Study Of mRCC Patients Research Articles

The role of mean corpuscular volume and red cell distribution width in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: the MARECAP retrospective study.

Tyrosine-kinase inhibitors (TKIs) and immunotherapy represent the backbone treatment for metastatic renal cell carcinoma (mRCC) patients. The aim of the present study was to describe mean corpuscular volume (MCV) and red cell distribution width (RDW) in mRCC patients treated with pazopanib or cabozantinib, and to explore their potential impact on oncological outcomes. We conducted a multicenter retrospective observational study in mRCC patients treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Descriptive statistics, univariate, and multivariate analyses were performed. The primary endpoints were the incidence and trend over time of anemia, macrocytosis (elevated MCV), and anisocytosis (elevated RDW). The secondary endpoints were the correlations of MCV and RDW with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 301 patients were enrolled; mean Hb value was 12.5 g/dl, a mean increase of 1 g/dl was observed at day 15 and maintained at 3 months. Most patients had baseline macrocytosis (MCV levels > 87 fl), with a significant mean increase after 3 months of treatment. At univariate analysis patients with macrocytosis had better ORR, longer PFS, and OS. About one third of patients had baseline anisocytosis (RDW > 16%), with a significant mean increase after 3 months of treatment. At univariate analysis, patients with RDW values ⩽ 16% had higher ORR, longer PFS, and OS. At multivariate analysis, baseline macrocytosis was significantly associated with better PFS in patients treated with pazopanib and baseline anisocytosis with shorter OS in all patients. mRCC patients treated with pazopanib or cabozantinib may have baseline macrocytosis and anisocytosis. A significant increase of Hb, MCV, and RDW after TKIs start was observed. Baseline macrocytosis is positively correlated with PFS in patients treated with pazopanib and baseline anisocytosis affects survival of patients treated with TKIs.

Immunotherapy with nivolumab in metastatic renal cell carcinoma in resource constraint settings: Impact of increasing intervals between standard doses, and stopping treatment early in responding patients.

e16078 Background: Nivolumab is now a standard 2nd line treatment for patients of metastatic Renal cell cancer (mRCC) who progress on 1st line Sunitinib or Pazopanib. Most western centers use Nivolumab for either 2 years duration, or indefinitely, or till severe side effects. Due to high drug cost and lack of insurance, it is difficult for most of our Indian patients to afford this duration of treatment. So, we decided to study the impact of increasing intervals between standard doses of Nivolumab, and stopping treatment early in responding patients of mRCC. Methods: This is a single centre, retrospective study of mRCC patients. Nivolumab was given at either 3 mg/kg or 240mg at 2 weekly intervals for the initial 6 cycles. If the patient were found to have either Complete Response (CR), Partial Response (PR) or stable disease, the interval between cycles was extended to 3 weeks (at same dose). After 9 months, the doses were extended to 4 weekly intervals (at same dose). The treatment was stopped at 18 doses in patients with CR or PR. The endpoints were objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: Between May 2016 and Dec 2018, 28 patients received Nivolumab. 24 patients had received oral TKIs initially- 13 Sunitinib, 10 Pazopanib, and 1 Sorafinib. 4 patients received Nivolumab as 1st line therapy (2 as single agent, 2 with oral TKI). Response was assessed by RECIST criteria. 3 patients (11%) achieved CR, 7(25%) achieved PR, 7 (25%) had stable disease and 11(39%)had progressive disease. Treatment was stopped after 18 doses in the 3 patients who had CR. The duration of followup after stopping treatment ranges from 8 months to 18 months, and all 3 patients continue to be in CR. 3 patients with stable disease have received more that 18 cycles (1 at 22 cycles, 2 at 19 cycles). OS at 1 year is 60% and median OS has not been reached. Conclusions: In our experience, Nivolumab is an effective agent in mRCC, even when the dosage intervals are increased, and when the treatment is stopped early in responding patients. An ORR of 36% and a OS at 1 year of 60% is the best we have seen. Long-lasting responses, even after discontinuing therapy, have been seen. This enables us to reduce the cost of treatment without possibly losing efficacy, and this could be an important step forward for treating more patients with Nivolumab in our resource constraint setting.

Effects of sunitinib and pazopanib on patients physical, social, and emotional function: Result of a prospective patients reported outcome tool.

