PO OD Research Articles

Isolated and Dynamic Peripheral Blood Residual Disease Status Characterized By Mass Spectrometry Predicts Outcome in Patients with High Risk Smoldering Multiple Myeloma Treated in the GEM-CESAR Trial

Background: GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the rate of minimal residual disease (MRD) negativity in the bone marrow (BM) assessed by next generation flow (NGF) after autologous stem cell transplantation (ASCT) and sustained 3 and 5 years afterwards. Here, we update the preliminary results presented at ASH2019 about the clinical value of quantitative immunoprecipitation mass spectrometry to assess treatment response in this group of patients. Methods: Pts received induction with six 4-week cycles of KRd (K: 36mg/m 2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d: dexamethasone 40mg po weekly), high-dose melphalan followed by ASCT, consolidation with two further cycles of KRd and up to 2 years of maintenance with Rd (R: 10mg po od, d: 20mg po weekly). Peripheral blood Residual Disease(PRD) was analyzed post-ASCT and at treatment completion (after 2 years of maintenance) using Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads using the EXENT ® Solution (The Binding Site, part of Thermo Fisher Scientific). From the 90 pts enrolled in the trial, 61 were analyzed post-ASCT and 35 at the end of treatment. Isotype-matched immunoparesia (IMI) was also evaluated post-ASCT using the heavy/light chain pairs. Kaplan-Meier curves were plotted either from the specific time point investigated or from the last one if dynamics were analyzed. Results: First,PRD was analyzed post-ASCT and at treatment completion and deemed to be positive in 54% (33/61) and 20% (7/35) of patients, respectively. At both time points, PRD assessment discriminated two groups of patients with a very significantly different prognosis: median PFS in PRD+cases post-ASCT was 4.27 years vs not reached in PRD- cases (p=0.0071) (Fig 1A) and after 2 years of maintenance, the median PFS in PRD- cases was not reached vs 1.43 years in PRD+ cases (p=0.0011) (Fig 1B). Importantly, standard response criteria and, more specifically, the achievement of complete response (CR) or better, was not associated with disease outcome. And further, among samples in ³CR, PRD+ was also able to discriminate a group of patients with poorer outcome, with a median PFS of 4.42 years vs not reached in PRD- cases (p=0.0136) Interestingly, when we combined the analysis of the M-protein by mass spectrometry with the identification of severe isotype-matched suppression (uHLC < 50%), PRD+ patients post-ASCT could be further stratified in two subgroups with significantly different median PFS (not reached in those with no severe IMI vs 3.85 years in those with severe IMI, p=0.0384) (Fig 1C). A similar tendency was observed among PRD+cases after 2 years of maintenance (mPFS in those with no severe IMI of 2.5 years vs 9 months in those with severe IMI) although the difference did not reach statistical significance. Then, we analyzed PRD dynamics after ASCT and at the end of treatment. Sustained PRDnegativity during this period was observed in 12 pts (33.3%), and sustained positivity in 6 (16.6%). In 5 pts (13.8%) PRD converted from positive to negative, and in 1 (2.7%) from negative to positive. Whereas sustained PRD+ was associated with a very short median PFS of 1.66 years, patients with sustained PRD- or who converted from PRD+ to PRD- displayed a very favorable outcome with median PFS not reached and significantly different compared to the sustained PRD+ group (p<0,0001) (Fig 1D). Interestingly, the only patient that converted from PRD-to PRD+ had a very poor outcome with a mPFS 3.8 months. By contrast, sustained CR or better according to standard response criteria was not significantly associated with clinical outcome. Conclusion: In this cohort of high-risk smoldering MM patients treated intensively with a curative intention, whereas standard CR or better was not associated with clinical outcome, PRD status defined by mass-spectrometry segregated two groups of patients with different PFS at the 2 time points analyzed. Furthermore, this outcome was better predicted when PRD dynamics were analyzed and/or with the evaluation of severe IMI on PRD+ patients, highlighting once again the relevance of immune recovery as a determinant factor in the evolution of the disease.

A pilot study of the neoadjuvant use of vemurafenib plus cobimetinib in patients with BRAF-mutant melanoma with palpable lymph node metastases: Survival results.

