Patients Required Dose Modification Research Articles

Practice patterns and outcomes with the use of regorafenib in metastatic colorectal cancer: Results from the Regorafenib in Metastatic colorectal cancer - An Indian exploratory analysis study.

Background:Regorafenib is considered a standard of care as third-line therapy in metastatic colorectal cancers (mCRCs).Materials and Methods:The study was based on a computerized clinical data form sent to oncologists across the country for entry of anonymized patient data. The data entry form was conceived and generated by the coordinating center's (Tata Memorial Hospital) gastrointestinal medical oncologists and disseminated through personal contacts at academic conferences as well as through E-mail to various oncologists across India.Results:A total of 19 physicians contributed data resulting in 80 patients receiving regorafenib who were available for the evaluation of practice patterns. The median age was 55 years (range: 24–75). Majority had received oxaliplatin-based (97.5%), irinotecan-based (87.5%), and targeted therapy (65%), previously. Patients were primarily started on reduced doses of regorafenib upfront (160 mg – 28.8%, 120 mg – 58.8%, and 80 mg – 12.5%). The median duration of treatment (treatment duration) with regorafenib was 3.1 months (range: 0.5–18), while the median progression free survival was 3.48 months (range: 2.6–4.3). Forty-five percent of patients required dose modifications due to toxicities, and the most common were (all grades) hand-foot syndrome (68.8%), fatigue (46.3%), mucositis (37.6%), and diarrhea (31.3%).Conclusions:Majority of physicians in this collaborative study from India used a lower dose of regorafenib at the outset in patients with mCRC. Despite a lower dose, there was a significant requirement for dose reduction. Duration of treatment with regorafenib as an efficacy end point in this study is similar to available data from other regions as it is the side effect profile.

Clinical Outcomes and Molecular Responses in Children with Langerhans Cell Histiocytosis Treated with MAPK Pathway Inhibitors

Background: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplasia. Activating somatic mutations in MAPK pathway genes have been identified in almost all cases of LCH with BRAF-V600E as the most common somatic mutation, occurring in approximately 60% of lesions. Enforced expression of BRAF-V600E in myeloid precursors recapitulates an LCH-like phenotype in mice, supporting a central pathogenic role for MAPK activation in LCH. Given the near universal occurrence and central pathogenic role of activating MAPK pathway gene mutations in LCH, targeted inhibition of the MAPK pathway is a rationale therapeutic strategy to explore in patients with relapsed disease.Design/Methods: Medical records from 20 pediatric patients with LCH (systemic and/or LCH-associated neurodegeneration) from 12 institutions were systematically reviewed; 2 patients had disease which was mixed LCH with juvenile xanthogranuloma (JXG) and 2 patients had secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). All patients had failed at least one prior systemic therapy and had a proven MAPK pathway somatic mutation. Response assessment was based on applicable criteria for each individual including PET (metabolic) criteria, bone marrow evaluation, brain MRI, clinical history and physical exam.Results: All patients in this series were less than 21 years old (median age at start of therapy 6.9 years; range: 0.4-20.7 years) with median disease duration of 4 years prior to start of MAPK inhibitor (range 0.07-18.4 years). Twelve patients had LCH-ND diagnosed clinically and/or by radiographic imaging, while the remaining 8 patients had systemic disease with no LCH-ND (7 with high risk organ involvement).In terms of best response, 3 patients (15%) achieved a complete response (CR) and eleven patients (55%) achieved a partial response (PR), while 3 patients (15%) only achieved stable disease (SD), and 1 patient (5%) died early on in therapy due to progressive disease (PD) complicated by secondary HLH/MAS. Of the 12 patients who had LCH-ND, none achieved a CR, but 10 (83%) had a best response of PR by either clinical or radiographic assessment. Median progression free survival (PFS) was 11.8 months (range 2-36 months), while median time to disease progression or recurrence was 4.6 months (range 1-46 months). Four of the 20 patients (20%) had a Grade 3 or 4 toxicity; 2 of these patients required dose modification in order to successfully resume therapy.Seven patients had measurable peripheral blood mononuclear cells (PBMC) or bone marrow cells with detectable BRAF-V600E mutation just prior to start of MAPK inhibitor with subsequent assessments obtained during therapy.Conclusions: MAPK pathway inhibitors may be a relatively safe salvage therapy for refractory systemic LCH and LCH-ND but the efficacy and durability of responses with this strategy remains to be delineated. Children with relapsed/refractory high-risk LCH who were at the highest risk of death from disease generally benefited from this strategy. Patients with longstanding neurodegenerative disease seem to have the least benefit from MAPK inhibitors. However, patients with relatively early onset neurodegenerative disease, especially without clinical manifestations, seem to have the greatest benefit. While the presence of persistent BRAF-V600E+ circulating cells appears to be associated with risk of relapse and type of LCH organ involvement, quantifiable changes in these levels did not consistently correlate with clinical disease activity or response (in contrast to those treated with chemotherapy). We hypothesize that inhibition of the MAPK pathway may confer clinical benefit by blocking differentiation and proliferation of lesions, but may not have cytotoxic effect on precursor cells. This is supported by the observation that MAPK regulates lesion progression by inhibiting CCR7 expression, thereby blocking emigration of LCH cells from the lesion. Persistence of BRAF-V600E+ mononuclear cells in blood and bone marrow even in patients with impressive clinical responses may underlie the high rates of eventual progression/relapse with this type of treatment. Future prospective trials of MAPK pathway inhibitors for patients with refractory LCH possibly in combination with chemotherapy will be needed in order to directly compare their efficacy and toxicity relative to other current salvage strategies. DisclosuresNo relevant conflicts of interest to declare.

