Curtis, Kelly K.

10521 Background: Sarcomas are rare cancers, with > 50 subtypes, and require multi-disciplinary care. Their management benefits from multi-institutional input due to the paucity of concentrated experience with each subtype. However, sarcoma tumor boards, wherein a patient-specific, consensus treatment approach is determined, are predominantly conducted in isolation at individual centers. Methods: Since March 2010, we have conducted a weekly multi-institutional, multi-disciplinary sarcoma tumor board to combine knowledge and experience in the management of our most challenging patients. The Mayo Clinic bridge links sites by interactive videofeed. Each site may contribute cases. De-identified history, radiology and pathology are reviewed. A didactic series reviews a rotation of seminal papers, newly published research, or our own data. An “Expert Guest" series allows outside experts to connect to one conference. A yearly participant survey assesses quality. Conference is free to sites and is CME accredited. Results: Currently, 8 sarcoma programs connect Mondays from 8-9am ET. Median attendance is 20 (range: 8-27). In 2012, 342 cases were reviewed over 43 conferences (median: 8 cases/conference; range: 4-12 cases/conference). The 2012 survey revealed 96% (25/26) agreed HIPAA rules are followed; 93% (25/27) agreed conference is educational; 93% (25/27) agreed recommendations are evidenced-based or reasonable; 100% (27/27) agreed participants are respectful; and 86% (18/21) agreed input from other sites has changed their management. Staff attendance (quantity) rated as meets/exceeds needs was 100% (25/25) for medical oncology; 96% (26/27) for pathology; 93% (25/27) for orthopedic oncology; 92% (23/25) for radiation oncology, surgical oncology and radiology; and 61% (17/23) for thoracic oncology. Conclusions: To our knowledge, this is the only weekly multi-institutional sarcoma tumor board in existence. It permits consistent oncology care across a wide geographic area, and is a model for providing consensus recommendations regardless of the remoteness of the patient and care team. Future plans for this group include prospective collection of outcomes data.

TPS2621 Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.

8053 Background: Lenalidomide (LEN) is an immunomodulatory agent that has shown significant single-agent anti-lymphoma activity in patients with relapsed disease and in combination may enhance the efficacy of rituximab by various mechanisms. There is limited data on the role of LEN in combination regimens for treatment-naïve patients. This phase II single arm trial was designed to evaluate tumor response, toxicity (AE) and survival with a combination of LEN, rituximab, cyclophosphamide (CTX) and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with low grade B-cell non-Hodgkin lymphoma. Methods: Eligibility required age ≥18, ECOG PS ≤2, confirmed diagnosis of low-grade B-cell lymphoma (FL1-2, SLL, MZL or LPL/WM), measurable nodes ≥2cm or IgM ≥400mg/dL(LPL/WM), ANC ≥1400/mm3, platelets ≥100,000/mm3, creatinine ≤2mg/dL, signed informed consent and in need of therapy. Treatment consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1-21, CTX 250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 28 day cycle. Treatment continued 2 cycles beyond best response (max 12). Toxicity was assessed by NCI CTCAE v3.0. Results: 28 patients have enrolled at Mayo Clinic with 25 evaluable for toxicity and 21 for response: Median age 65(43-83), 72% male, FL 24%, MZL 28%, LPL/WM 38%, and SLL 4%. Median number of cycles given was 5. Overall response in 21 patients with response data is 95% (95% CI 76-100%) with 19% CR (95% CI 5-42%), and 76% PR (confirmed and unconfirmed, 95% CI 53-92%). The ORR in 8 patients with LPL/WM with response data was 88%, all PR (95% CI 47-100%). At a median f/u of 14.7 months 96% are alive without progression. 1 death (unrelated) occurred 7.7 months after completing 12 cycles of treatment. The most common grade ≥3 AEs were neutropenia (37.5%), leukopenia (16.7%), anemia (12.5%) and fatigue (12.5%). Conclusions: The combination LR-CD with the novel agent LEN is feasible, well tolerated and produces high response rates in symptomatic patients with low grade B-cell NHL. Toxicities are manageable and similar to reported data of single agent LEN.

3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.