9579 Background: Melanoma patients with palpable nodal metastases have a very poor prognosis with the majority recurring within the first 2-3 years post-resection with survival ranging from 20-50% at 5 years. We aimed to ascertain if patients with a BRAF V600 mutation that receive vemurafenib and cobimetinib before surgery (neoadjuvantly) have a higher probability of resectability, pathologic complete response (pCR), and a lower risk of local recurrence and a longer disease free survival (DFS), distant metastatic free survival (DMFS) and overall survival (OS). Methods: This was a single arm, prospective, multi centre phase II study in patients with histologically confirmed, BRAF V600 mutated Stage IIIB and IIIC melanoma (AJCC 7th Edition) with palpable nodal disease. Patients received vemurafenib 960mg PO BID and cobimetinib 60mg PO OD for 4 months prior to resection followed by 8 months of adjuvant therapy post-surgery. CTscans were performed at baseline and before resection and every 6 months for the first 3 years and yearly in year 4 and 5. Biopsies for correlative studies and diagnosis were performed at baseline prior to starting therapy. The primary outcomes were the proportion of patients achieving resectability, radiologic response as per RECIST and the proportion of patients achieving a pCR. Presented here are the LRFS, DMFS, DFS and OS. Results: Twenty-four patients were enrolled and received neoadjuvant vemurafenib and cobimetinib and 21 underwent resection. Following resection and pathological evaluation 12 (57%; 95% CI 34.02-78.18)) patients achieved a pCR, 8 (38%; 95% CI 18.11-61.56) had a partial pathologic response and 1 had no pathologic response. Of the 24 patients, 2 patients (8%) developed local recurrence, 6 patients (25%) developed distant metastasis, and 8 patients (33%) had either local or distant recurrences. 7 patients (29%) died due to metastatic disease. At 60 months, LRFS was 89.5% (76.7-100%), DMFS was 75.0% (59.5-94.5%), DFS was 85.7% (72.0-100%), and OS was 63.9% (95% CI 43.5-93.8). Among total 20 evaluable patients, 17 patients had CR/PR and 3 had PD/SD as best response. There was no significant difference between patients with CR/PR or SD/PD (log-rank p-value = 0.0548) with 48 month survival of 82.4% for CR/PR population compared to 33.3% with SD or PD. Conclusions: In this small phase II study, neoadjuvant vemurafenib and cobimetinib led to a higher LRFS, DMFS, DFS and OS of all resected patients with bulky nodal disease compared to historical survival rates. Clinical trial information: NCT02036086 .

Clinical Impact of Next Generation Flow in Bone Marrow Vs Qip-Mass Spectrometry in Peripheral Blood to Assess Minimal Residual Disease in Newly Diagnosed Multiple Myeloma Patients Receiving Maintenance As Part of the GEM2014MAIN Trial

Introduction: GEM2014MAIN is a phase 3, multicenter, open-label, randomized trial exploring maintenance treatment with lenalidomide and dexamethasone (Rd) vs lenalidomide, dexamethasone and ixazomib (IRd) after autologous stem cell transplantation in newly diagnosed patients with multiple myeloma (MM). The study includes yearly analysis of minimal residual disease (MRD) in bone marrow (BM) by Next Generation Flow (NGF) and the results at year 2 guide further management. Mass spectrometry methods measuring low-level immunoglobulins have shown potential for peripheral-blood (PB) based MRD assessment in MM. Aim: In this study, we analyzed and compared the results and clinical impact of MRD evaluation in BM by NGF and in PB by quantitative immunoprecipitation mass-spectrometry (QIP-MS) during maintenance in patients enrolled in the GEM2014MAIN trial. Patients and Methods: Patients achieving at least stable disease at the end of the GEM2012MENOS65 trial were included in the GEM14MAIN, and randomized to receive Rd (lenalidomide 15mg po od days 1-21 and dexamethasone 20mg po od days 1-4 and 9-12) or IRd (Rd plus ixazomib 4mg po od days 1, 8 and 15) in cycles of 28 days. After two years of treatment, BM samples were analyzed by NGF (sensitivity of 3x10-6) as per protocol: if MRD was undetectable, maintenance was discontinued; if detectable, Rd with reduced dexamethasone at 20mg po od only days 1-4 was continued for 3 additional years. At the same time point, MRD was assessed in PB by QIP-MS with anti IgG/A/M, total k and total l beads using the EXENT system (The Binding Site, in development). The association of MRD detection by either method with progression-free survival (PFS) was assessed by the Kaplan-Meier method. Landmark analyses of PFS at 2 years post-maintenance were performed to minimize lead-time bias. Additional survival analyses were carried out to evaluate the clinical impact of MRD evolution during the study period. Results: 156 patients with paired BM/PB samples available after 2 years of maintenance were included in the analysis. NGF detected residual disease in 29% (45/156) of cases and EXENT in 24% (37/156). The results of both techniques were concordant in 85% of cases and discordances were due to 16 patients (10%) NGF+/EXENT- and 8 (5%) NGF-/EXENT+. Of note, 8/16 cases NGF+/EXENT- corresponded to light-chain MM (anti-free light chain beads were not used in this study). Therefore, overall, and considering NGF as a reference, the negative predictive value (NPV) of EXENT was 87% and the positive predictive value (PPV) of 78% (p<0.0001). With a median follow-up of 66 months from the start of the GEM14MAIN, MRD detection by either method associated with a shorter PFS at 5 years as compared to patients with undetectable MRD: NGF: 57% vs 89%, respectively; HR= 6.54 (2.92-14.67); p<0.0001; EXENT: 62%% vs 86%, respectively; HR= 4.79 (1.99-11.53); p=0.0005. We also analyzed the evolution of MRD between enrollment and after 2 years of maintenance, since we already had MRD results by both methods at the end of the GEM2012. Patients were grouped into 1) those with persistent MRD positivity at the two time points or converting from MRD- to + by either method and 2) those with sustained MRD negativity at the two time points or converting from MRD+ to - by either method. Both NGF and EXENT showed that persistent MRD+ or conversion from MRD- to MRD+ were associated with a shorter PFS at 66 months, compared to patients who remained MRD- or converted from MRD+ to MRD-: NGF: 54% vs 89%, respectively; HR = 8.9 (3.55-22.08); p <0.0001; EXENT: 61% vs 86%, respectively; HR: 4.95 (1.91-12.9); p=0.0010. Conclusions: Our study shows that, during maintenance, the identification of MRD by NGF and EXENT and its evolutionary pattern are both associated with a comparable clinical value in terms of PFS. Supported by a NPV of 87% as compared to NGF, mass spectrometry could be used to define the optimal time-point for BM-based MRD assessments as well as, alongside with standard methods, to introduce MRD adapted treatment approaches.

