number of clinical sites included in the trials ; the length of time required to enroll suitable patient subjects ; and the efficacy and safety profile of the drug candidate . we test potential drug candidates in numerous preclinical studies for safety , toxicology and immunogenicity . we may then conduct multiple clinical trials for each drug candidate . as we obtain results from trials , we may elect to discontinue or delay clinical trials for certain drug candidates in order to focus our resources on more promising drug candidates . an element of our business strategy is to pursue the research and development of a broad portfolio of drug candidates . this is intended to allow us to diversify the risks associated with our research and development expenditures . to the extent we are unable to maintain a broad range of drug candidates , our dependence on the success of one or a few drug candidates increases . regulatory approval is required before we can market our drug candidates as therapeutic products . in order to proceed to subsequent clinical trial stages and to ultimately achieve regulatory approval , the regulatory agency must conclude that our clinical data are safe and effective . historically , the results from preclinical testing and early clinical trials ( through phase 2 ) have often not been predictive of results obtained in later clinical trials . a number of new drugs and biologics have shown promising results in early clinical trials but subsequently failed to establish sufficient safety and efficacy data to obtain necessary regulatory approvals . 63 furthermore , our business strategy includes the option of entering into collaborative arrangements with third parties to complete the development and commercialization of our drug candidates . in the event that third parties take over the clinical trial process for one of our drug candidates , the estimated completion date would largely be under control of that third party rather than us . we can not forecast with any degree of certainty which proprietary products , if any , will be subject to future collaborative arrangements , in whole or in part , and how such arrangements would affect our development plan or capital requirements . our programs may also benefit from subsidies , grants , contracts or government or agency-sponsored studies that could reduce our development costs . as a result of the uncertainties discussed above , among others , it is difficult to accurately estimate the duration and completion costs of our research and development projects or when , if ever , and to what extent we will receive cash inflows from the commercialization and sale of a product . our inability to complete our research and development projects in a timely manner or our failure to enter into collaborative agreements , when appropriate , could significantly increase our capital requirements and could adversely impact our liquidity . these uncertainties could force us to seek additional , external sources of financing from time to time in order to continue with our business strategy . our inability to raise additional capital , or to do so on terms reasonably acceptable to us , would jeopardize the future success of our business . during the past five years through december 31 , 2017 , we incurred an aggregate of $ 470.9 million in research and development expenses . the following table indicates the amount incurred for each of our significant research programs and for other identified research and development activities during the years ended december 31 , 2017 , 2016 and 2015. the amounts disclosed in the following table reflect direct research and development costs , license fees associated with the underlying technology and an allocation of indirect research and development costs to each program . replace_table_token_10_th clinical development programs glembatumumab vedotin glembatumumab vedotin is an antibody-drug conjugate , or adc , that consists of a fully human monoclonal antibody , cr011 , linked to a potent cell-killing drug , monomethyl auristatin e , or mmae . the cr011 antibody specifically targets glycoprotein nmb , referred to as gpnmb , that is over-expressed in a variety of cancers including breast cancer , melanoma , non-small cell lung cancer , uveal melanoma and osteosarcoma , among others . the adc technology , comprised of mmae and a stable linker system for attaching it to cr011 , was licensed from seattle genetics , inc. and is the same 64 as that used in the marketed product adcetris® . the adc is designed to be stable in the bloodstream . following intravenous administration , glembatumumab vedotin targets and binds to gpnmb , and upon internalization into the targeted cell , glembatumumab vedotin is designed to release mmae from cr011 to produce a cell-killing effect . glembatumumab vedotin is being studied across multiple indications in company-sponsored trials and in collaborative studies with external parties . the u.s. food and drug administration , or fda , has granted fast track designation to glembatumumab vedotin for the treatment of advanced , refractory/resistant gpnmb-expressing breast cancer . a companion diagnostic is in development for certain indications , and we expect that , if necessary , such a companion diagnostic must be approved by the fda or certain other foreign regulatory agencies before glembatumumab vedotin may be commercialized in those indications . treatment of metastatic breast cancer : glembatumumab vedotin has been evaluated for the treatment of metastatic breast cancer ( mbc ) in multiple studies including a single-arm phase 1/2 study ( journal of clinical oncology , september 2014 ) ; a randomized , controlled phase 2b study compared to investigator 's choice chemotherapy in patients with gpnmb-positive mbc called emerge ( journal of clinical oncology , april 2015 ) ; and the ongoing randomized , controlled phase 2b study in patients with triple negative , gpnmb overexpressing breast cancer , called metric . we expect to report topline primary endpoint data from the metric study during the second quarter of 2018. story_separator_special_tag data ( n=36 ) from the phase 1 dose-escalation portion of the study were presented in an oral presentation at the american society of clinical oncology annual meeting in june 2017. the majority of patients had pd-l1 negative tumor at baseline and presented with stage iv , heavily pre-treated disease . 80 % of patients enrolled presented with refractory or recurrent colorectal ( n=21 ) or ovarian cancer ( n=8 ) , a population expected to have minimal response to checkpoint blockade . the primary objective of the phase 1 portion of the study was to evaluate the safety and tolerability of the combination . the combination was well tolerated at all varlilumab dose levels tested without any evidence of increased autoimmunity or inappropriate immune activation . marked changes in the tumor microenvironment including increased infiltrating cd8+ t cells and increased pd-l1 expression , which have been shown to correlate with a greater magnitude of treatment effect from checkpoint inhibitors in other clinical studies , were observed . additional evidence of immune activity , such as increase in inflammatory chemokines and decrease in t regulatory cells , was also noted . notable disease control was also observed ( stable disease or better for at least 3 months ) , considering the stage iv patient population contained mostly ( 80 % ) colorectal and ovarian cases : 0.1 mg/kg varlilumab + 240 mg opdivo : 1/5 ( 20 % ) , 1 mg/kg varlilumab + 240 mg opdivo : 5/15 ( 33 % ) and 10 mg/kg varlilumab + 240 mg opdivo : 6/15 ( 40 % ) . 69 three partial responses ( pr ) were observed . a patient with pd-l1 negative , mmr proficient ( msi-low ) colorectal cancer , typically unlikely to respond to checkpoint blockade monotherapy , achieved a confirmed pr ( 95 % decrease in target lesions ) and following completion of combination treatment , continues to receive treatment with opdivo monotherapy at 31+ months . a patient with low pd-l1 ( 5 % expression ) squamous cell head and neck cancer achieved a confirmed pr ( 59 % shrinkage ) and experienced pfs of 6.7 months . a patient with pd-l1 negative ovarian cancer experienced a single timepoint pr ( 49 % shrinkage ) but discontinued treatment to a dose-limiting toxicity ( immune hepatitis , an event known to be associated with checkpoint inhibition therapy ) . a subgroup analysis was conducted in patients with ovarian cancer based on an observed increase of pd-l1 and tumor-infiltrating lymphocytes in this patient population . in patients with paired baseline and on-treatment biopsies ( n=13 ) , only 15 % were pd-l1 positive ( ³ 1 % tumor cells ) at baseline compared to 77 % during treatment ( p=0.015 ) . patients with increased tumor pd-l1 expression and tumor cd8 t cells correlated with better clinical outcome with treatment ( stable disease or better ) . the phase 2 portion of the study opened to enrollment in april 2016 and completed enrollment in january 2018 with cohorts in colorectal cancer ( n=21 ) , ovarian cancer ( n=58 ) , head and neck squamous cell carcinoma ( n=24 ) , renal cell carcinoma ( n=14 ) and glioblastoma ( n=22 ) . the primary objective of the phase 2 cohorts is orr , except glioblastoma , where the primary objective is the rate of 12-month os . secondary objectives include pharmacokinetic assessments , determining the immunogenicity of varlilumab when given in combination with opdivo , evaluating alternate dosing schedules of varlilumab and further assessing the anti-tumor activity of combination treatment . we plan to work with bms to present data from the study at future medical meetings in 2018. third-party sponsored studies : we have also entered into a crada with the nci under which nci is sponsoring a phase 2 study of varlilumab in combination with nivolumab in relapsed or refractory aggressive b-cell lymphomas . patients receive either nivolumab alone or the combination . the primary outcome measure is orr . secondary outcome measures include dor , safety , pfs and os . the study opened to enrollment in january 2018 and is expected to enroll 106 patients . cdx-3379 cdx-3379 is a human monoclonal antibody with half-life extension designed to block the activity of erbb3 ( her3 ) . we believe erbb3 may be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies and is expressed in many cancers , including head and neck , thyroid , breast , lung and gastric cancers , as well as melanoma . we believe the proposed mechanism of action for