Citations

4032 Background: PNET has long had few effective therapies other than chemotherapy. 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 was 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: 55 pts were eligible for response assessment. Confirmed PR was documented in 20 of 55 patients (37%). 44 of 55 (80%) patients were progression-free at 6 months. Of 49 pts evaluable for this endpoint, 12 month PFS is 49%. 15 patients remain on therapy. For evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (18%), hyperglycemia (13%), fatigue (11%). leukopenia (9%), headache (9%), proteinuria (7%), and hypokalemia (7%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 37%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Phase III trials of combined VEGF/mTOR inhibition in PNET should be pursued. Clinical trial information: NCT01010126.

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.

534 Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p <0.002) and d8 compared to BL (p <0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]

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.

Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.

260 Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <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 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 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.