799P A pilot study of the neo-adjuvant use of vemurafenib plus cobimetinib in patients with BRAF mutant melanoma with palpable lymph node metastases

Melanoma patients with palpable nodal metastases have a very poor prognosis with the majority recurring within the first 2-3 years with survival ranging from 20-50% at 5 years. We aimed to ascertain that patients with a BRAF V600 mutation that receive vemurafenib and cobimetinib before surgery (neoadjuvantly) will have a higher probability of resectability, pathologic complete response, a lower risk of local recurrence and a longer DFS, PFS and OS. This was a single arm, prospective, multi centre phase II study in patients with confirmed BRAF V600 mutated Stage IIIB and IIIC melanoma ( AJCC 7th Edition) with palpable nodal disease. Patients received vemurafenib 960mg PO BID and cobimetinib 60mg PO OD for 4 months prior to resection followed by 8 months of adjuvant therapy post-surgery. CTscans were performed at baseline and before resection and every 6 months for the first 3 years and yearly in year 4 and 5. Biopsies for correlative studies and diagnosis were performed at baseline prior to starting therapy. The primary outcomes were the proportion of patients achieving resectability, radiologic response as per RECIST and the proportion of patients achieving a pathological response. Secondary objectives were local-regional recurrence rates, DMFS, DFS and OS. Twenty-four patients were enrolled and received neoadjuvant vemurafenib and cobimetinib and 21 underwent resection. At time of surgery 1 (20%; 95% CI 0.15-24.87) had a complete response, 16 (80%; 95% CI 56.34-94.27) had a partial response, and 2 (10%; 95% CI 1.23-31.70) had stable disease. One patient progressed as per RECIST but had a partial response upon resection. Following resection and pathological evaluation 12 (57%; 95% CI 34.02-78.18)) patients achieved a complete pathologic response, 8 (38%; 95% CI 18.11-61.56) had a partial pathologic response. Treatment related Grade 3-4 events occurred in 10 patients with no deaths due to AEs. Only 2 patients had a local recurrence. OS at 60 months was 63.9% (95% CI 43.5-93.8). Neoadjuvant vemurafenib and cobimetinib led to all patients being resectable with a high response rate, pathologic response rate and low local recurrence rate in melanoma patients with palpable lymph nodes.

A126 GIST – GLUE IN STROMAL TUMOR

Abstract Background Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and typically located in the stomach. Gastrointestinal bleeding is a frequent complication of GISTs with surgery being the treatment of choice. Managing GIST bleeding endoscopically can be challenging by an underlying friable neovascularization. The use of cyanoacrylate basis glue has well-established utility in the endoscopic management of variceal bleeding. However, the role of cyanoacrylate basis glue in the management of GIST bleeding is exceptionally rare. Aims We present a case of a bleeding GIST that was successfully managed through the utilization of cyanoacrylate basis glue allowing for elective surgical resection. Methods A chart review was undertaken. Also, a literature review of the topic was also conducted using the terms “GIST, Cyanoacrylate Glue, Bleeding” Results A 75-year-old male presented with a four week history of exertional chest pain. He had noticed persistent black stools for the previous two weeks. His past medical history was relevant for coronary artery disease; two years earlier he had drug eluting stents placed. His medications included ASA 81mg PO OD and Pantoprazole 40mg OD. Physical examination revealed stable vital signs, a soft abdomen and melena on rectal examination. Laboratory investigations showed a hemoglobin of 75 g/L, and 2 weeks prior his hemoglobin had been 120 g/L. Platelets were 149. His liver enzymes and liver function tests were unremarkable. His BUN was 9.9 mmol/L and creatinine of 96.0 umol/L. An esophagogastroduodenoscopy (EGD) revealed a 5cm smooth mass with a central deep depression, in the antrum, that was actively bleeding. Attempts to clip were unsuccessful due to the width of the central depression which was the source of bleeding. (See image 1). The endoscopist chose to inject 1cc of cyanoacrylate basis glue directly into the bleeding site. A subsequent CT scan revealed a 5.2cm polypoid mass in the gastric antrum, favored to be a GIST with no evidence of metastatic disease. Surgery and Cardiology were involved in the care of this patient, and emergency surgery was delayed due to the patient having an intercurrent acute coronary syndrome. Post EGD, the patient underwent an angiogram and the culprit coronary artery was stented and patient was started on dual antiplatelet therapy. Patient then successfully underwent a laparoscopic gastric wedge resection for his GIST, this was completed 1 week after EGD. The pathology of the resected area was in keeping with a GIST. Of note, the patient’s hemoglobin had been stable from the time of EGD until surgical intervention. Conclusions Managing GIST bleeding endoscopically can be challenging, and surgical resection is the recommended treatment modality. In situations where surgical intervention is contraindicated, endoscopic therapy with cyanoacrylate basis glue can be considered to achieve hemostasis in GIST bleeding. Funding Agencies None

Analysis of treatment efficacy in the GEM-CESAR trial for high-risk smoldering multiple myeloma patients: Comparison between the standard and IMWG MRD criteria and QIP-MS including FLC (QIP-FLC-MS).

