Citations

10062 Background: 17-AAG is a benzoquinone ansamycin that binds to and inhibits the HSP90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0–2, and adequate hematologic, hepatic, renal and cardiac functions received CNF1010 by 1 h intravenous infusion, twice-a-week, three weeks out of four, starting at 6 mg/m2 per dose. Doses were escalated sequentially in single pts (6 and 12 mg/m2) and 3–6 pts (≥ 25 mg/m2) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles were obtained on days 1 and 18. Biomarkers were measured in PBMC’s (HSP70) and plasma (HER-2 ectodomain (HER-2 ECD)). Results: 30 pts (M/F: 14/16; median age 63, range 48–78) with colorectal cancer (11), pancreatic cancer (5), melanoma (5), ovarian (2), others (7) were treated with a median of 2 courses (range: 1–10). There was no dose-limiting toxicity up to 175 mg/m2. One pt at 175 mg/m2 died on study, but drug relation was unclear. Grade 1–2 gastrointestinal toxicities (nausea, vomiting, diarrhea) and serum creatinine elevation were observed. Severe toxicities (grade 3 but no grade 4) consisted of reversible hepatic enzyme elevation, hyperbilirubinemia, fatigue, anemia and hyperglycemia. There were no hematological toxicities. Plasma 17-AAG PK appeared dose-proportional (AUC, Cmax); CL (17 L/h/m2) and t1/2 (5.2 h) were dose independent and unchanged after repeated dosing (day 18). Post-treatment increases in HSP70 were observed in PBMCs and decreases in plasma HER-2 ECD were observed at doses ≥ 83 mg/m2. Minor tumor regressions were seen in 1 pt with duodenal cancer (83 mg/m2), 1 pt with gastric carcinoid (175 mg/m2) and 1 pt with melanoma (175 mg/m2). Conclusion: The threshold of biologic activity for CNF1010 administered by a twice a week schedule appears to be 83 mg/m2. This dosing regimen appears to be optimal and supported by the pharmacokinetic and pharmacodynamic data. The MTD has not yet been determined. Dose escalation of CNF1010 continues at 225 mg/m2. [Table: see text]

4043 Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104. No significant financial relationships to disclose.

14118 Background: Triapine is a small molecule iron chelator that has been shown to inhibit ribonucleotide reductase (RR) at the M2 subunit. Early trials suggested activity in pancreatic cancer. The P2C initiated a study of single agent Triapine as both first-line therapy and for pts with gemcitabine-refractory disease. Correlatives included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy (EPR). Methods: Standard eligibility criteria were used, however, pts with G6PD deficiency were excluded. Triapine was given 96 mg/m2 IV over 2 hours, days 1–4 and 15–18, repeated q 28 days. Primary goals - evaluate survival (S) at 6 mos (previously untreated pts) and 4 mos (refractory pts). Interim analyses were planned when 28 previously untreated and 20 refractory pts were enrolled. Results: 14 eligible pts were enrolled in 10 mos (13 refractory, 9 male). The previously untreated pt received only 1 cycle secondary to progressive disease. Of the 13 refractory pts, 7 pts received at most 2 cycles; 6 received 1. Disease progression precluded further treatment in 11 pts. 6 pts had Gr 4 toxicities at least possibly related to drug, including: neutropenia-4, hyperkalemia-1, hyponatremia-1, leukopenia-1, thrombocytopenia-1, hypophosphatemia-1. 6 pts had a Gr 3 fatigue. One refractory patient expired on study. No responses were seen. Estimated 4 mos S in refractory pts is 16% (95% CI 3–94). EPR studies showed that Triapine led to a loss of the RR tyrosine radical EPR signal. Conclusions: Enrollment was suspended due to excess toxicity and lack of activity in pts refractory to gemcitabine. Correlative studies confirm the mechanism of action of Triapine as a chelating agent on RR. Supported by NCI Grant N01 CM17104 and the NCI Translational Research Fund. No significant financial relationships to disclose.