Abstract Abstract 2682 Background: The PI3K-Akt pathway is critical to tumor growth in lymphoid malignancies and mTOR inhibitors have shown promising activity in lymphoid malignancies. However, alternate signaling pathways allow cells to escape the effect of mTOR inhibition. Pre-clinical studies have shown that the combination of LBH589, an HDAC inhibitor, with the mTOR inhibitor RAD001 results in potent synergy. We then explored this combination in a phase I/II clinical trial. Patients and Methods: Patients with relapsed multiple myeloma (MM), non-Hodgkin lymphoma (NHL) or Hodgkin Lymphoma (HL) were enrolled into a phase I trial of escalating doses of LBH589 and RAD001. The doses are shown in the table. The study utilized a 3+ 3 design with MTD defined as the maximum dose resulting in less than 2 dose limiting toxicities (DLT) during the first cycle among 6 patients treated at that dose. DLT was defined as a grade 4 neutropenia or thrombocytopenia lasting >= 7 days, febrile neutropenia or any other grade >=3 non-hematologic toxicity considered possibly related to the drugs. Once MTD was determined, patients were enrolled into two separate phase 2 studies, one for relapsed MM and another for relapsed NHL or HL. Results: Twenty-six patients were enrolled to the phase 1 study; 23 were eligible for MTD analysis. There were 16 patients with NHL, 4 with HL and 3 with MM. Median age was 61 (range, 24–73) and 17 were male. The median number of prior therapies was 4 (range 2–11), including a prior stem cell transplant in 11 (48%). No DLT was observed at any of the doses tested in the trial (See below). Hematological toxicities were the most common AEs observed, with a grade 3 or 4 hematologic AE in 15 patients and grade 3 or 4 non-hematologic AEs in 6 patients across all cycles administered. Grade 3 and 4 hematologic AEs included 10 patients with neutropenia and 8 patients with thrombocytopenia. Grade 3 and 4 non-hematologic AEs included hyperglycemia, hypertriglyceridemia, hypophosphatemia, diarrhea, pneumonia and mucositis in one patient each. Overall, 10 responses (43%) were seen (Table). Conclusions: The combination of LBH589 and RAD0001 is tolerated at the doses tested, with hematological toxicities being the most common adverse events. The recommended phase II dose is LBH 40 mg MWF every other week along with 5 mg RAD001 every day in 4-week cycles. Clinical efficacy was seen in all diseases tested with partial responses seen in NHL and HL as well as a minor response in a patient with refractory myeloma, who had previously failed single agent RAD001. Phase 2 trials are ongoing in both disease groups. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding. Reeder:Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

Abstract Abstract 2741 Background: The novel agent lenalidomide (LEN) has shown significant single-agent activity in patients with relapsed lymphoma through anti-proliferative and immunomodulatory mechanisms. In combination LEN may synergistically improve the efficacy of rituximab. However, there is limited data on the efficacy and safety of LEN in multi-drug combination regimens for treatment-naïve patients. We designed a phase II single arm trial to evaluate tumor response, toxicity (AE) and survival with a combination of LEN, rituximab, cyclophosphamide (CTX) and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with indolent B-cell lymphoma. (NCT00784927). Methods: Eligibility required age ≥18, ECOG PS ≤2, confirmed diagnosis of indolent B-cell lymphoma (FL1–2, SLL, MZL or LPL/WM), measurable nodes ≥2cm or IgM ≥400mg/dL (LPL/WM), ANC ≥1400/mm3, platelets ≥100,000/mm3, creatinine ≤2mg/dL, and signed informed consent. Only patients needing therapy were considered eligible. Treatment consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1–21, CTX 250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 28 day cycle. Treatment continued 2 cycles beyond best response up to a maximum of 12 cycles. Toxicity was assessed by NCI CTCAE v3.0. Results: Thirty-one patients have enrolled at Mayo Clinic with 28 evaluable for toxicity and response (1 deemed ineligible, 1 withdrew before treatment, 1 treatment violation). Four patients continue on study at this time. Patient characteristics: median age 68.5(43–83), 71% male, stage IV 86%, FL 28%, MZL 25%, LPL/WM 39%, and SLL 4%. Median number of cycles given was 6 and 71% completed the study per protocol. The best overall response is 89% with 32% CR and 57% PR. In subgroup analysis, the response rates for LPL/WM was 91% (all PR) and for FL 88% (CR 63%, PR 25%). The most common grade ≥3 AEs were neutropenia (35.7%), leukopenia (17.8%), anemia (14.3%) and thrombosis (14.3%). The LPL/WM subgroup experienced more grade ≥3 anemia (36%) compared to the group as a whole. Patients (57%) required at least one dose reduction of LEN (n =10), CTX (n = 9) or DEX (n = 7). At a median f/u of 14.5 (1.8–36.5) months 86% are progression free (fig. 1) and the OS is 96% (fig. 2). One death unrelated to treatment occurred 7.7 months after completing 12 cycles of treatment. Conclusion: Lenalidomide can be safely combined with other active agents and in the combination LR-CD produces high response rates in symptomatic patients with indolent B-cell lymphoma. The regimen is well tolerated with manageable toxicities which are similar to that seen with single agent LEN. The encouraging results seen in patients with LPL/WM have led to expansion of this cohort for additional study. Disclosures: Reeder: Celgene: Research Funding. Off Label Use: lenalidomide use in non-Hodgkin lymphoma. Stewart:Celgene: Consultancy, Honoraria.