cdx-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent erbb3 signaling by binding to a unique epitope . it has a favorable pharmacologic profile , including a longer half-life and slower clearance relative to other drug candidates in this class . we believe cdx-3379 also has potential to enhance anti-tumor activity and or overcome resistance in combination with other targeted and cytotoxic therapies to directly kill tumor cells . tumor cell death and the ensuing release of new tumor antigens has the potential to serve as a focus for combination therapy with immuno-oncology approaches , even in refractory patients . cdx-3379 has been evaluated in three phase 1 studies for the treatment of multiple solid tumors that express erbb3 and is currently being evaluated is a phase 2 study in combination with cetuximab in cetuximab-resistant , advanced head and neck squamous cell carcinoma . the most recent data for cdx-3379 were reported from a phase 1a/1b study conducted in solid tumors . the study included a single-agent , dose-escalation portion and combination expansion cohorts . the single-agent , dose-escalation portion of the study did not identify an mtd , and there were no dose limiting toxicities . the most common adverse events included rash and diarrhea and

liquidity and capital resources our cash equivalents are highly liquid investments with a maturity of three months or less at the date of purchase and consist primarily of investments in money market mutual funds with commercial banks and financial institutions . we maintain cash balances with financial institutions in excess of insured limits . we do not anticipate any losses with respect to such cash balances . we invest our excess cash balances in marketable securities , including municipal bond securities , u.s. government agency securities and high-grade corporate bonds that meet high credit quality standards , as specified in our investment policy . our investment policy seeks to manage these assets to achieve our goals of preserving principal and maintaining adequate liquidity . the use of our cash flows for operations has primarily consisted of salaries and wages for our employees ; facility and facility-related costs for our offices , laboratories and manufacturing facility ; fees paid in connection with preclinical studies , clinical studies , contract manufacturing , laboratory supplies and services ; and consulting , legal and other professional fees . to date , the primary sources of cash flows from operations have been payments received from our collaborative partners and from government entities . the timing of any new collaboration agreements , government contracts or grants and any payments under these agreements , contracts or grants can not be easily predicted and may vary significantly from quarter to quarter . at december 31 , 2017 , our principal sources of liquidity consisted of cash , cash equivalents and marketable securities of $ 139.4 million . we have had recurring losses and incurred a loss of $ 93.0 million for the year ended december 31 , 2017. net cash used in operations for the year ended december 31 , 2017 was $ 99.9 million .


 Write a concise suspicious activity report of the following text delimited by triple backquotes. Return your response as a formal report which covers the key points highlighting the location,dates,entity names and account holder information in chronological order of the text.
     ```liquidity and capital resources our cash equivalents are highly liquid investments with a maturity of three months or less at the date of purchase and consist primarily of investments in money market mutual funds with commercial banks and financial institutions . we maintain cash balances with financial institutions in excess of insured limits . we do not anticipate any losses with respect to such cash balances . we invest our excess cash balances in marketable securities , including municipal bond securities , u.s. government agency securities and high-grade corporate bonds that meet high credit quality standards , as specified in our investment policy . our investment policy seeks to manage these assets to achieve our goals of preserving principal and maintaining adequate liquidity . the use of our cash flows for operations has primarily consisted of salaries and wages for our employees ; facility and facility-related costs for our offices , laboratories and manufacturing facility ; fees paid in connection with preclinical studies , clinical studies , contract manufacturing , laboratory supplies and services ; and consulting , legal and other professional fees . to date , the primary sources of cash flows from operations have been payments received from our collaborative partners and from government entities . the timing of any new collaboration agreements , government contracts or grants and any payments under these agreements , contracts or grants can not be easily predicted and may vary significantly from quarter to quarter . at december 31 , 2017 , our principal sources of liquidity consisted of cash , cash equivalents and marketable securities of $ 139.4 million . we have had recurring losses and incurred a loss of $ 93.0 million for the year ended december 31 , 2017. net cash used in operations for the year ended december 31 , 2017 was $ 99.9 million .