8512 Background: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of sustained minimal residual disease (MRD) negativity in the bone marrow (BM) by next generation flow (NGF). The value of BM MRD assessment in MM is proven, but alternative, non-invasive methods, accurately reflecting disease burden are needed. Methods: Pts received six 4-week cycles of KRd as induction (K:36mg/m2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d:dexamethasone 40mg po weekly) followed by melphalan 200mg/m2, two further cycles of KRd as consolidation and up to 2 years of Rd (R:10mg/d, d:20mg/week). Efficacy was analyzed in parallel in BM samples by NGF and in serum by SPEP/IFE and QIP-MS/QIP-FLC-MS in 52 out of the 90 pts enrolled in the trial. Standard and MRD responses were carried out as per the IMWG guidelines. For QIP-MS serum immunoglobulins were purified using polyclonal antibodies (anti-IgG, -IgA, -IgM, -total κ and -total λ light chain, -free κ and -free λ light chain). Mass spectra were generated on a MALDI-TOF-MS system. Results: Overall response rate (ORR) was 98% post-induction, 98% post-ASCT, and 100% post-consolidation; 38.4%, 61.5% and 68.6% of pts reached ≥ complete response at each time-point and, among them, 23%, 44% and 55% achieved flow MRD-negativity. Using the combination of QIP-MS/QIP-FLC-MS, the percentage of pts without detectable disease at each timepoint lowered to 12%, 27% and 38% reflecting the higher sensitivity of the method. Against NGF, QIP-MS/QIP-FLC-MS provided negative predictive values of 67%, 92% and 89% (p = 0,0206; p &lt; 0,001; p = 0,003) and identified disease in 95%, 97% and 92% of pts that were positive by NGF-MRD at each respective timepoint. Three pts from this cohort have progressed so far: two were NGF+/MS+ at the three timepoints whilst 1 remained NGF- but QIP-MS/FLC-MS+ throughout. Conclusions: The GEM-CESAR treatment strategy induces a high ORR in HRsMM pts, and the % of cases achieving flow-MRD negativity post-ASCT meets the primary endpoint of the trial. The combined use of QIP-MS and FLC-MS offers higher sensitivity relative to standard methods and may provide relevant information about the right timing for performing a BM aspirate/biopsy. Clinical trial information: NCT02415413 .

SUN-512 Graves’ Disease Induced Renal Tubular Acidosis

Thyroid gland can affect kidney function in different ways. Thyroxine as a master hormone of metabolism and growth works in many cellular levels include the renal tubules.We present a 34-year-old Emirati gentleman who presented with multiple episodes of hypokalemic periodic paralysis. Blood test revealed thyrotoxic state, with highly positive serology for thyroid peroxidase, anti-thyroglobulin and thyrotropin receptor antibodies. Thyroid uptake scan confirmed homogenous diffuse uptake consistent with toxic diffuse goitre [Graves’ disease]. In view of recent fracture, bone profile and DXA scan were done. Investigations revealed vitamin D deficiency and below expected for age bone mass density.The patient was started on symptomatic treatment with propranolol, IV and oral potassium along with IVF hydration. Routine blood work during admission showed a persistent normal anion Gap metabolic acidosis, serum bicarb 15 mmol/l. 24 hours urine electrolytes revealed normal potassium, sodium, high magnesium, low calcium and PH levels. Biochemical lab results suggested type 1 renal tubular acidosis. As the patient had hypokalaemia, high urine magnesium and low urine calcium and limbs weakness, Gitleman Syndrome was considered in the differential diagnosis. Whole Exome Sequencing (CentoXome GOLD®) was sent which came back negative. The following gene panels were studied: Renal tubular acidosis panel: ATP6V0A4, ATP6V1B1, CA2, EHHADH, HNF4A, SLC34A1, SLC4A1, SLC4A4. Bartter Syndrome panel: ATP6V1B1, BSND, CA2, CASR, CLCNKA, CLCNKB, CLDN16, CLDN19, FXYD2, HSD11B2,KCNJ1, KCNJ10, KLHL3, NR3C2, SCNN1A, SCNN1B, SCNN1G, SLC12A1, SLC12A2, SLC12A3, SLC4A1, SLC4A4, WNK1. Gene related to Gitelman syndrome: SLC12A3Renal tubular acidosis was treated with KCL 600mg PO TID, Na bicarb 1200mg PO BID and spironolactone 25 mg PO OD. The patient received radioactive iodine (RAI) as the ultimate treatment for Graves’ disease. He developed hypothyroidism post RAI ablation and commenced on levothyroxine. Improvement of the metabolic acidosis was noticed in line with improvement of thyroid function. Na bicarb and spironolactone tablets were stopped eventually as the patient was euthyroid clinically and biochemically.Overt hyperthyroidism is associated with accelerated bone remodelling, leading to hypercalciuria, which can predispose to nephrocalcinosis and renal tubular damage, and therefore causes type 1 renal tubular acidosis. Once the patient becomes euthyroid, bone remodelling and urine calcium return to normal levels and that would correct the renal acidosis.This case report serves to highlight the effect of Graves’ disease on renal tubules which may result in type 1 renal tubular acidosis. This effect could be reversible with normalization of thyroid function.