3021 Background: 17DMAG is a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17AAG), the first geldanamycin compound to enter clinical trials. 17DMAG causes oncoprotein degradation by binding to heat shock protein 90 (HSP90) & has greater in-vitro activity than 17AAG. In animals treated with 17DMAG, liver toxicity is dose-limiting. The objectives of this first-in-human study are to: establish the dose-limiting toxicity (DLT); recommend a phase 2 dose; & characterize the PK & PD of 17DMAG. Methods: Using a modified accelerated schema, escalating doses of 17DMAG are given IV over 1 h daily x 5 (schedule A) or daily x 3 (schedule B) every 3 weeks. Plasma 17DMAG concentrations during cycle 1 are quantitated by LC/MS. HSP70 & ILK levels in peripheral mononuclear cells are measured by western blot at baseline & 24 h on d 1. Results: 37 pts have been enrolled. On schedule A, dose levels are 1.5, 3, 6, 9, 12 & 16 mg/m2/d (n = 20). On schedule B, the starting dose was 2.5 mg/m2/d. Based on safety information from schedule A, subsequent schedule B dose levels were 14, 19, 25 & 34 mg/m2/d (n = 17). One DLT was noted in schedule A (16 mg/m2) & consisted of reversible liver enzyme elevation. End-of-infusion (EOI) 17DMAG concentrations (33–2074 ng/ml) & AUC0–24 (200–5200 ng/ml x h) increase linearly with dose. Interpatient PK variability was substantial, with CV% of 16–59%. The daily administration schedule precluded precise definition of 17DMAG t1/2 & clearance, but estimates of t1/2 & clearance ranged from 10.8 to 77 h & 19–160 ml/min/m2, respectively. Between 0 & 24 h, 20.5 ± 8.6% (range 4–43.8%) of the administered dose was excreted in urine. HSP70 increased between 0.2 & 3.7 fold above baseline in PBMCs at 24 h at 12, 16, & 25 mg/m2. There is an indication of ILK degradation in 3 of 4 patients evaluated at 25 mg/m2. Conclusions: 17DMAG is well tolerated at current dose levels & maximal tolerated dose has not been reached. 17DMAG plasma PK are linear over the doses delivered to date, & there is evidence of a target effect as manifested by↑HSP70 & ↓ILK. Support: U01CA099168–01, U01CA62502, U01CA69912, R01CA90390 & NIH/NCCR/GCRC grants #5M01 RR 00056 & M01 RR00080 No significant financial relationships to disclose.

4504 Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225. No significant financial relationships to disclose.

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.

Abstract Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design: Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1−/− T47D breast cancer cell line. Conclusions: This matched case–control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