```    
 Suspicious Activity Report : number of clinical sites included in the trials ; the length of time required to enroll suitable patient subjects ; and the efficacy and safety profile of the drug candidate . we test potential drug candidates in numerous preclinical studies for safety , toxicology and immunogenicity . we may then conduct multiple clinical trials for each drug candidate . as we obtain results from trials , we may elect to discontinue or delay clinical trials for certain drug candidates in order to focus our resources on more promising drug candidates . an element of our business strategy is to pursue the research and development of a broad portfolio of drug candidates . this is intended to allow us to diversify the risks associated with our research and development expenditures . to the extent we are unable to maintain a broad range of drug candidates , our dependence on the success of one or a few drug candidates increases . regulatory approval is required before we can market our drug candidates as therapeutic products . in order to proceed to subsequent clinical trial stages and to ultimately achieve regulatory approval , the regulatory agency must conclude that our clinical data are safe and effective . historically , the results from preclinical testing and early clinical trials ( through phase 2 ) have often not been predictive of results obtained in later clinical trials . a number of new drugs and biologics have shown promising results in early clinical trials but subsequently failed to establish sufficient safety and efficacy data to obtain necessary regulatory approvals . 63 furthermore , our business strategy includes the option of entering into collaborative arrangements with third parties to complete the development and commercialization of our drug candidates . in the event that third parties take over the clinical trial process for one of our drug candidates , the estimated completion date would largely be under control of that third party rather than us . we can not forecast with any degree of certainty which proprietary products , if any , will be subject to future collaborative arrangements , in whole or in part , and how such arrangements would affect our development plan or capital requirements . our programs may also benefit from subsidies , grants , contracts or government or agency-sponsored studies that could reduce our development costs . as a result of the uncertainties discussed above , among others , it is difficult to accurately estimate the duration and completion costs of our research and development projects or when , if ever , and to what extent we will receive cash inflows from the commercialization and sale of a product . our inability to complete our research and development projects in a timely manner or our failure to enter into collaborative agreements , when appropriate , could significantly increase our capital requirements and could adversely impact our liquidity . these uncertainties could force us to seek additional , external sources of financing from time to time in order to continue with our business strategy . our inability to raise additional capital , or to do so on terms reasonably acceptable to us , would jeopardize the future success of our business . during the past five years through december 31 , 2017 , we incurred an aggregate of $ 470.9 million in research and development expenses . the following table indicates the amount incurred for each of our significant research programs and for other identified research and development activities during the years ended december 31 , 2017 , 2016 and 2015. the amounts disclosed in the following table reflect direct research and development costs , license fees associated with the underlying technology and an allocation of indirect research and development costs to each program . replace_table_token_10_th clinical development programs glembatumumab vedotin glembatumumab vedotin is an antibody-drug conjugate , or adc , that consists of a fully human monoclonal antibody , cr011 , linked to a potent cell-killing drug , monomethyl auristatin e , or mmae . the cr011 antibody specifically targets glycoprotein nmb , referred to as gpnmb , that is over-expressed in a variety of cancers including breast cancer , melanoma , non-small cell lung cancer , uveal melanoma and osteosarcoma , among others . the adc technology , comprised of mmae and a stable linker system for attaching it to cr011 , was licensed from seattle genetics , inc. and is the same 64 as that used in the marketed product adcetris® . the adc is designed to be stable in the bloodstream . following intravenous administration , glembatumumab vedotin targets and binds to gpnmb , and upon internalization into the targeted cell , glembatumumab vedotin is designed to release mmae from cr011 to produce a cell-killing effect . glembatumumab vedotin is being studied across multiple indications in company-sponsored trials and in collaborative studies with external parties . the u.s. food and drug administration , or fda , has granted fast track designation to glembatumumab vedotin for the treatment of advanced , refractory/resistant gpnmb-expressing breast cancer . a companion diagnostic is in development for certain indications , and we expect that , if necessary , such a companion diagnostic must be approved by the fda or certain other foreign regulatory agencies before glembatumumab vedotin may be commercialized in those indications . treatment of metastatic breast cancer : glembatumumab vedotin has been evaluated for the treatment of metastatic breast cancer ( mbc ) in multiple studies including a single-arm phase 1/2 study ( journal of clinical oncology , september 2014 ) ; a randomized , controlled phase 2b study compared to investigator 's choice chemotherapy in patients with gpnmb-positive mbc called emerge ( journal of clinical oncology , april 2015 ) ; and the ongoing randomized , controlled phase 2b study in patients with triple negative , gpnmb overexpressing breast cancer , called metric . we expect to report topline primary endpoint data from the metric study during the second quarter of 2018. story_separator_special_tag data ( n=36 ) from the phase 1 dose-escalation portion of the study were presented in an oral presentation at the american society of clinical oncology annual meeting in june 2017. the majority of patients had pd-l1 negative tumor at baseline and presented with stage iv , heavily pre-treated disease . 