Citations

TPS1608 Background: Metformin may have growth inhibitory effects on many cancer types including breast cancer. NCIC MA.32 is a randomized placebo-controlled trial examining the effects of 5 years of metformin in women with breast cancer ( http://clinicaltrials.gov/show/NCT01101438 ). This trial offers us the opportunity to explore the effects of metformin on breast cancer biomarkers to gain an understanding of the potential chemo preventive effects of this drug. The primary aim of this companion to MA.32 (Alliance trial # A211201) is to examine the effects of 1 year of metformin vs placebo on breast density for women with Estrogen Receptor negative (ER-) breast cancer. Secondary aims of this study include: evaluation of breast density following 2 years of metformin use, and correlation of density with fasting insulin, glucose and Homeostasis Model Assessment (HOMA). Exploratory aims include examination of the effects of metformin on second cancer rates. Methods: Eligible women must have been enrolled on MA.32 (North America accrual completed January 23, 2013), have hormone receptor-negative breast cancer, and breast composition on mammography >25% glandular density, have a digital mammogram within 12 months of registration on MA.32 and have an intact, unaffected contralateral breast. Women enrolled on this study must provide menstrual cycle data (if premenopausal) and digital mammograms. All other study related information is gathered through participation in MA.32. Mammographic density will be calculated using Cumulus software (the Boyd method). Our accrual goal is 458 patients (229 per arm) and with an assumption of 20% drop out due to drug intolerance and another 20% due to ineligibility. Therefore, with a sample size of 274 (137 per arm) we will have at least 85% power to detect a 4% difference between study arms, i.e., 5% change from baseline to one year of treatment for metformin vs. 1% for placebo, using the two-sided two-sample t-test at a significance level of 5%. This study was activated in the United States on 8/22/2012 and 15 patients have been accrued to date. This study is sponsored by the NCI and the Alliance for clinical trials. Clinical trial information: NCT01666171.

4047 Background: PNET has long had few effective therapies other than chemotherapy. Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: Confirmed PR was documented in 13 of the first 25 (52%) evaluable patients. 21 of 25 (84%) patients were progression-free at 6 months. Both endpoints exceeded the protocol-defined criteria to continue enrollment. For 36 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (14%), leukopenia (11%), lymphopenia (11%), hyperglycemia (11%), mucositis (8%), hypokalemia (8%), and fatigue (8%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 52%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 84% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing.

1557 Background: Peripheral neuropathy (PN), a common and intrusive side effect of chemotherapy in clinical trials, has been assessed via the clinician-rated common terminology criteria for adverse events (CTCAE) and/or patient-reported outcome (PRO) measures (Morton, ASCO, 2005). We assessed the relative sensitivity of CTCAE and PRO measures for evaluating interventions for preventing and ameliorating CIPN. Methods: Data from285 patients in two prevention trials (N05C3, N04C7) and 432 patients from three intervention trials (N00C3, N01C3, N06CA) were analyzed separately. CTCAE version 3.0 item for neuropathy was compared to 2 NCCTG numerical analogue CIPN items, 6 EORTC CIPN20 individual items, 2 McGill Pain Questionnaire items, and one Brief Pain Inventory item. The sample size provided over 80% power to detect a true Spearman rank correlation of 0.15 assessed the relationship between CTCAE and PRO measures. Results: Results from both the prevention and treatment trials were similar in terms of the relationship between the CTCAE and PRO measures. No correlation coefficients between the CTCAE and any of the PRO items at baseline were above 0.35, with the majority around 0.2. Higher scores for the numbness items were observed than for the CTCAE in 47% of the patients at baseline and 39% during treatment in the treatment trials. Many patients had severe numbness PRO scores but mild CTCAE scores (12%) at baseline and (8%) during treatment in the treatment trials. Results for the numbness and tingling PRO measures were redundant. The correlations of the CTCAE with pain were weak, all below 0.35 at baseline with differences as much as 29 points on average on a 0-100 transformed scale. Conclusions: The CTCAE and PRO measures of PN measure different constructs. The CTCAE includes both functional and ADL/motor aspects which may or may not be related to the singular constructs of pain, numbness, tingling, or adjectival characteristics of pain assessed by the PRO measures. The two measures cannot be used in place of each other.