Abstract Backgrounds B cell receptor (BCR) signals and microenvironment protection have been recognized to have key influences on CLL survival and activation. Akt activation is down-stream of the BCR signaling cascade and is critical in the mediation of the bi-directional interactions between CLL B-cells and bone marrow stroma. MK2206 is an allosteric Akt inhibitor previously tested for safety in solid tumor patients. Our preclinical data has demonstrated the synergy of MK2206 with bendamustine (B) to induce CLL apoptosis in vitro. MK2206 also abolished the signal activation and cytokine production induced by BCR ligation in CLL leukemic cells (Ding, ASH 2012). Therefore, we conducted a phase 1 trial testing the safety and efficacy of MK2206 in combination with bendamustine and rituximab (BR) for patients with relapsed/refractory CLL. Methods A phase 1 dose-escalation study was designed to define the maximum tolerated dose (MTD) as well as the safety and efficacy of 3 dose levels (90 mg or 135 mg or 200 mg weekly) of the oral Akt inhibitor MK2206 in combination with bendamustine (70 mg/m2 daily for 2 days in each cycle) and rituximab (cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2) therapy in relapse/refractory CLL patients. To test the targeting efficacy of MK2206 on Akt and downstream signals, we designed a one-week “run-in” of single agent MK2206 before the initiation of BR during cycle 1. MK2206 was then given along with BR on day 1 of cycles 2-6. Tumor response was evaluated 2 months after the 6th/last cycle of therapy based on IWCLL 2008 criteria. Correlative laboratory studies included assessment of Akt signaling and the plasma cytokine levels (multiplex beads assay (Invitrogen)) at baseline and after one week of first dose of single agent MK2206. Results Nine patients (median age 68) were enrolled in the phase I portion of this trial. All 9 patients had unmutated immunoglobulin heavy chain variable region genes (IGHV) and 4 had del(11q). Six had received prior chemoimmunotherapy (CIT: FCR or PCR or PCO) and 5 had high risk disease defined as early progression within 26 months of the last CIT. Three had received alemtuzumab containing regimen. We have observed potent lymphocyte mobilization in all evaluated patients (n=7) after one-dose of MK2206 during week 1 (mean increase ALC: 35%) as well as reductions of plasma CCL3, CCL4 and CCL2 in the majority of the patients. A single dose-limiting toxicity (DLT) (febrile neutropenia and hemolytic anemia) was observed at dose level 1 (90 mg weekly) among 6 patients treated at this dose. Two patients with dose-limiting toxicities at dose level 2 (135 mg weekly) were observed where one patient had a rash and one patient had dehydration and febrile neutropenia among three patients treated at this dose. Accordingly, the 90 mg once weekly dose was determined to be the MTD for phase 2 trial testing. The most frequent grade 3 or 4 adverse events observed to date were neutropenia (44%) including febrile neutropenia (22%), rash (22%), diarrhea (22%), nausea and vomiting (11%), dehydration (11%), hemolytic anemia (11%) and thrombocytopenia (11%). The frequency of cytopenias was similar to the published German experience with BR (50% grade 3 or 4 hematological toxicities compared to 44% in N1087) in relapsed CLL patients (Fischer, JCO 2011). The median number of cycles received was 6 (range 1-6). Using an intent to treat analysis, two patients achieved complete response (CR, n= 2, 22%), one patient achieved nodular partial response (nPR, n=1, 11%) and five patients achieved a partial response (PR, n=5, 56%). The overall response rate (ORR) is 89%. Conclusion The Akt inhibitor MK2206 in combination with BR is well tolerated in patients with relapsed/refractory CLL. Single dose of MK2206 inhibits Akt phosphorylation, mobilizes leukemic cells and decreases plasma cytokines involved in BCR signals. The preliminary efficacy of this combination demonstrated promising results with a 89% ORR and 22% CR albeit in the small phase 1 cohort. These results compare favorably to BR alone (9% CR and 59% ORR) in relapsed/refractory CLL patients. Phase 2 testing of this combination is now underway. Acknowledgment This work was supported by the funding from NCI grant K23CA160345 (WD), NCI grant CA95241 (NEK) and Alliance for Clinical Trials in Oncology (CA025224 and CA33601). Disclosures: Off Label Use: MK2206, used in a phase 1 trial of relapsed CLL disease. Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Zent:Novartis: Research Funding; GlaxSmithKline: Research Funding; Biothera: Research Funding; Genzyme: Research Funding; Genentech : Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Abstract Abstract 4954 Background Multiple Myeloma (MM) remains incurable with current approaches and newer therapies targeting the abnormal disease biology need to be developed. The malignant plasma cell is highly dependent on the marrow microenvironment, which promotes tumor cell proliferation as well as survival. There is increased bone marrow vascular density in patients with MM and the degree of neo-angiogenesis appear to be prognostic in this disease. Studies have also shown that vascular endothelial growth factor (VEGF) is intricately involved in the interaction between the marrow microenvironment and the myeloma cell. These findings suggested that the VEGF pathway may be a valuable target for therapeutic approach in this disease. Patients and Methods We designed a phase 2 trial of Sunitinib in patients with relapsed multiple myeloma who had received less than three prior therapies. Sunitinib malate (SU11248; Sutent) is a novel, multi-targeted, small molecule inhibitor of the receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor-1 (VEGFR-1), -2, and -3, and platelet-derived growth factor receptor (PDGFR) -α and -β. The treatment consisted of Sunitinib 37.5 mg given daily in a continuous fashion in six-week cycles. Toxicities were graded according to CTCAE response version 3.0 and responses were assessed according to the International Myeloma Working Group consensus criteria. Response rate of single agent Sunitinib was the primary endpoint of the study. Results 13 patients were accrued between July of 2007 and April 2009 before the study was closed. The median age of the study population was 61 years (range, 53 - 84), and included nine females (69%). The median time from diagnosis to registration was 39.2 months (range, 4.5 - 88) and 10 patients had received previous stem cell transplant. Previous therapy included lenalidomide in 7 patients, thalidomide in 5 patients and bortezomib in 2 patients. All 13 patients were alive at last follow up with a median follow-up of 11.2 months (range, 1.3 -21.2). All patients have gone off study, disease progression being the most common cause (9 patients), followed by adverse events (3 pts) and alternate treatment in the remaining patient. A hematological grade 3 or higher adverse event was documented in 6 patients and a grade 3 or higher non-hematological adverse event was seen in 8 patients. A grade 3 or higher neutropenia was observed in 5 pts and thrombocytopenia in 2 pts. Fatigue was common and was seen in 11 pts. The median number of cycles administered was one (range, 1-5) and the total number of cycles across 13 patients was 22. Treatment delays or interruptions were seen in five and six patients respectively. The most common reason for treatment delays was hematologic adverse events. No responses (PR or better) were seen, and stable disease was seen in eight of the 13 patients as the best response. The median time to progression was 2.9 months. Conclusions Single agent Sunitinib has no clinically relevant efficacy in this group of patients with relapsed myeloma with one or two previous therapies. Hematological toxicity was higher than anticipated. Whereas these results indicate that VEGFR TK inhibitors are not active in previously treated myeloma, it does not preclude the possibility that VEGF targeting strategies may enhance the efficacy of other therapies. Disclosures Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding.