Camoriano, John

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.

Abstract Background: Myelofibrosis with myeloid metaplasia (MMM) is a progressive and fatal myeloproliferative disorder with limited therapeutic options. R115777 is a non-peptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) which we recently reported has in vitro activity against aberrant myeloid progenitors from MMM patients (Leukemia2003;17:849). This observation, coupled with the clinical activity demonstrated in high risk acute myeloid leukemia (Blood2001;97:3361) and chronic myeloid disorders (Blood2003;101:1692) led us to perform a Phase II trial in patients (pts) with MMM. Methods: Eligible pts had histologically confirmed MMM and were symptomatic, defined by anemia (hemoglobin<10g/dL or transfusion dependent) or palpable hepatosplenomegaly. Pts received 300 mg of R115777 orally twice daily for the first 21 days of a 28 day cycle. Dose escalations (up to 1200mg/day) and reductions (down to 100mg/day) were allowed based on activity and toxicity. The primary endpoint was response as defined by improvement in either anemia or organomegaly. Results: 34 pts (median age 65 yrs, range 55–80; 71% male) were enrolled in the trial. All pts displayed symptomatic disease at enrollment, with 10 who were erythrocyte transfusion dependent; and 19 (56%) had a Lille MMM prognostic score ≥1; no pts were significantly thrombocytopenic at entry by enrollment criteria. Median pre-study spleen and liver sizes were 12 cm (range: 0–35) and 2 cm (range: 0–15) below the left and right costal margin, respectively. Median time to discontinuation of therapy was 5.5 months (95% CI:2.9–6.4). Reasons for early termination were progression (7), adverse reactions (5), co-morbidities (2), refusal of further treatment (2), and death on study (1). One pt died of grade 5 pneumonitis two weeks after study enrollment, which was felt to be unrelated to study treatment. Significant toxicities (≥ grade 3) were seen for myelosuppression (n=13), neuropathy (n=2), fatigue (n=1), rash (n=1) and hyponatremia (n=1). Overall, R115777 resulted in little improvement in anemia, with the exception of one anemia-based partial response. However, the myelosuppressive aspects of the agent may have masked improvements in cytopenias. In contrast, R115777 did result in clinically relevant decreases in organomegaly in 11 pts (33%) (splenomegaly in 3 pts, hepatomegaly in 5 pts, and both in an additional 3 pts.) Across all pts who had some reduction in splenomegaly, the median maximal reduction was 42.5% (of palpable component; range: 8–100%). Likewise, all patients with baseline hepatomegaly had resolution of this problem at some point during therapy. Four pts remain on the agent (from 14 to 22 months) for continued and sustained improvement in organomegaly. Responses observed did not significantly correlate with reductions in bone marrow fibrosis, osteosclerosis, neoangiogenesis, or resolution of baseline karyotypic abnormalities. Conclusions: R115777 has demonstrated preliminary activity against MMM associated organomegaly. Whether this latter benefit is independent of R115777 induced myelosuppression is unclear. The myelosuppression observed was generally mild and without clinical consequence, although it was difficult to differentiate between myelosuppression versus disease progression. Pts continue to be followed to evaluate durability of observed responses, long term effects on anemia and intramedullary manifestations of the disease.