2053 Mesalamine-Induced Myocarditis in a Patient With Newly Diagnosed IBD

INTRODUCTION: Mesalamine, a 5-ASA agent, is used as first line treatment in mild to moderate IBD. Adverse reactions include GI symptoms and often do not require discontinuation of therapy. Inflammation of the myocardium (myocarditis) is a rare but potentially lethal complication of mesalamine treatment. Early recognition and intervention is vital to prevent progression of inflammation and adverse patient outcomes. CASE DESCRIPTION/METHODS: A 62-year-old woman presented with an 8 month history of GI symptoms. Colonoscopy demonstrated patchy colonic inflammation which was biopsy confirmed. She was treated with mesalamine 500 mg PO OD. At a 6-week follow up visit, she had mild dyspnea and chest discomfort, but a direct causal relationship with mesalamine was not delineated. Due to persistent GI symptoms, her mesalamine dose was increased to 2 g PO BID. After 9 days her cardiorespiratory symptoms worsened. She was advised to discontinue mesalamine and seek emergency care. She was admitted to the CCU where an echocardiogram demonstrated an EF of 15%. Ischemic heart disease was ruled out with cardiac catheterization. Cardiac MRI was consistent with myocarditis. She was started on prednisone 20 mg OD. Following discontinuation of mesalamine with prednisone treatment, her cardiorespiratory symptoms improved. Follow-up echocardiogram showed minimal improvement (EF 20%). DISCUSSION: Mesalamine associated myocarditis is a rare phenomenon that presents 2-4 weeks after initiation of therapy. It is associated with severe clinical sequelae including myocardial dysfunction and death. Early case reports suspected the cause was the sulfapyridine group of sulfasalazine. There have been subsequent case reports of myocarditis from 5-ASA alone. The mechanism is believed to be a hypersensitivity reaction rather than direct cardiotoxicity. Supporting this theory are reports of return of symptoms when a 5-ASA agent is reintroduced. Clinical presentation is variable, and patients may present with normal laboratory and imaging studies. Myocarditis can rarely represent an extra intestinal manifestation of IBD. The improvement of this patient’s symptoms with discontinuation of mesalamine, and the temporal relationship between symptom onset and initiation of mesalamine favors mesalamine induced myocarditis. Given the significant consequences of this rare adverse reaction, dyspnea and chest discomfort in a patient on mesalamine should evoke prompt and permanent discontinuation of the drug. Delayed recognition can lead to patient morbidity.

NRG GY012: A randomized phase II study comparing single-agent olaparib, single agent cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent or metastatic endometrial cancer.

TPS5609 Background: The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Mutations in classical homologous recombination genes occur in 22% of EC, ARID1A 41% and PTEN loss occurs in 55% of EC. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination may be an effective therapeutic strategy in EC (Hansen 2016). Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study has been designed to compare 2 experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J (Bender 2015). Methods: This is a multicenter randomized three arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1 to cediranib PO 30 mg OD; olaparib 300 mg PO BID or the combination of cediranib 20 mg PO OD with olaparib 300 mg PO BID. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect an increase in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy is allowed; ECOG PS ≤ 2; adequate hepatic, bone marrow, coagulation and renal function. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 24 patients are enrolled to date . Amendments are planned to include additional arms investigating combination strategies targeting DNA repair and angiogenesis. Clinical trial information: 03660826.

Carbamazepine Induced Drug Rash with Eosinophilia and Systemic Symptoms

Stabilizes inactivated state of sodium channels, thereby making neurons less excitable may reduce activity of nucleus ventralis of the thalamus or decrease synaptic transmission or summation of temporal stimulation leading to neuronal discharge.A adult of 68 years old patient came to dermatology department with chief complaints of neuralgia over scalp to relieve the symptoms physician prescribed carbamazepine 200mg Po OD. During his 2ndweek of treatment patient developed pain,fever,sore throat followed by skin rash.Better vigilance is necessary for implementation of safe and effective treatment for each individual patient.in order to prevent serious adverse drug reactions of this drug,close monitoring drug treatment course, creating awareness, recognition of the problem and careful management of all the patients who receive medication are essential,because use of carbamazepine causes thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus,Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure, Pancreatitis ,Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia&#x0D; Keywords: Carbamazepine, Induced Drug Rash with Eosinophilia and Systemic Symptoms, adverse drug reaction.

Anti-epileptic activity of Nelumbo nucifera fruit.

Epilepsy is the most commonly encountered neurological disorder affecting around 70 million people worldwide, out of which approximately 80% belongs to developing countries. Several shortcomings appeared with the use of conventional antiepileptic agents like, inadequate seizure control, side effects and cost which limit their use. Thus extensive studies are necessary to investigate the pharmacological effects of plants, which would facilitate discovery of novel drugs from herbal source permitting their use to benefit mankind. Hence current study was focused to evaluate the anti-epileptic potential of Nelumbo nucifera fruit in order to ascertain its therapeutic potential. Anti-epileptic activity was assessed using strychnine induced seizure model in 35 male Wister rats divided in five groups i.e. control, reference and 3 test groups. Each group was composed of 7 animals and was given 2% gum tragacanth (control), diazepam 1mg/kg PO (reference) and N. nucifera fruit 50, 100 and 200mg/kg PO (test) OD for 15days. N. nucifera fruit extract at 200mg/kg exhibited extremely noteworthy delay in the inception of convulsions as compared to control however duration of convulsions was increased significantly but intensity of convulsions was reduced resulting in better survival rate i.e. 42.85% which was comparable to diazepam. Therefore it can be concluded that N. nucifera fruit may be valuable in managing epilepsy but further studies are required on large number of animals to confirm these findings.