35 Background: Studies suggest cancer patients frequently misunderstand information about cancer treatment. Doctors and nurses often give cancer patients written information such as internet-downloaded printouts about chemotherapy. We observed that cancer patients at Mayo Clinic often cannot recall cancer drug names and expected side effects, despite receiving written information. We investigated whether pocket cards [PC] could improve drug name and side effect recall compared to written information alone. Methods: We randomized 100 cancer patients starting chemotherapy to receive PC plus written information or written information alone. Each PC listed the drug name and 3-5 common drug side effects. Written information included a Mayo Clinic produced drug information sheet and printed information from the CareNotes System (Thomson Reuters), with each sheet listing a drug’s name and common side effects. Cancer patients were tested for drug names and side effects recalled at treatment start, again at 4-6 weeks, and again at 8-10 weeks. Results: Of 100 cancer patients randomized (50 to PC plus written information and 50 to written information alone), 66 completed the study. Demographics: median age 64 years (24-81 years); 41 male; 59 female. At 8-10 weeks, no significant difference between groups was observed for drug names recalled correctly (p = 0.79) or median side effects recalled (p = 0.34). Drug name recall declined at 8-10 weeks (29% named drug names correctly at treatment start versus 20% at 8-10 weeks). Median side effects recalled was unchanged at 8-10 weeks (p = 0.19). Conclusions: PC do not appear to improve cancer patients’ drug name recall better that written information alone, nor do PC increase recall of drug side effects. Patient recall of drug names decreases over time. Additional education provided several weeks after chemotherapy has begun may be warranted to reinforce patient knowledge of important treatment-related information.

Purpose: To report the outcomes of patients with favorable risk oropharyngeal cancer that underwent adjuvant radiation therapy with omission of the primary site from the clinical target volume (CTV). Material/Methods: A retrospective study of 40 patients treated with transoral surgery (TOS) followed by neck only radiation using intensity modulated radiation therapy (IMRT) with exclusion of the primary site. For all patients, a CTV of the primary surgical bed was contoured to obtain the estimated incidental dose to the primary site. Results: Median follow-up was 51 months (range, 13-155 months). The median radiation therapy (RT) dose to the neck was 6000 cGy (range, 5400-6400 cGy). The mean incidental dose to the primary tonsillar site was 4320 cGy (SD ± 480 cGy) and to the primary base of tongue site was 4060 cGy (SD ± 420 cGy). There were no local failures and only 1 regional failure, resulting in 97.5% locoregional control rate at 4 years. Two patients developed distant metastases, without evidence of locoregional recurrence, for a 4-year overall survival rate of 97%. Conclusions: Our analysis suggests that mucosal sparing RT after TOS in favorable risk oropharyngeal cancer patients may provide comparable oncologic and improved functional outcomes compared to conventional treatment in selected patients.