667 Background: Sunitinib and pazopanib are are effective treatment options for metastatic Renal cell carcinoma (mRCC) and both may impair patient’s quality of life (QOL). There has been no direct comparison between these agents and their effect on these domains. Methods: A prospective study of mRCC patients who had received Sunitinib or Pazopanib as a first line treatment was conducted. A set of questionnaires has been developed in-house, influenced by existing recognised tools, such as EORTC-C 30 and PHQ-9, and is tailored to focus on relevant QoL issues patients face. This questionnaire named as Patient reported outcome tool. They primarily relate to physical, emotional and social functioning in the quality of life of patients. Each category has 4 questions. The questions are quite generic and allow patients to apply them to what’s important in their lives. Answers are on a scale of 0-10. The purpose of the questionnaire is to assess a balance of physical, cognitive and independence related aspects of their life over the course of their treatment. All patients are asked to complete the baseline questionnaire and then in every clinical visit. Results: Data were collected prospectively of metastatic RCC patients who had received Sunitinib or Pazopanib from May 2017 to Aug 2018. Total 45 patients were included, 23 received Pazopanib and 22 were on Sunitinib. There was a higher rate of significant worsening for the physical well-being subscale for Sunitinib versus Pazopanib. Patients on Sunitinib reported worsening tiredness, skin problems and sleep disturbance. Socially, patients on Sunitinib reported more closer to family, better interaction with friends and more motivated to go out. Problem with feeling sad, fear of death and anxiousness were more pronounced on Pazopanib arm. Conclusions: Our study suggested that there are marked differences between Sunitinib vs Pazopanib and their effects on patients physical, emotional and social wellbeing. Physical function was more influenced by sunitnib while pazopanib has more effect emotional wellbeing. Further studies are warranted to confirm these findings.

Patterns of practice and pharmacoeconomic analysis of the management of patients with metastatic renal cell carcinoma (mRCC) in Greece––the CRISIS study. A retrospective analysis by the Hellenic Genitourinary Cancer Group (HGUCG)

ABSTRACTBackground:Metastatic RCC (mRCC) treatment has been revolutionized with 11 approved targeted agents. We report patterns of practice, outcomes and pharmacoeconomic analyses after the introduction of targeted therapy.Patients and methods: CRISIS was a retrospective multicenter study of mRCCpatients who received targeted therapy . Results were related to the start of 1st-line therapy, with a cut off at 1 January 2011 in order to depict the impact of increased availability of effective options.Results: 164 patients, were included. 70.1% and 44.5% received 2nd and 3rd-line therapy, respectively. More patients were treated in 2nd-line after 1 January 2011. After a median follow-up of 55.1 months, median progression-free (PFS) and overall survival (OS) were 10.7 (95% confidence intervals [CI]: 8.3–13.7), 7.3 (95% CI: 5.1–8.6), 5.8 (95% CI: 3.8–7.8) and 34 (95% CI: 28.5–39.8), 22.4 (95% CI: 16–32.1), 18.3 (95% CI: 12.4–26.4) months for first, second and third line, respectively. Efficacy of sunitinib and pazopanib in 1st-line were similar. The mean total cost/patient was 35,012.2 Euros (standard deviation [SD]: 28,971.5).Conclusions: Our study confirms previous real-world data suggesting that continuing advances in the treatment of mRCC produce favorable outcomes in everyday practice. Pharmacoeconomic analyses are important for cost-effective utilization of emerging novel therapies.

Targeting bacteroides in the stool microbiome and response to treatment (Rx) with first-line VEGFTKI in metastatic renal cell carcinoma (mRCC).