Abstract Abstract 5061 Background: Ruxolitinib was approved for commercial use for the therapy of intermediate- and high-risk myelofibrosis (MF) in the USA in November 2011. We sought to assess the initial clinical experience on the use of ruxolitinib outside of the clinical trial setting at our high volume MPN program. Methods: Twenty-eight patients with intermediate- or high-risk myelofibrosis (including PMF, post-PV and post-ET myelofibrosis) prescribed ruxolitinib at our center within the first seven months after FDA approval were included in this analysis. Baseline disease information, treatment history, dynamics of ruxolitinib dosing, impact on cytopenias, splenic response, and symptoms were assessed. Results: A total of 28 patients with post-ET MF (n=7), post-PV MF (n=6) and primary MF (n=15) began ruxolitinib between November, 2011 and May, 2012. Twenty-seven patients had been treated with previous therapies. The JAK2V617F mutation was present in 79% of patients. The mean number of weeks from diagnosis of MF to treatment with ruxolitinib was 218 (8–929). The average spleen size at the start of therapy was 11. 5cm (0–36) below the left costal margin. DIPSS Plus scores classified patients as Intermediate-1 (53%), Intermediate-2 (29%) and High risk (18%). Symptoms at the start of therapy included fatigue (78%), early satiety (25%), night-sweats (68%), abdominal pain (61%), pruritis (32%), weight-loss (57%), bone pain (21%), and fevers (11%). The average hemoglobin concentration, WBC count and platelet counts were 10. 9 g/dL (7. 6–13. 8), 13. 5 × 10(9)/L (3. 1–53. 8) and 295 × 10(9)/L (32–844) respectively. The median duration to follow-up was 72 days (4–144 days). The majority of patients began therapy at 20 mg BID (68%). Most patients seen in follow-up experienced reduction in splenic size (64%), 36% of which had complete resolution of palpable splenomegaly within a mean follow-up of 78 days (10–142). Significant improvements were noted in symptoms including fatigue (68%), early satiety (71%), night sweats (47%), abdominal pain (71%), pruritis (55%), weight loss (69%), bone pain (33%) and fevers (33%). Dosage reductions were required for four patients with anemia (n=3) and thrombocytopenia (n=1). Two patients required the addition of anagrelide/hydroxyurea for platelet counts >1, 000 × 10(9)/L. Excluding patients with preexisting thrombocytosis >600 × 10(9)/L, the percentage reduction of platelets from baseline by weeks 4, 9 and 15 were 34%, 13%, and 12% respectively. Eight patients required red blood cell transfusions for anemia, three of which who had begun therapy with hemoglobin concentrations under 9 g/dL. Excluding the 8 transfusion-dependent patients, the percentage reduction in hemoglobin concentration from baseline by weeks 4, 9, and 15 was 7%, 6%, and 14% respectively. Non-hematological toxicities requiring dosage adjustments included hyperkalemia (n=1) and fatigue/dizziness/headaches (n=1). Five patients underwent dose increases for lack splenic (n=3) and symptomatic (n=2) response. Six patients discontinued the drug for disease progression requiring stem cell transplant (n=2), lack of constitutional symptom improvement (n=1), diarrhea (n=1), thrombocytopenia (n=1) and anemia (n=2). Five patients had platelet counts below 100 × 10(9)/L (19–94 × 10(9)/L) and began therapy at reduced starting doses. All patients seen in follow-up reported significant improvements in symptoms and splenomegly was reduced >50% in two patients seen in follow-up within 4 weeks of initiating therapy. Two patients underwent dose increases after 5 months of therapy to enhance response. No bleeding events were reported. By week 15, no decrease was noted in platelet levels from baseline in the 3 patients seen in follow-up. Two patients required danzol (n=1) or platelet transfusions (n=1) for thrombocytopenia. Conclusion: Randomized controlled trials have proven ruxolitinib's efficacy in reducing constitutional symptoms, cytopenias and splenomegaly in myelofibrosis patients. This study represents a confirmation of the efficacy this drug provides in reducing splenomegaly and symptoms observed in clinical trials when utilized in a standard practice setting. Toxicities are minimal and have been generally well controlled with dose reductions, even in patients with baseline thrombocytopenia. In conclusion, ruoxlitinib appears to be an efficacious and well-tolerated therapy with limited adverse effects. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

5510 Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT02657928.

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetites in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetites and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P = .03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P = .06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.

AbstractPatients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m2 day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m2 days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenström's macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long‐term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 × 106/L, an absolute neutrophil count >1,000 × 106/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60–84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1–26). The median duration of response has not been reached and median progression‐free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single‐agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM. Am. J. Hematol. 89:237–242, 2014. © 2013 Wiley Periodicals, Inc

Purpose The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenström macroglobulinemia (WM). Patients and Methods Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 × 10 6 /L, a neutrophil count more than 1,000 × 10 6 /L, and a creatinine and bilirubin less than 2 × the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% CI, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% CI, 64% to 89%) and 62% (95% CI, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusion Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.

Purpose A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma. Patients and Methods Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life. Results Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook. Conclusion The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.