5517 Background: Anti-angiogenic therapy is active in OC; the combination of VEGF and mTOR inhibitors is hypothesized to further improve activity. This report is the OC cohort of a multi-histology phase II study assessing the activity and toxicity of B/T. Methods: Patients (Pts) with recurrent epithelial OC who had received ≤ 2 chemotherapy regimens and no prior treatment with a VEGF or mTOR inhibitor were eligible. A two-stage design was used with second stage accrual if >6 pts had objective responses (OR) or >10 pts of the first 25 remained progression-free (PF) at six months (mo). Pre-defined end-points for a recommendation for further clinical trial evaluation included at least 15/50 with OR or 26/50 PF at six mo. Treatment included T 25 mg IV wkly and B 10 mg/kg IV q14 days on 28 day cycles. Results: 58 pts were enrolled (the first 50 pts are used to determine a final recommendation). Median age=62 (range 35-82). A median of 4 (range 1-23) cycles were administered. 24 were platinum-sensitive, 34 resistant. Off-study reasons included 13 adverse events and disease progression in 38. 3 refused further therapy due to toxicity. 14 of the first 50 pts had partial response (PR) (9 platinum-resistant); 25/50 remained PF (8 PR, 15 SD, 2 non-progressing) at 6 mo. Grade (gr) 3/4 toxicities occurring >2 events include: fatigue (4), stomatitis (7), hypertension (5), neutropenia (4), thrombocytopenia (4), hypokalemia (3). One rectal and one vaginal fistula, and two colonic perforations (one gr 2 and one gr 3 during cycles 3 and 1 respectively) were observed. Episodes of gr 1/2 oral, nasal, pulmonary, vaginal and gastrointestinal hemorrhage were also observed. Conclusions: Although the OR and PFS did not reach pre-defined standards, the numbers of OR and 6 mo PFS suggest potential enhanced activity with a combination of mTOR inhibitor with anti-angiogenic therapy. Other combinations of these targeted agents may result in more satisfactory activity with less toxicity. N01-CM-62203 (PMH) N01-CM-62208 (Southeast Phase 2) N01 CM-62209 (CCCP) N01-CM-62204 (NYCC) N01-CM-2011-0071C (Chicago) N01-CM62205 (Mayo) Clinical trial information: NCT01010126.

5077 Background: A standard of care (SOC) for the adjuvant treatment of ovarian and primary peritoneal cancer is a platinum-based intravenous (IV) chemotherapy doublet. Intraperitoneal (IP) chemotherapy is also a SOC, but the high incidence of grade 3/4 adverse events has limited its acceptance among clinicians. To identify genetic markers for completion of IP chemotherapy, we analyzed SNPs in four genes known to play a role in metabolism of platinum or taxane drugs. Methods: Patients diagnosed with primary or recurrent stage III or IV epithelial ovarian or primary peritoneal cancer who had primary or secondary debulking surgery at Mayo Clinic (Rochester, MN) between January 2007 and February 2009 followed by IP chemotherapy were included in this study. A cycle was defined as IV paclitaxel (135mg/m2) on day one, IP cisplatin (100mg/ m2) on day two, and IP paclitaxel (60mg/ m2) on day eight. With prior consent from the patient, peripheral blood was obtained before treatment for extraction of germline DNA. Using a custom Illumina BeadXpress 96-plex panel, SNPs in GSTM1 (N=7), ABCB1 (N=57), CYP3A4 (N=7), and CYP2C8 (N=25) were genotyped. The association between SNPs in these subsets of genes and completion of IP chemotherapy was analyzed using linear regression. Results: Thirty-seven patients were included in this study and 16 (43.2%) completed IP chemotherapy. Twenty-two out of the fifty-seven ABCB1 SNP’s were associated with the number of cycles (p<0.15). There were no significant associations for GSTM1, CYP3A4 and CYP2C8 SNP’s. The minor A allele at missense SNP rs2229109 in the ABCB1 gene was present in five (31.2%) who completed treatment and only one (4.8%) who did not (p<0.007). However, the later was due to catheter complication. There was no association between rs2229109 and overall or progression-free survival. Conclusions: Our findings suggest that SNP rs2229109 in ABCB1 gene is associated with completion of IP chemotherapy, and potentially, less toxicity from chemotherapy. Thus, these patients may be optimal candidates for IP chemotherapy. Further studies in a larger population are needed.