Modified 5-fluorouracil/leucovorin/irinotecan as a feasible and efficacious second-line chemotherapeutic regimen in advanced gastric cancers.

Background:Modified 5-fluorouracil/leucovorin/irinotecan (mFOLFIRI) is a commonly used combination second-line chemotherapeutic regimen in advanced gastric cancer (AGC).Materials and Methods:Patients diagnosed with AGC, receiving biweekly mFOLFIRI between July 2013 and June 2016, as second-line chemotherapy were retrospectively analyzed for tolerance, prognostic factors, event-free survival (EFS), and overall survival (OS).Results:Overall, 91 patients were administered a median of 6 cycles of therapy. Response rate was 29.7% and clinical benefit rate was 57.2%. With a median follow-up of 11.5 months, median EFS was 3.98 months (95% confidence interval [CI]: 2.54–5.41) and median OS was 7.73 months (95% CI: 5.30–10.15). Common Grade 3 and Grade 4 adverse events were neutropenia (18.7%), febrile neutropenia (9.9%), thrombocytopenia (7.7%), and vomiting (4.4%). Nearly 33% of patients required dose modification during therapy.Conclusions:mFOLFIRI regimen as a second-line therapy in AGCs appears feasible and efficacious in clinical practice.

Side effect profile of hepatitis C treatment with peginterferon alpha-2b and ribavarin