584 Background: Diarrhea occurs in ~50% patients with mRCC receiving VEGFTKIs, and is a common cause of VEGFTKI Rx dose reductions/delays/interruptions. Stool bacteroides level directly correlates with diarrhea in these patients on Rx with VEGFTKI (Pal SK, Clinical Cancer Research 2015, PMID:26152743). Hypothesis was that mRCC patients on incidental antibiotics (ABX) which also target stool bacteroides will have less diarrhea, leading to improved Rx compliance, and improved outcomes on VEGFTKI. Methods: A retrospective study of mRCC patients with MSKCC intermediate or poor risk mRCC on 1st line VEGFRTKIs between 2005-2017. ABX usage was categorized by ABX bacteroides sensitivity at anytime during Rx with 1st line VEGFTKI along with the total number of days on ABX. 1st line VEGFRTKI progression free survival (PFS) was assessed by Kaplan-Meier and Cox proportional hazard models. Results: 145 patients with intermediate (n = 123, 85%) or poor risk (n = 22, 15%) mRCC on a VEGFTKI were identified. ABX were prescribed incidentally in 50 (34%) patients. 18 patients were prescribed ABX with bacteroides coverage of which 13 had ABX with high sensitivity for bacteroides. The median number of days supplied of all ABX was 7 (IQR 1-15 days). The median number of days supplied of ABX with bacteroides coverage was 6 (IQR 1.5-15.5 days). The median PFS in those prescribed ABX with bacteroides sensitivity was 18 months versus 8 months in those prescribed no ABX (p = 0.067), and 9 months in those prescribed ABX without bacteroides sensitivity. Duration of bacteroides ABX coverage resulted in a hazard ratio of 0.92 (95% CI 0.83-0.99, p = 0.043) for each additional day an ABX with bacteroides coverage was prescribed compared to those with no ABX. Conclusions: In these hypothesis generating data, incidental targeting of stool bacteroides with ABX correlated with improved PFS in mRCC patients on 1st line VEGFTKIs. Data need validation. Equal contribution: SAV, CDF, AWH

MP57-16 THE IMPACT OF SURGERY ON THE PROGNOSIS OF METASTATIC RENAL CELL CARCINOMA WITH IVC THROMBUS

INTRODUCTION AND OBJECTIVES: Biomarkers may be useful as prognostic indicators prior to and during systemic therapy. We evaluated change in platelet count (DPlt) as a biomarker for response to neoadjuvant tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC). METHODS: Multi-center retrospective study of mRCC patients undergoing neoadjvant TKI therapy from 5/2005-8/2013. DPlt was defined as post-treatment Plt after first cycle minus pre-treatment Plt. Primary outcome was response of disease to TKI defined by RECIST criteria for partial response (PR), stable disease (SD), and progressive disease (PD). Demographic and clinical characteristics were analyzed between subgroups with stable/increased (+DPlt) and decreased (-DPlt) counts. Cox proportional hazards model evaluated factors associated with changes in tumor response. Kaplan-Meier analysis estimated overall survival (OS) and compared Plt groups with log-rank test. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated for DPlt and disease response PR/SD. RESULTS: A total of 69 patients treated with neoadjuvant TKI therapy were analyzed for DPlt. Overall, 15 patients (22%) were noted to have +DPlt and 54 (78%) had eDPlt after neoadjuvant TKI therapy. There were no other differences in clinical or demographic variables between these two groups (comorbidities, ECOG, tumor size, number of metastases, stage, grade and number of TKI cycles). Patients with +DPlt count had a lower post TKI treatment creatinine (1.0 vs. 1.3, p1⁄40.041). PD was more common among +DPlt 86.7% vs. eDPlt 33.3%, (p1⁄40.001), and SD/PR was more common in eDPlt 66.7% vs. +DPlt 13.3%, (p1⁄40.001). On MVA, -DPlt below baseline was a significant predictor of SD/PR (OR 6.96, p1⁄40.028). A Kaplan Meier analysis (Figure) demonstrated a higher overall survival in -DPlt versus +DPlt (p1⁄40.009), with median survival 13.8 of and 5.7 months respectively. -DPlt had sensitivity of 94.7%, specificity of 41.9%, PPV of 66.7% and NPV of 86.7% for PR/SD after neoadjuvant TKI therapy. CONCLUSIONS: Patients with -DPlt were more likely to respond to TKI therapy and had longer median overall survival. Further investigation is requisite to determine the utility of DPlt as a biomarker for RCC response to TKI.

Comparative outcomes of everolimus, temsirolimus and sorafenib as second targeted therapies for metastatic renal cell carcinoma: a US medical record review

Objective:To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US.Research design and methods:Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments.Results:A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42–0.85; p = 0.004) and PFS (HR 0.73; CI 0.54–0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44–0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib.Limitations:Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected.Conclusions:In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients: Updated phase I results of the Disruptor-1 trial.

4563 Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Biomarker samples (pre- and post-dose during Cycle 1) were analyzed for 70 plasma analytes including VEGF, PDGF and other markers associated with angiogenesis and vascular responses. Results: Updated results from the completed phase I component confirm the BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single Grade 3 events of anemia and pericardial effusion. Grade 2 events of fatigue, anemia and oral mucositis were also observed. Eight of the 12 phase I subjects achieved disease stabilization. Across all subjects a median of 6 cycles (range: 1-24) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: Full dose BNC105P (16 mg/m2) can be combined with full dose everolimus (10 mg) and is being further evaluated in a randomized phase II study. Clinical trial information: NCT01034631.