Phase II trial of capecitabine +/- erlotinib in advanced colorectal cancer, with retrospective KRAS and primary tumor site analysis.

781 Background: Palliative capecitabine (X) monotherapy for advanced colorectal colorectal cancer (aCRC) is generally well tolerated by elderly or frail pts. Epidermal growth factor receptor (EGFR) monoclonal antibodies improve efficacy when added to combination chemotherapy for mCRC. Erlotinib (E), an oral EGFR tyrosine kinase inhibitor (TKI) may add benefit when added to X. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of X and E in aCRC. Methods: Pts with untreated aCRC who were either deemed unfit for, or chose against, combination chemotherapy were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), and safety. Tumours were designated as left-sided if there were distal to the transverse colon. KRAS status was retrospectively analyzed for 72 of 82 pts. Results: From 2004 to 2008, 82 pts were randomized to X alone (40 pts) or XE (42 pts). TTP was not different between X and XE (7.9 m vs. 9.2 m; p = 0.890), however, KRAS subgroup analysis revealed pts with KRAS mutations did significantly worse when treated with XE compared to X alone (1.9m vs 7.4m; HR = 2.63; P = 0.038). Pts with KRAS wild-type (WT) treated with XE had an improved TTP compared to those treated with X (11.7m vs. 8.4m, HR = 0.73; Wilcoxon P = 0.061). KRAS-WT pts treated with XE with left-sided disease had an improved OS compared to pts with right-sided disease (16m vs. 12.1m, not significant). KRAS-WT pts with left-sided primaries treated with XE had a non-significant improvement in TTP compared to pts treated with X alone (11.7m vs 8.4m). XE was well tolerated but had significantly higher rates of diarrhea and acneform skin rash. Conclusions: The addition of E to X is generally well tolerated but associated with additional toxicities. E may benefit pts with KRAS-wild-type CRC, specifically those with left-sided primary tumours, and likely harms those with KRAS-mutated CRC. Further study of oral EGFR-TKIs in left-sided KRAS-wild-type aCRC is warranted.

Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers.

Oral tyrosine kinase inhibitor (gefitinib and erlotinib) have been used in the palliative treatment of head and neck cancers with limited success. In this report, we aim to quantify the symptomatic benefit, progression-free survival (PFS) and overall survival (OS) when erlotinib is given as second-line treatment in Head and neck cancers. This was a post-hoc retrospective analysis of a randomized study comparing metronomic chemotherapy with cisplatin. A patient who progressed on chemotherapy and had a PS0-2 were offered second-line chemotherapy. Patients who had received erlotinib (150 mg PO OD) as second line treatment were selected for this analysis. Erlotinib was discontinued in case of either progression of disease or if the patient had intolerable side effects. Patient were monitored 1-week after the start of erlotinib and subsequently at monthly intervals. The toxicity was recorded in accordance with CTCAE version 4.02 (NCI,USA) and the response were graded in accordance with RECIST version 1.1. All of these patients were followed-up till death. Twenty-three patients were identified. The median age of these patients at the start of the second line was 47 years (interquartile range 40.5-51.75 years). The primary site of distribution was oral cavity primary in 17 patients (77.3%) and nonoral cavity primary in 05 (22.7%) patients. The immediate last chemotherapy regimen received was cisplatin in 9 patients (40.9%) and metronomic chemotherapy in 13 patients (59.1%). Symptomatic benefits post second-line erlotinib was seen in 18 patients (81.8%). The most common adverse events (any grade) seen were anemia in 20 patients (90.9%), rash in 10 patients (45.5%) and diarrhea in 7 patients (31.8%).The best radiological response documented were a partial response in 04 patients (19.2%). The median estimated PFS and OS were 110 days (95% confidence interval [CI]: 61-175 days) and 156 days (95% CI: 126-185 days) respectively. Erlotinib single agent has promising activity in the second line and needs to be explored in future studies.

A phase Ib study exploring the combination of everolimus and dovitinib in VEGF-refractory clear cell renal cancer.

531 Background: Everolimus (mTOR inhibitor) and dovitinib (VEGF and FGF-2 inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. In this study we establish the tolerability and an early activity signal of this combination. Methods: Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalated doses of daily oral everolimus (5-10 mg PO OD) and dovitinib (200-500mg 5/7 days PO) Dose-limiting toxicities (DLTs) were assessed determine the MTD. An expansion cohort (n=15) was treated to obtain additional efficacy and safety information. Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg PO OD and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (CTC grade 1-4) of patients respectively. Frequent biochemical abnormalities occurred such as hypertrygliceridaemia in 67%. Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% CI 2.2-11 months). Conclusions: Dovitinib and everolimus had modest activity, but did not meet all of the the planned efficacy endpoints. Fatigue was the dose limiting toxicity. Clinical trial information: NCT01714765.

A phase Ib study of an anti-HER2 inhibitor, lapatinib, in combination with a c-MET and VEGFR inhibitor, foretinib, in HER2-positive metastatic breast cancer (MBC): Results from NCIC CTG IND.198.