Background: The major types of side effects include fatigue, influenza-like symptoms, gastrointestinal disturbances, neuropsychiatric symptoms and hematologic abnormalities. These side effects may be treatment limiting and require dose reduction or drug discontinuation objectives of the study was to assess the side effect profile of hepatitis C treatment (peginterferon alpha-2b and ribavarin) in Kashmiri patients attending the Department of Gastroenterology skims.Methods: In this study, all consecutive patients of hepatitis C infection on peginterfron and ribavarin treatment were enrolled after written consent. The patients underwent intervention treatment taking pegylated interferon α-2b (Viraferon, Schering Plough Corp., Kenilworth, NJ) and ribavirin in accordance with the standard protocol. Patients were monitored through weekly referrals while taking the medications. A detailed history was taken and complete physical examination done each time the patient presented to the hospital necessary blood sampling was taken.Results: During the study period of 2 years,105 Patients were enrolled 55 (52.4%) were males with a male:female ratio of 1.1:1.0. and mean age 37.6 years with a range of 13-75 years 7 patients (6.6) had a history of needle pricks, 4 patients (2.2%) of sharing same razors at barber’s shop. 4 (3.8%) patients of drug abuse; out of which 3 (2.8%) were intravenous drug abusers, Anemia occurred in 17 (16.2%) patients with requirement of dose modification w in 11 (10.4%) patients and dose stoppage in 1 (0.95%) patient in whom Hb dropped to less than 7, thrombocytopenia occurred in 27 (25.7%) patients with requirement of dose modification in 13 (12.3%) patients and dose stoppage in 1 (0.95%) patients due to platelet count decreasing to less than 30,000. Neutropenia as defined by ANC less than 1500 occurred in 22 (20.9%) patients.Conclusions: Dose modification was required in 48 (45.7%) patients, 30 (28.5%) patients required dose modifications due to labortory abnormalities and 18 (17.1%) due to other side effects. In 8 (7.6%) patients dose was discontinued due to adverse events (including psychosis in 1, severe flu like symptoms in 3, dermatitis in 1, depression in 3).

Efficacy of alternating-week fixed dose rate gemcitabine (FDR gem) plus capecitabine (CAP) in advanced pancreatic cancer (APC).

e15758 Background: Phase III trials support the use of FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel as first-line treatment options in patients with APC. However, these treatments have significant side effects including cumulative neuropathy and cytopenias that limit their use. Our group previously reported results from a phase II trial evaluating a regimen of alternating-week FDR GEM/CAP showing promising efficacy as well as good tolerability. In the current analysis, we examined a larger retrospective cohort of APC patients treated using this strategy. Methods: Eligible patients received FDR GEM (1000 mg/m2) infusion on days 1 and 15, along with CAP 1,000 mg/m2 on days 1 to 7 and 15-22, in 28-day cycles. We evaluated OS, PFS, and objective radiologic response (ORR) by RECIST 1.1; as well as tabulated adverse events that necessitated dose or schedule modification. Results: 62 patients were treated at UCSF from 2008-2016 (52% male; and 48% female with a median age of 64.3 years. 49 had metastatic disease and 13 were locally advanced. Median OS was 10.3 and 12.0 months in the metastatic and locally advanced cohorts, respectively; median PFS was 5.4 and 5.6 months. ORR in evaluable patients with metastatic disease was 19% (all partial responses), with a disease control rate of 64%. In total, 37% of patients required dose modification at some point during therapy; the most common reason was hand-foot syndrome. Conclusions: FDR GEM/CAP represents an active and safe regimen for patients with APC, with OS and PFS rates comparable to those achieved with other first-line treatments. This regimen, based on its ease of administration and tolerability, may represent a suitable alternative option in select patients.

Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: feasible and efficacious.

A median progression free survival (PFS) of 18-20 months and median overall survival (OS) of 51-57 months can be achieved with the use of imatinib, in metastatic or advanced gastrointestinal stromal tumor (GIST). Sunitinib and regorafenib are approved options for patients progressing on imatinib, but with markedly decreased survival. pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR receptors and has shown promising activity in phase 2 trials in GIST. All patients who received pazopanib for GIST between March 2014 and September 2015 in our institution were reviewed. Patients were assessed for response with CT or PET CT scans. Patients continued pazopanib until progression or unacceptable toxicity. Survival was evaluated by Kaplan Meier product method. A total of 11 consecutive patients were included in our study. Median duration of follow up was seven months. The median lines of prior therapy was 2 [1-5]. Partial response (PR) was observed in seven patients and two had stable disease (SD). Two patients died within one month of start of pazopanib. Five of ten patients had progressed during the study with eight patients still alive. The median PFS was 11.9 months and the median OS was not reached. Common adverse events seen were hand-foot-syndrome (HFS) in four patients, anemia in four patients and fatigue in three patients. Grade 3/4 adverse events were uncommon. Three patients required dose modification of pazopanib. Pazopanib is a reasonably efficacious well tolerated TKI and can be explored as a treatment option in advanced GIST that has progressed on imatinib.

Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma

Sirolimus, an oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases, by vertical disruption of vascular epithelial growth factor receptor (VEGFR) signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients and also by directly inhibiting tumor cell proliferation. We conducted this phase 1 study to investigate the maximum tolerated dose (MTD) for this combination of sunitinib and sirolimus in humans. Sunitinib was given at 50mg daily×28 every 6weeks. The first cohort received sunitinib alone for cycle 1 (50mg daily for 2weeks followed by 2weeks off) and received sunitinib at standard dose 50mg daily for 4weeks followed by 2weeks off in combination with sirolimus 4mg weekly; this dose and schedule were further investigated in second cohort. The third cohort received decreased dose of sunitinib at 37.5mg daily for 4weeks followed by 2weeks off in combination with sirolimus at 4mg weekly. Sirolimus dose was escalated to 8mg weekly in fourth cohort. Eighteen patients with ECOG PS of 0 or 1 were enrolled, median age 57years (range 24-76), M:F ratio: 11:7. Median number of prior treatments is 2 (range 0-5); six patients had no prior systemic therapy. Half of patients from the first two cohorts required dose reduction or early discontinuation of treatment; therefore, sunitinib dose was decreased to 37.5mg daily in third and fourth cohort. In third and fourth cohort, one-third of patients required dose modification during cycle 1 or cycle 2. Multiple patients had significant toxicities including fatigue and hand-foot syndrome. One patient developed interstitial pneumonitis, and one patient died suddenly on day 8 due to progressive disease. There were six patients who tolerated four or more cycles. Among these six patients, two patients with renal cell carcinoma (RCC) achieved partial response; one subsequently underwent surgical resection of residual renal mass and lymph node dissection and achieved complete response afterward. One with metastatic melanoma also achieved complete response after metastatectomy. There was no apparent pharmacokinetic interaction between sunitinib and sirolimus. 4mg weekly sirolimus did not reduce the sunitinib-induced circulating VEGF production but stimulated more VEGF production through some unknown compensatory mechanism. Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.

Adjuvant sorafenib for liver cancer: wrong stage, wrong dose

Adjuvant sorafenib for liver cancer: wrong stage, wrong dose

Osteosarcoma in Patients with Rothmund–Thomson Syndrome

Background: Rothmund–Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited. Procedure: Seven patients with osteosarcoma, treated in the Cooperative Osteosarcoma Study Group-trials, had a diagnosis of RTS. Their patient-, tumor- and treatment-related variables and outcome were reviewed retrospectively. Results: Median age at diagnosis of osteosarcoma was 13 years (range 7–16), five were female, two male. Tumor involved proximal tibia (n = 4), distal tibia (n = 1), distal fibula (n = 1) and proximal ulna (n = 1). Three patients had metastatic disease at diagnosis. All patients received surgery and chemotherapy. Four of seven patients required dose modifications and three of them terminated treatment prematurely. Complete resection of the primary tumor was achieved in all individuals. Two of three affected patients failed to achieve surgical clearance of their primary metastases and died. The third patient relapsed with multiple metastases and died. Two of four patients with localized disease were alive in first complete remission, a third patient in second complete remission after recurrence and a fourth patient died of acute leukemia, while still in first complete remission of osteosarcoma. Conclusions: Patients with RTS and osteosarcoma may be cured of their cancer with appropriate multimodal therapy. They should be treated like other osteosarcoma patients but preexisting disorders, needs for special support and development of toxicities have to be considered.