Retrospective analysis of sorafenib as first- or second-line targeted therapy in patients with mRCC: Three-year Italian experience.

415 Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. Methods: RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. Results: From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 – 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. Conclusions: The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.

Updated phase I results of a phase I/II trial of BNC105P with everolimus in patients with metastatic renal cell carcinoma (mRCC).

397 Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during cycle 1. Results: Updated results from the completed phase I component confirm the BNC105P/everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia, and oral mucositis were also observed. 8 of the 12 phase I subjects achieved disease stabilization (7 of these subjects had a minimum time on therapy of 18 weeks, 6 cycles). Across all subjects a median of 6 cycles (range: 1-21) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in a randomized phase II study. Clinical trial information: NCT01034631.

813P - The Novel Cancer Vaccine, Consisting of Genetically Modified Allogeneic Tumor Cells and Immunomodulator MGN1601: Updated Results of a Phase 1-2 Study in Patients with Advanced Renal Cell Carcinoma

ABSTRACT Background MGN1601 consists of two active pharmaceutical ingredients: genetically modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 and a TLR9 agonist, synthetic DNA-based immunomodulator dSLIM®. The first-in-man phase 1–2 clinical trial (ASET trial) has been conducted in patients with advanced renal cell carcinoma failed previous therapy lines and without further available standard therapy. Methods The ASET study is a multicentric, open, single-arm phase 1-2 clinical study and consists of the treatment, extension and follow up phases. The safety, efficacy and immunogenicity parameters were evaluated based on clinical and laboratory assessments, monitoring of patients' quality of life (QoL) with QLQ-C30, immunological tests, and central radiological investigations according to RECIST 1.1 as well as immune related Response Criteria. Results Ten of nineteen study patients completed the treatment per protocol (TPP). Two patients with disease control after 12-weeks continued treatment in the extension phase. One of them is still under therapy showing tumor remission since 48 weeks. The second patient developed radiological PD after 60 weeks of treatment. Seven patients from the TPP population are still alive with stable disease for up to 65 weeks. Evaluation of the QoL showed that patients of the TPP group have improved median symptom score from 45.8 to 58.3 in course of treatment. Drug-related AE included mild fever, edema, exanthema, pruritus, intermittent arthralgia, fatigue, and moderate soft tissue infection. Local reactions on injection site consisted mostly of redness up to 50 mm, which were available up to 7 days. The local reactions have no negative impact on the quality of life and daily activities of the patients. Six of ten TPP patients showed significant improvement in the immune status in lymphocyte transformation test. Conclusions The allogeneic tumor cell-based cancer vaccine MGN1601 shows promising efficacy and a favourable safety profile in the late stage mRCC patients. A phase 2 clinical study in mRCC patients with MGN1601 as third-line therapy is under development. Disclosure M. Schroff: Board member of Mologen. M. Schmidt: Mologen employee. E. Weith: Mologen empoyee. M. Tschaika: Mologen employee. B. Wittig: Member of Scientific Advisory Board of Mologen. All other authors have declared no conflicts of interest.

Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors.

4603 Background: BNC105P is an investigational agent that destabilizes tubulin polymers leading to selective damage of tumor vasculature, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Preclinical investigations have demonstrated that BNC105P is effective at selectively damaging the vasculature in both primary and metastatic lesions. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. It follows that the combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: The phase I component has been completed. The BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia and oral mucositis were also observed. Seven phase I subjects achieved at least disease stabilization with a minimum time on therapy of 18 weeks (6 cycles). Across all subjects a median of 6 cycles (range: 1-15) was administered. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.

Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group).

373 Background: BNC105P is a Vascular Disruption Agent (VDA) that destabilizes tubulin polymers leading to selective damage of tumor vasculature, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. Preclinical investigations demonstrated that BNC105P is effective at selectively damaging the vasculature in primary and metastatic lesions. Furthermore, BNC105P monotherapy compared well with sunitinib in mice bearing kidney tumors. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6 and 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: In the clinic the BNC105P / everolimus combination was well tolerated and no DLTs were observed in any of the phase I patients. Toxicities deemed to be drug-related included single events of Grade 2 anemia, thrombocytopenia and mucositis. Of the 12 patients enrolled to the phase I, 7 remain on treatment. The medium number of cycles is 3 (range: 1–14) and 3 patients have been administered >6 cycles of treatment. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.