80 % of patients enrolled presented with refractory or recurrent colorectal ( n=21 ) or ovarian cancer ( n=8 ) , a population expected to have minimal response to checkpoint blockade . the primary objective of the phase 1 portion of the study was to evaluate the safety and tolerability of the combination . the combination was well tolerated at all varlilumab dose levels tested without any evidence of increased autoimmunity or inappropriate immune activation . marked changes in the tumor microenvironment including increased infiltrating cd8+ t cells and increased pd-l1 expression , which have been shown to correlate with a greater magnitude of treatment effect from checkpoint inhibitors in other clinical studies , were observed . additional evidence of immune activity , such as increase in inflammatory chemokines and decrease in t regulatory cells , was also noted . notable disease control was also observed ( stable disease or better for at least 3 months ) , considering the stage iv patient population contained mostly ( 80 % ) colorectal and ovarian cases : 0.1 mg/kg varlilumab + 240 mg opdivo : 1/5 ( 20 % ) , 1 mg/kg varlilumab + 240 mg opdivo : 5/15 ( 33 % ) and 10 mg/kg varlilumab + 240 mg opdivo : 6/15 ( 40 % ) . 69 three partial responses ( pr ) were observed . a patient with pd-l1 negative , mmr proficient ( msi-low ) colorectal cancer , typically unlikely to respond to checkpoint blockade monotherapy , achieved a confirmed pr ( 95 % decrease in target lesions ) and following completion of combination treatment , continues to receive treatment with opdivo monotherapy at 31+ months . a patient with low pd-l1 ( 5 % expression ) squamous cell head and neck cancer achieved a confirmed pr ( 59 % shrinkage ) and experienced pfs of 6.7 months . a patient with pd-l1 negative ovarian cancer experienced a single timepoint pr ( 49 % shrinkage ) but discontinued treatment to a dose-limiting toxicity ( immune hepatitis , an event known to be associated with checkpoint inhibition therapy ) . a subgroup analysis was conducted in patients with ovarian cancer based on an observed increase of pd-l1 and tumor-infiltrating lymphocytes in this patient population . in patients with paired baseline and on-treatment biopsies ( n=13 ) , only 15 % were pd-l1 positive ( ³ 1 % tumor cells ) at baseline compared to 77 % during treatment ( p=0.015 ) . patients with increased tumor pd-l1 expression and tumor cd8 t cells correlated with better clinical outcome with treatment ( stable disease or better ) . the phase 2 portion of the study opened to enrollment in april 2016 and completed enrollment in january 2018 with cohorts in colorectal cancer ( n=21 ) , ovarian cancer ( n=58 ) , head and neck squamous cell carcinoma ( n=24 ) , renal cell carcinoma ( n=14 ) and glioblastoma ( n=22 ) . the primary objective of the phase 2 cohorts is orr , except glioblastoma , where the primary objective is the rate of 12-month os . secondary objectives include pharmacokinetic assessments , determining the immunogenicity of varlilumab when given in combination with opdivo , evaluating alternate dosing schedules of varlilumab and further assessing the anti-tumor activity of combination treatment . we plan to work with bms to present data from the study at future medical meetings in 2018. third-party sponsored studies : we have also entered into a crada with the nci under which nci is sponsoring a phase 2 study of varlilumab in combination with nivolumab in relapsed or refractory aggressive b-cell lymphomas . patients receive either nivolumab alone or the combination . the primary outcome measure is orr . secondary outcome measures include dor , safety , pfs and os . the study opened to enrollment in january 2018 and is expected to enroll 106 patients . cdx-3379 cdx-3379 is a human monoclonal antibody with half-life extension designed to block the activity of erbb3 ( her3 ) . we believe erbb3 may be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies and is expressed in many cancers , including head and neck , thyroid , breast , lung and gastric cancers , as well as melanoma . we believe the proposed mechanism of action for cdx-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent erbb3 signaling by binding to a unique epitope . it has a favorable pharmacologic profile , including a longer half-life and slower clearance relative to other drug candidates in this class . we believe cdx-3379 also has potential to enhance anti-tumor activity and or overcome resistance in combination with other targeted and cytotoxic therapies to directly kill tumor cells . tumor cell death and the ensuing release of new tumor antigens has the potential to serve as a focus for combination therapy with immuno-oncology approaches , even in refractory patients . cdx-3379 has been evaluated in three phase 1 studies for the treatment of multiple solid tumors that express erbb3 and is currently being evaluated is a phase 2 study in combination with cetuximab in cetuximab-resistant , advanced head and neck squamous cell carcinoma . the most recent data for cdx-3379 were reported from a phase 1a/1b study conducted in solid tumors . the study included a single-agent , dose-escalation portion and combination expansion cohorts . the single-agent , dose-escalation portion of the study did not identify an mtd , and there were no dose limiting toxicities . the most common adverse events included rash and diarrhea and