Sa1052 Triple Therapy Under Real Life Conditions: Telaprevir (TVR) in Combination With Peginterferon-Alfa-2A Plus Ribavirin (P/R) in NaïVE Patients Infected With Chronic Hepatitis C, Genotype 1. The PAN Study

the first 12weeks 11.9% and 5.9% of the patients required dose modifications of ribavirin and peginterferon alfa-2a, respectively and 2 (3.0%) and 17 (25.4%) patients had haemoglobin ,8.5 g/dL and ≥8.5 but ,10 g/dL respectively. Adverse events reported in at least 15% of patients included fatigue (52.9%), nausea (26.5%), headache (25.0%), skin disorder (23.5%), dysgeusia (19.1%), pruritus (19.1%), myalgia (17.6%), anaemia (16.2%) andarthralgia (16.2%). Conclusion: Real world experience with BOC plus peginterferon alfa2a/ribavirin in Germany show similar virological outcomes and side effects to the phase 3 trials. Week 8 HCV RNA values essential to determine suitability for reduced treatment duration were not collected in a significant proportion of patients.

Abstract 870: A clinical study of ABT-806, a humanized recombinant anti-EGFR monoclonal antibody, in patients with recurrent glioblastoma multiforme.

Abstract Background: Glioblastoma (GBM), the most common primary CNS malignancy, has a dismal prognosis with a median survival of under 15 months. Epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in GBM and has been implicated in tumor growth and resistance to therapy. ABT-806 is a humanized recombinant IgG1k monoclonal antibody that binds to a unique EGFR epitope exposed only in the untethered, (activated) state of EGFR or when the de2-7 (EGFRvIII) deletion mutation is present. ABT-806 has shown significant antitumor activity over other EGFR antibodies in both in vitro and in vivo models of GBM. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of ABT-806 in a cohort of recurrent GBM patients treated at the recommended phase 2 dose determined from the dose-escalation portion of this phase 1 study. Methods: Patients with recurrent, EGFR-amplified GBM and measurable disease by RECIST (v1.1) were included. ABT-806 was administered at 24 mg/kg intravenously every other week until disease progression or study withdrawal. Tumor response by MRI or CT was assessed every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.0. Serum samples for determination of ABT-806 concentration and antidrug antibody were collected at multiple time points throughout the study. Archival tumor analysis for EGFR amplification/mutation was also performed. Results: Among 11 patients; median age was 60 years (range 39 to 69) and 9 were male. Median number of prior therapies was 2 (range 1 to 7). Six patients had prior bevacizumab exposure. No patients required dose modification. Hypophosphatemia was the only treatment-related emergent AE that occurred in 2 or more patients. Best responses were n=3 stable disease, n=7 progressive disease. One patient withdrew consent prior to the first post-baseline tumor assessment. Median time to disease progression and median progression free survival [95% CI] were 43 [22,57] and 29 [25,57] days, respectively. PK and EGFRde2-7 data were not available at the time of abstract submission. Conclusions: While ABT-806 related AEs were infrequent, there was little evidence of a clinical benefit in this refractory GBM population. Whether the lack of significant anti-tumor effect was due to poor binding to intracranial tumors, lack of response to the mechanism of action, or the refractory population is to be determined. A study is ongoing to evaluate the biodistribution of 111Indium-labeled ABT-806 in pts with advanced solid tumor types, including GBM. Further preclinical efforts to increase the potency of ABT-806 are also ongoing. Citation Format: David A. Reardon, James M. Cleary, Hao Xiong, Wijith P. Munasinghe, Ya-Hui Hsu, Edward B. Reilly, Jiang Qian, Michelle S. Pedersen, Rod A. Humerickhouse, Kyle D. Holen. A clinical study of ABT-806, a humanized recombinant anti-EGFR monoclonal antibody, in patients with recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 870. doi:10.1158/1538-7445.AM2013-870

920P - ARN-509 in Men with High Risk Non-Metastatic Castration-Resistant Prostate Cancer