518 Background: The mechanisms of resistance to targeted anti-HER 2 therapy are unclear. Proposed pathways include MET, VEGF and AXL. Multi-targeted pathway inhibition may delay or prevent acquired resistance to HER2 inhibition. Foretinib, an oral multi-kinase inhibitor of MET and VEGFR2, as well as PDGFRB, AXL, FLT3, TIE-2, RET and RON kinases, has pre-clinical anti-tumor activity in breast tumor models. This phase 1b study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of this combination of oral tyrosine kinases inhibitors in a cohort of HER-2 positive MBC patients. Methods: Women with HER2 positive (determined locally) MBC, PS 0-2, and no limit on number of prior chemotherapies or lines of anti-HER2 therapies were enrolled. A 3+3 dose escalation design was utilized. 4 dose levels were planned with starting doses of foretinib 30 mg and lapatinib 750 mg PO OD (dose level 1) on a q 4 weekly cycle. Correlative studies from primary archival tissue are planned. Results: 19 patients were enrolled, all of whom were evaluable for toxicity assessment and 16 were evaluable for response. Median age was 60 years (34-86), 95% were PS 0-1, 53% were ER- and 95% had at least one prior anti-HER2 based regimen. A median of 2 cycles (range: 1-20) was delivered across 4 dose levels. At the 4th dose level (foretinib 45 mg/lapatinib 1250 mg) dose limiting toxicities were documented in 4/7 patients. These included grade 3 fatigue (2 cases); grade 3 ALT elevation; grade 3 diarrhea and grade 2 joint effusion. There was only one grade 4 non-hematological toxicity (grade 4 vomiting: dose level 1) across all dose levels. One patient discontinued treatment due to toxicity with grade 3 limb edema and grade 3 proteinuria. PK of both drugs from DL1-3 did not appear to demonstrate a significant interaction. The RP2D was declared to be foretinib 45 mg and lapatinib 1000 mg PO OD. The full efficacy data and correlative studies will be presented at the meeting. Conclusions: The combination of foretinib and lapatinib can safely be delivered together, though at lower doses than either agent alone.

Randomized phase II placebo-controlled trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone receptor-positive metastatic breast cancer (MBC): OCOG Zamboney study—NCT00811369.

574 Background: Biomarkers of bone turnover, including urine N-telopeptide (uNTx) and serum C-telopeptide (sCTx) reflect tumor-related bone breakdown and have been used as surrogate measures of response to therapy in trials. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases (BM). We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in patients with BM. Methods: Postmenopausal patients with bone only, or bone predominant, hormone receptor positive MBC were randomised to F (500mg IM day 1, 14, 28, then monthly) with either vandetanib (100mg PO OD) (FV) or placebo (FP) until progression. The primary objective was uNTx response (&gt;30% reduction from baseline). uNTx was collected at baseline, weekly to wk 4, at wk 12 and then every 12 wks. Secondary objectives included PFS, OS, RECIST response, pain and toxicity. Results: 61 patients were allocated to FV and 68 to FP. Median age was 59. 18% had received 1 prior chemotherapy regime and 73% prior endocrine therapy for MBC. uNTx response (n=124 pts) was 64% for FV vs. 52% for FP (p=0.20). No difference was detected between groups for median PFS; 6 months for FV vs. 4.8 months for FP, HR=0.93 (95% CI: 0.64 to 1.36). 16 patients died in FV arm vs. 21 in the FP arm, HR=0.71 (95% CI: 0.37 to 1.36). For those patients with measurable disease, clinical benefit rates were 41% and 43%, respectively, p=1.00. Serious adverse events were similar, 3.3% for FV vs. 5.9% for FP. Elevated baseline uNTx (&gt;65 nM BCE/mmol Cr) was prognostic for PFS, HR=1.62 (95% CI: 1.08 to 2.43 and for mortality, HR= 2.4 (95% CI: 1.2 to 4.6). In an exploratory analysis uNTx was predictive of responsiveness to FV for PFS, HR=0.60 when uNTx &gt;65 vs. HR=1.37 when uNTx &lt;65, P = 0.025 for interaction. Conclusions: The addition of vandetanib to F did not improve biomarker response, PFS or OS compared to F alone in patients with bone predominant disease. Exploratory analyses confirmed that baseline bone turnover markers are prognostic for PFS and OS. Clinical trial information: NCT00811369.

477 Chronic Recurrent Severe Lip Angioedema in Young Child Secondary to Allergic Rhinitis

Background and AimsAllergic rhinitis (AR) is a significant disease that affects children and adults and often under-diagnosed which has a deleterious impact on quality of life. Chronic recurrent severe lip...

Pharmacokinetics of Dasatinib in a Patient with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia During Treatment with Anti-Tuberculosis Therapy

