts) with recurrent, taxol and platinum refractory, ovarian or primary peritoneal carcinoma. Eligible pts should have protective anti-MV antibody (ab) titers and normal CEA levels. A standard phase I cohorts of three statistical design is employed. MV-CEA is administered IP via a port-a-cath, q 4 wks for up to 6 cycles. Results: To date, 12 pts have received viral doses from 103 to 106 TCID50. No dose-limiting toxicity has been observed. Most common toxicities included grade 1–2 nausea (4 pts); grade 1–2 fatigue (4 pts); grade 1 fever (3 pts); grade 1 abdominal pain (2 pts). One pt had grade 2–3 arthralgias in cycles 4–6. There was no treatment induced immunosuppression as assessed by DTH, CD4, CD8, immunoglobulin and complement levels, no significant increase in the titers of anti-MV abs in serum or ascites in response to treatment, and no development of anti-CEA abs. Viral genomes were detected in the peripheral blood mononuclear cells of 2 asymptomatic pts by QRT-PCR. No CEA elevation in the serum was observed in the dose range tested, and there was no viral shedding in urine or mouth gargle specimens. Testing of pt tumor samples for CD46 by IHC demonstrated overexpression of the target receptor in 7/8 pts. Best objective response was stable disease (2 - 9 mo duration) in 5 pts, while 3 pts had significant decrease in CA125 levels, of 44%, 72%, and 78%, respectively. Conclusions: In this first human application of an engineered oncolytic MV strain, we have observed excellent tolerance after repeat IP administration of the virus. Despite the low doses employed so far, there is early evidence of biologic activity. Dose escalation continues to the target dose of 109 TCID50. No significant financial relationships to disclose.

5534 Purpose: A number of patients with advanced/recurrent cervical cancer do not respond to cisplatin-based chemotherapy. A pool analysis of three published phase III GOG studies was undertaken to identify the predictive factors and develop a model predictive of (non-) response to chemotherapy. Methods: The study population consisted of patients who received single-agent cisplatin or a cisplatin-containing combination in GOG protocols 110, 169 and 179. Prognostic variables (age, race, performance status, stage, histology, grade, disease site, prior chemotherapy—with primary radiation, time to recurrence, single-agent versus combination) were analyzed and multivariate analysis was conducted to identify factors independently predictive of response and survival. These analyses were used to establish a predictive model. Results: 816 patients were evaluable for response. In addition to single-agent treatment, multivariate analysis identified six factors (age, African-American, PS > 0, pelvic disease, prior radiosensitizer, recurrence ≤ one year) independently predictive of poor response. Those factors, but not age and African-American, were also independently associated with increased risk of death. 428 patients treated with a cisplatin- containing combination were classified into three risk groups based on the total number of risk factors (low risk: 0–1 factor; mid risk: 2–3 factors; high risk: 4–5 factors). Patients with 4–5 of risk factors were predicted to have a treatment response of only 13% (observed 10%), and median progression-free and overall survival of PFS of 2.8 months and 5.5 months, respectively. This subgroup of patients consist ∼14% of the target population in clinical practice. The predictive model was externally validated using GOG protocol 149 data that were not used for model development and further supported the predictive accuracy. Conclusions: High risk patients should be directed to non-cisplatin chemotherapy or investigational trials. No significant financial relationships to disclose.

Abstract Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

3 Background: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab (B), a humanized anti-VEGF monoclonal antibody, has shown single-agent activity in pretreated recurrent disease. We aimed to evaluate B in chemotherapy (CTX)-naive recurrent/persistent/metastatic cervical cancer. Methods: Using a 2x2 factorial design, patients were randomly assigned to CTX with or without B 15 mg/kg. The CTX regimens included cisplatin 50 mg/m2 plus paclitaxel 135-175 mg/m2 and topotecan 0.75 mg/m2 d1-3 plus paclitaxel 175 mg/m2d1. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response. Overall survival (OS) was the primary endpoint with a reduction in the hazard of death by 30% using anti-VEGF therapy considered important (90% power, 1-sided alpha=2.5%). Final analysis was planned when 346 deaths were observed. Results: 452 patients were accrued from 4/6/09 to 1/3/12. The scheduled interim analysis occurred after 174 patients had died and showed that the topotecan-paclitaxel backbone was not superior to the cisplatin-paclitaxel backbone. A second interim analysis was conducted after 271 deaths. A total of 225 patients received CTX alone and 227 patients received CTX plus B. The randomized treatment groups were similar with regard to age, histology, performance status, previous platinum as a radiosensitizer, and recurrence, persistence, or advanced disease. The B-to-no-B hazard ratio (HR) of death was 0.71 (97.6% CI 0.54-0.95; 1-sided p=0.0035). Median survival was 17 m (CTX plus B) and 13.3 m (CTX alone). The RR were 48% (CTX plus B) and 36% (CTX alone) (p=0.0078). Treatment with B was associated with more grade 3-4 bleeding (5 vs 1%) thrombosis/embolism (9 vs 2%), and GI fistula (3 vs 0%). Conclusions: For the first time a targeted agent significantly improved OS in gynecologic cancer. The second interim analysis crossed the boundary for efficacy, warranting early release of this information. The nearly 4-month increase in median OS with the addition of B to CTX in women with recurrent cervical cancer is considered to be clinically significant. Clinical trial information: NCT00803062.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m2 given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and ½ normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m2 IV for 1 hour in 500 mL of dextrose and ½ NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m2 IV for 2 to 3 hours in 750 to1,000 mL of dextrose and 5% water onday 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P = .429) and overall survival (P = .545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.