ABSTRACT Background ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC (high risk non-metastatic CRPC, metastatic treatment-naive CRPC, and progressive disease after abiraterone acetate). Preliminary results for the cohort of patients with high-risk non-metastatic CRPC are presented here. Methods All patients had CRPC, no radiographic evidence of metastases (pelvic lymph nodes Results Fifty patients were enrolled between November 2011 and May 2012. The median age was 72 years (range 51 to 86) and at baseline, patients presented with ECOG performance status 0 (67%), Gleason Score 8-10 (38%), and median PSA of 11.5 ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 8 weeks, only one patient discontinued the study (due to inability to comply with the protocol). The most common adverse events (AE) were fatigue (13%), diarrhea (9%), nausea (6%) and abdominal pain (6%). There were no Grade > 2 AEs and no patients required dose modifications. At 12 weeks, 17/19 patients (89.5%) of patients had a PSA response. The median decrease in PSA from baseline to week 12 was 83.3%. Conclusion In men with high-risk non-metastatic CRPC, ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA response rates. Disclosure E. Chow-Maneval: As an employee of Aragon Pharmaceuticals, I have stock ownership in Aragon Pharmaceuticals.All other authors have declared no conflicts of interest.

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).

Phase II Trial of Weekly Docetaxel, Vinorelbine, and Trastuzumab in the First-Line Treatment of Patients with HER2-Positive Metastatic Breast Cancer

Background The combinations of trastuzumab/docetaxel and trastuzumab/vinorelbine are highly active in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We investigated the feasibility and safety of a 3-drug combination of trastuzumab, docetaxel, and vinorelbine as first-line therapy in this patient group. Patients and Methods Sixty patients with previously untreated, measurable HER2-positive MBC (immunohistochemistry 3+ and/or fluorescence in situ hybridization positive) were treated with docetaxel 30 mg/m 2 intravenously (I.V.) and vinorelbine 25 mg/m 2 I.V. on days 1 and 8 of each 3-week cycle. Trastuzumab was given weekly (4-mg/kg loading dose followed by 2 mg/kg/week). Patients were evaluated after 6 weeks; responders/stable patients continued treatment until progression. Results Patients received a median of 11 treatment cycles (range, 1–22 cycles). Forty-one of 60 patients (68%) had major responses (16 complete responses [27%], 25 partial responses [42%]). An additional 13 patients (22%) had stable disease for ≥ 6 months. After a median follow-up of 58 months, median progression-free survival was 12 months (95% CI, 9.1–16.3 months), and the median overall survival was 40.8 months (95% CI, 25-not reached). Neutropenia (72% grade 4) was the most common hematologic toxicity; 8 patients were hospitalized for febrile neutropenia. A total of 67% of patients required dose modifications for neutropenia during cycles 1 or 2. Other grade 3/4 toxicities included fatigue (12%), hyperglycemia (7%), and myalgias (7%). There were no treatment-related deaths. Conclusion The combination of trastuzumab, docetaxel, and vinorelbine is highly active as first-line treatment for patients with HER2-positive MBC. However, this regimen offers no obvious advantages over other less myelosuppressive trastuzumab-containing regimens, and its routine use is not supported by the study.

A Single-Center Study To Evaluate the Safety and Efficacy of Intravenous/Oral Fludarabine in Untreated Gastric MALT Lymphoma. Impact of t(11;18)(q21;q21) in Molecular Response Rates.