Abstract 5006 Objectives:Dasatinib is a second generation protein-tyrosine kinase inhibitor (TKI) indicated for first line treatment of chronic myeloid leukemia (CML) and second line treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) in patients who are imatinib resistant or intolerant.In this study, we present the case of a patient with Philadelphia chromosome- positive ALL, intolerant to imatinib, who developed reactivated tuberculosis (TB) while receiving dasatinib during maintenance chemotherapy. The purpose of our study was to determine the effects of concomitant anti-TB therapy on dasatinib exposure by measuring plasma dasatinib levels using three different oral doses of the drug in this patient. Methods:The patient was treated with isoniazid, rifampin, ethambutol, pyrazinamide and pyridoxine for 2 months, followed by isoniazid, rifampin and pyridoxine for an additional 4 months. Dasatinib therapy was continued at the initiation of TB therapy using 100 mg po od, and titrated by 50 mg increments to 200 mg po od. Dasatinib plasma levels were measured prior to initiating anti-TB treatment and at regular intervals during concomitant treatment using three different dasatinib doses. Results:Eight days after initiation of anti-tuberculosis therapy, the apparent clearance of dasatinib had increased from 1410 to 2174 L/h at 100 mg. However, at 150 mg and 200 mg doses, apparent clearance had decreased to levels lower than baseline. As expected, the direction of peak plasma concentration changes was inverse to the changes in apparent clearance: Cmax values were 30 at baseline, and 22, 46, 102 ng/mL for the 3 doses of dasatinib during anti-TB therapy, respectively. Conclusions:Our findings suggest dasatinib clearance is increased by approximately 50% shortly after initiating anti-tuberculosis treatment and increasing the dose of dasatinib during anti-TB therapy was able to restore dasatinib plasma levels to those observed before initiation of anti-TB therapy.(This work was supported by an unrestricted grant from Bristol Myers Squib) Disclosures:No relevant conflicts of interest to declare.

Randomized phase II trial of capecitabine (X) versus X plus erlotinib (E) in patients (pts) with metastatic colorectal cancer (mCRC): Differential impact of KRAS.

e14031^ Background: Palliative X monotherapy of mCRC is generally tolerated by elderly, and/or medically unfit pts. Epidermal growth factor receptor (EGFR) inhibitors improve efficacy when added to combination chemotherapy for mCRC. It is unknown whether biologic agents add benefit to alone in pts who either opt against, or are not candidate for, combination chemotherapy. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of low-dose X and E in this pt population. Methods: Eligible pts with mCRC were either deemed unfit for, or chose against, 1st-line combination chemotherapy. Pts were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. A 3rd arm (E alone) was ineffective, and discontinued after a preplanned interim analysis. Imaging was performed every 9 weeks until progression. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), safety and quality of life. Results: From June 2004 to June 2008, 95 pts [median age: 67; range 40-84; ECOG PS: 0 (45pts), 1 (38 pts), or 2 (22 pts)] were randomized to X alone (40 pts), XE (42 pts), or E alone (13 pts). KRAS status, where possible, was analyzed for pts in the first 2 arms only. As compared to X alone, XE was associated with significantly more Gr 3+ toxicity: (diarrhea: 29% vs 5%; fatigue: 12% vs 0%; anorexia 7% vs 0%; stomatitis 7% vs 0%). One pt discontinued treatment in the X arm vs 2 in XE. There was 1 toxic death in XE. TTP was not different for the whole trial (X=7.9 m, XE=9.2 m; p=0.8897), but exploratory subgroup differences emerged (below). Conclusions: The addition of E to X is associated with additional toxicity. E may benefit pts with KRAS-wild-type CRC and may harm those with KRAS-mutated CRC. Further study of XE in elderly/unfit pts with KRAS-wild-type CRC is warranted. Supported by grant from Roche. Median TTP (m) X XE p All pts (n = 40 / 42) 7.9 9.2 0.8897 KRAS wt (n =18 / 24) 8.4 11.7 * KRAS mut (n = 18 / 12) 7.4 1.9 * *Cox regression p=0.0236 for interaction of study arm by Kras status.

Use of genetic instability to predict biochemical recurrence in intermediate-risk prostate cancer.

42 Background: Biomarkers of local and systemic recurrence are needed to individualize patient risk categories and better define treatment. We hypothesized that genomic instability, as measured by percent genome alteration (PGA), can predict for biochemical failure in intermediate- risk prostate cancer. Methods: High-resolution array comparative genomic hybridization (arrayCGH) was used to identify PGA in frozen biopsies from 120 intermediate-risk prostate cancer patients. Our cohort included 39 T1c tumors, 78 T2 tumors and 2 T3 tumors. The Gleason score was 6 in 32 tumors, 7 in 82 tumors and 8–9 in 6 tumors. PSA ranged from 2.1–33 (median 8.0). Patients were treated with intensity-modulated radiotherapy (IMRT) with doses of 75.6–79.8 Gy in 1.8–2Gy fractions, or 60–66 Gy in 3 Gy fractions.. Twenty-five percent of patients also received neoadjuvant-concurrent bicalutamide (150mg po od). Biochemical failure, defined by Phoenix criteria or the initiation of salvage therapy, was observed in 35 patients after median follow-up of 5.4 years (range 0.9–8.8). Results: Array CGH showed variable PGA ranging from &lt;1% to 35% (median 6.7%). PSA and the use of hormonal therapy independently influenced biochemical relapse, and formed a baseline clinical model to which PGA was added. PGA was found to be a strong predictor of biochemical relapse (p&lt;0.0001) independent of the clinical prognostic factors (pre-treatment PSA, Gleason score and T-category). PGA was also found to be associated with unique tumour suppressor and oncogene gene loci clusters involved in genetic stability (e.g. loss of PTEN, p53, RB, NKX3.1, ATM, PARP-1 and gain of c-MYC; validated by in situ FISH). Conclusions: This is the first report to show genetic instability can independently predict for biochemical recurrence in intermediate-risk prostate cancer. Current studies are associating specific gene loci regions with clinical outcome. Our results could provide a way forward for individualized medicine for non-indolent prostate cancer based on initial daignostic biopsy material. Supported by Prostate Cancer Canada, The Terry Fox Foundation and the Canadian Cancer Society. No significant financial relationships to disclose.