5025 Background: We report the interim results of the endometrial arm of a multi-tumor protocol using temsirolimus and bevacizumab in endometrial cancer (EMCA) patients at the time of their initial recurrence. The primary aim of this trial is to assess treatment efficacy in terms of both confirmed tumor response and 6-month progression free survival (PFS). Methods: Women with a performance status of 0 or 1 who have had their first recurrence for EMCA were eligible. Subjects who had chemotherapy as part of their adjuvant treatment after front line surgical staging were also eligible. The regimen included Temsirolimus 25 mg IV weekly followed by bevacizumab 10mg/kg IV on days 1 and 15 of a 28 day cycle. A modified two-stage Simon design with fixed sample size was adopted with the null hypothesis being that the true tumor response rate is at most 25% and the true 6 month PFS rate is at most 50%. Results: We enrolled 26 evaluable subjects to the first stage of which one did not proceed with treatment. The median age at enrollment was 60 (range 40-80). 22 (85%) were white and 19 (73%) were not Hispanic/Latino. 19 (73%) of subjects had prior raditation therapy, with 4 having a prior para-aortic boost. 5 (20%) subjects had a confirmed PR and 12 (48%) were progression-free at 6 months, which fell short of the futility stopping rule. An additional 5 (20%) subjects had a best response of confirmed SD, so 10 (40%) had overall clinical benefit from this regimen. AEs attributable to treatment were modest and included 16 grade 3 adverse events, of which the most common ones included hypertension, hyperglycemia, and neutropenia. There were 2 grade 4 events that were possibly treatment related including a duodenal perforation and an anorectal infection. Conclusions: While there was clinical benefit of this regimen in women at the time of their first recurrence of EMCA, the combination of temsirolimus and bevacizumab did not achieve our prespecified efficacy assumptions. This differs from what has been reported with this combination as a second line therapy for recurrent EMCA, where prespecified response assumptions differ. Also, the regimen had comparable safety and toxicity to other cytotoxic chemotherapy regimens used in this setting.

4099 Background: There is strong rationale to combine an m-TOR inhibitor (TEM) with a VEGF inhibitor (BEV) as a potentially active and well tolerated treatment for HCC. Both agents have shown modest single agent activity in HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage Simon design planned 25 or 50 patients (pts) to test the null hypothesis that true tumor response rate is at most 10% andtrue 6-mo progression-free survival rate (PFS) (by RECIST) is at most 65%, or no better than single agent BEV (6 mo PR >2 pts or PFS 6 mo >18 out of 25.) Toxicity, TTP, PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with disease unresectable or amenable to other localised therapies, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR class of agents. TEM was administered at starting dose 25 mg IV d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle). Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85% male, PS 0/1: 35/65, 58% metastatic, >85% BCLC stage C. With med 6 cycles (range 1-14) delivered, most pts (88%) experienced a grade 3+ adverse event (a/e.) Common grade 3 a/es related to treatment included thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue (8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4% each). There was one possible treatment related death. Per protocol dose reductions/discontinuation for TEM-related a/es were most common. There were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt developed a late PR at cycle 13. Median TTP on study was 6 mos, median PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive. Accrual closed at end of stage 1 as neither the number of responses nor the PFS at 6 mos passed the futility stopping rule set for this combination. Conclusions: This multicenter study is the first HCC trial evaluating the BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did not surpass assumptions based on single agent BEV in HCC. Further study of BEV/TEM combination in this advanced HCC population is not recommended.

3598 Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression. BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell. Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu). 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells. Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD). Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (2.4 - 4.0 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days. Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB). Assessments of toxicity were performed with each cycle and clinical response was determined per RECIST criteria every other cycle. Results: The MTD for cohorts IA and IB was reached at a dose of 1250 mg of lapatinib and 3.2 mg/m2 of IV topotecan on days 1, 8 and 15. No DLT were seen during the dose escalation stage of cohorts IA and IB. Ten patients were enrolled at the MTD. There were no grade 4+ events. Thirteen grade 3+ events, considered to be related to treatment, were seen in 6 patients. The most common grade 3+ toxicities included dehydration (2) diarrhea (2), nausea (3), vomiting (2), neutropenia (1), thrombocytopenia (1), and fatigue (1). No abnormalities in left ventricular ejection fraction were noted. Stable disease was seen in 46% of the 37 patients. Conclusions: The combination of lapatinib and topotecan is a well-tolerated regimen. The MTD for the combination is lapatinib 1,250 mg orally once daily for 21 or 28 days and topotecan 3.2 mg/m2 on days 1, 8 and 15. Pharmacokinetic analysis for drug interaction will be available for presentation at the meeting. Supported in part by GSK and Mayo Clinic No significant financial relationships to disclose.