Background: The treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in the absence of H. pylori infection or when the lymphoma fails to regress after adequate antibiotic treatment remains controversial. Fludarabine (F) is an active agent for indolent lymphoma, however, its clinical activity in gastric MALT lymphoma has not been studied. The aim of the study is to assess the efficacy and safety of single-agent fludarabine in gastric MALT lymphoma and to analyze the molecular response (MR) after this treatment.Methods: Treatment consisted of fludarabine (25 mg/m2 IV) given on days 1–5, every 4 weeks, for 6 cycles; after the first cycle, oral fludarabine was allowed to be given orally at 40 mg/m2 with the same schedule. Molecular response (MR) was assessed by RT-PCR analysis of t(11;18) or by PCR assays for analysis of IgH gene rearrangements analyzing FR1, FR2 and FR3 in endoscopic biopsies.Results: Eight consecutive patients were included. Median age: 60 years (range: 45–77); 3 pts were in stage I, 2 stage II-1 and 3 stage IV according to Lugano system. Four out of 5 (80%) pts achieved a CR after three cycles and all eight cases (100%) achieved a CR after six cycles, for an overall response rate of 100%. After a median follow-up of 44 months (range 14.5–58 mo) no patient has shown clinical or endoscopic relapse. Hematological toxicity occurred in 75% of pts, mainly mild neutropenia and generally after the third cycle. Three cases received G-CSF (after the 2nd, 3rd and 6th cycle) and three patients required dose modification or delay (3–7 days) in the delivery of the following cycle. No blood transfusions were required. Only one patient had to be admitted because of non-neutropenic fever. None case of myelodisplasia has been detected at last follow-up. Four out of 8 pts (50%) achieved MR during the study-period (see figure). Four out of 5 (80%) pts without t(11;18) achieved MR. In contrast, no patient carrying t(11;18) achieved MR. Sequencing analysis of monoclonal PCR products will be presented.Conclusions: Fludarabine, either intravenous or oral, is safe and achieve a high response rate when given in gastric MALT lymphoma, with many pts achieving MR. In those pts carrying t(11;18), residual disease can be detected by PCR but do not determine relapse at present follow-up. [Display omitted]

HyperCKemia in CML Patients on Imatinib Mesylate.

Imatinib mesylate (IM) is the standard therapy for Philadelphia chromosome positive chronic myelogenous leukemia (CML). It is generally well tolerated with most non-hematologic toxicities being mild to moderate in severity. Muscle cramps and/or myalgia may occur in up to half of patients (pts) treated, particularly with doses of IM > 400 mg/day. Prompted by a case of rhabdomyolysis, we began to monitor creatine kinase (CK) levels in CML patients on IM in 2005. 71 patients with chronic phase CML (diagnosed between 1994 and 2007 and treated with IM between 2000 and 2007) had CK levels done every 3 months. Elevated CK occurred in 33/71 (47%) of patients (30% grade 1; 11% grade 2; 4% grade 3 and 2% grade 4); the majority (91%) (including those with ≥ grade 3 toxicity) were taking ≤ 400 mg/day of IM. Of these 33 patients, 21 had a normal baseline CK. The mean and median duration of IM exposure at the time of first documented CK elevation in these 21 patients was 82.5 weeks and 53 weeks respectively (range 4 – 300 weeks). 36% (12/33) of the patients with elevated CK levels reported associated symptoms (muscle cramps, muscle spasms and/or myalgia): the majority of the adverse events were ≤ grade 2 in severity, with some pts reporting more than 1 symptom. CK elevation was documented once in 8 patients, continuously in 9 patients and intermittently in 16 patients. 7 patients required dose modification; all subsequently had a reduction in CK levels to ≤ grade 1. Of the 38/71 who had normal CK levels, 24% (9/38) reported either grade 1 or 2 muscle cramps and/or myalgia: only 1 of these pts required dose reduction due to muscle related toxicity. Possible factors contributing to CK elevation included hypothyroidism (9 pts), vigorous physical activity (7 pts), antipsychotics (7 pts), cholesterol lowering agents (6 pts), alcohol use (2 pts), beta blockers and infection (1 pt each).Conclusions: 1.hyperCKemia is common in patients on IM for CML (1);2.hyperCKemia is not correlated with myalgia or muscle cramps;3.many patients had multiple potential etiologies for increased serum CK;4.hyperCKemia responds to IM dose modification.

3545 POSTER Long-term results of the phase II study on radiotherapy combined with nedaplatin and 5-FU for postoperative locoregional recurrent esophageal cancer

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m2), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47–75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4–59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m2 of gemcitabine and 100 mg/m2 of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.

Phase IIB Multicenter Trial of Vorinostat in Patients With Persistent, Progressive, or Treatment Refractory Cutaneous T-Cell Lymphoma

To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes. Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until disease progression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must have received at least two prior systemic therapies at least one of which included bexarotene unless intolerable. The primary end point was the objective response rate (ORR) measured by the modified severity weighted assessment tool and secondary end points were time to response (TTR), time to progression (TTP), duration of response (DOR), and pruritus relief ( > or = 3-point improvement on a 10-point visual analog scale). Safety and tolerability were also evaluated. Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients was 56 days. Median DOR was not reached but estimated to be >or = 185 days (34+ to 441+). Median TTP was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinued due to AE. Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.

Use of Sentinel Lymph Node Biopsy and High-dose Interferon in Pediatric Patients With High-risk Melanoma: The Hospital for Sick Children Experience

Melanoma comprises less than 3% of all cancers seen in children. Sentinel lymph node biopsy (SLNBX) is an important predictor of outcome in adult melanoma and has not been widely used in pediatrics. Furthermore, adjuvant interferon has only been rarely used in childhood high-risk disease. To review our experience with high-risk melanoma, the feasibility of SLNBX and the tolerance of high-dose interferon (HDI) therapy. We retrospectively reviewed the medical records of patients with the diagnosis of cutaneous melanoma at our center over a 10-year period. Eleven patients were identified (median age of 12 y). Six of 10 patients who underwent SLNBX had disease in the lymph nodes and no complications from this procedure were observed. After complete lymph node dissection in these 6 patients, 1 developed wound infection and 2 had chronic lymph edema. Five patients were treated with adjuvant HDI of whom 2 patients required dose modification due to myelosuppression and liver toxicity. After a median follow-up of 26 months, 10 out of 11 patients are in remission. SLNBX is feasible and safe in pediatric melanoma and offers the potential to identify patients at high risk for disease progression who could benefit from HDI.

Sildenafil citrate suppresses disease progression in patients with Waldenstrom’s macroglobulinemia

7556 Background: Responses to sildenafil citrate (Viagra), a phosphodiesterase-5 inhibitor used to treat erectile dysfunction, have been observed in patients with Waldenstrom’s Macroglobulinemia (WM). Moreover, sildenafil citrate induces apoptosis of WM lymphoplasmacytic cells (Clin Lymphoma 5:205, 2004). We therefore conducted a prospective phase II study of sildenafil citrate in patients with slowly progressing WM who did not meet consensus eligibility for active therapy (Semin Oncol 2003; 30:116). Intended therapy was as follows: Week 1 25 mg po qD Week 2 50 mg po qD Week 3 75 mg po qD Week 4, then Months 2–24 100mg po qD or Maximum Tolerated Dose Methods: Thirty patients were enrolled, 18 of whom were previously untreated. All patients demonstrated progressing disease prior to enrollment. Median age was 66 (range 43–85 yrs), baseline BM involvement was 30% (range 5–90%), serum IgM was 3,640 (range 790–6,720 mg/dL), hematocrit was 37.1% (range 32.7–58.5%), and B2M was 2.3 (range 1.5–8.9 mg/dL). Patients were evaluable for response after 3 months of therapy. Results: At a median of 3 months, serum IgM levels declined in 19/30 (63%) patients from a median of 3,640 (range 790–6,720 mg/dL) to 2,965 (range 1,170–6,110 mg/dL). 5/30 patients (17%) demonstrated at least a minor response (≥25% IgM decrease). Two patients were taken off study for non-response to therapy. Toxicities were mild and included headaches, sinus congestion, facial flushing, dyspepsia, and generally resolved on their own with prolonged sildenafil citrate usage. Only two patients required dose modification to 25 mg and 75 mg po qD, respectively. Corollary studies to determine putative mechanisms of action for sildenafil citrate in WM were also performed and will be updated at the meeting. Conclusions: This prospective clinical trial provides preliminary evidence for activity of sildenafil citrate in patients with advancing WM. With minimal toxicity, sildenafil citrate appears to have suppressed disease progression in more than half of patients and has resulted in objective responses, thus warranting further investigation in WM and possibly other B-cell disorders. No significant financial relationships to disclose.